Classifications

• • C—CHEMISTRY; METALLURGY
  • C23—COATING 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
  • C23C—COATING 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
  • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
  • C23C16/44—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating
  • C23C16/455—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating characterised by the method used for introducing gases into reaction chamber or for modifying gas flows in reaction chamber
  • C23C16/45523—Pulsed gas flow or change of composition over time
  • C23C16/45525—Atomic layer deposition [ALD]
  • C23C16/45527—Atomic layer deposition [ALD] characterized by the ALD cycle, e.g. different flows or temperatures during half-reactions, unusual pulsing sequence, use of precursor mixtures or auxiliary reactants or activations
  • C23C16/45536—Use of plasma, radiation or electromagnetic fields
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS 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
  • A61F2/00—Filters 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS 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
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/02—Inorganic materials
  • A61L27/10—Ceramics or glasses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS 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
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/02—Inorganic materials
  • A61L27/10—Ceramics or glasses
  • A61L27/105—Ceramics or glasses containing Al2O3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS 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
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/28—Materials for coating prostheses
  • A61L27/30—Inorganic materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS 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
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS 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
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/56—Porous materials, e.g. foams or sponges
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS 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
  • A61L31/00—Materials 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
  • A61L31/08—Materials for coatings
  • A61L31/082—Inorganic materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS 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
  • A61L31/00—Materials 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
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/146—Porous materials, e.g. foams or sponges
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS 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
  • A61L31/00—Materials 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
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/16—Biologically active materials, e.g. therapeutic substances
• • C—CHEMISTRY; METALLURGY
  • C23—COATING 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
  • C23C—COATING 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
  • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
  • C23C16/006—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterized by the colour of the layer
• • C—CHEMISTRY; METALLURGY
  • C23—COATING 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
  • C23C—COATING 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
  • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
  • C23C16/22—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the deposition of inorganic material, other than metallic material
  • C23C16/30—Deposition of compounds, mixtures or solid solutions, e.g. borides, carbides, nitrides
  • C23C16/40—Oxides
  • C23C16/403—Oxides of aluminium, magnesium or beryllium
• • C—CHEMISTRY; METALLURGY
  • C23—COATING 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
  • C23C—COATING 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
  • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
  • C23C16/22—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the deposition of inorganic material, other than metallic material
  • C23C16/30—Deposition of compounds, mixtures or solid solutions, e.g. borides, carbides, nitrides
  • C23C16/40—Oxides
  • C23C16/405—Oxides of refractory metals or yttrium
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS 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
  • A61L2400/00—Materials characterised by their function or physical properties
  • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment

Definitions

• the invention relates to extremely thin engineered nanoporous, nonconformal, amorphous metal coatings on a substrate.
• the surface deposited nanoporous metals can be used for controlled release of active agents, protective coatings, or scaffolds for cell adhesion.
• Vapor and plasma based deposition of materials onto substrate surfaces are receiving increasing attention, in part because of the potential to create new surface features with desirable attachment, protective or time release properties.
• Nontoxic thin film surface coatings for example, are of particular interest for implantable medical devices, where inflammation and fibrous encapsulation formation may cause significant problems. While nanostructured coatings would seem desirable for surgical implant purposes, highly adherent titanium porous coatings prepared with titanium sponge powders lack the appropriate roughness and/or porosity necessary for implants, and other coating techniques generally have been used to produce smooth, nonrough surfaces for nonmedical applications.
• Vacuum arc deposition of metal oxides can be controlled to some extent to provide structured surfaces.
• One type of vapor deposition, chemical vapor deposition is a chemical process in which one or more volatilized precursors are used to produce a highly conformal and pure thin film on a surface, primarily for applications in the electronic industry.
• a related process known as atomic layer deposition (ALD) utilizes alternating precursor exposure steps to produce conformal thin films in a layer by layer fashion.
• ALD can be used to coat complex shapes with conformal material of high quality and is typically used to create smooth thin surfaces on microelectronic devices or to hermetically seal electronic equipment.
• ALD has been used to deposit ultrathin films on silica nanoparticles (Hakim, et al.,
• the coatings exhibited complete coverage, uniformity and extreme conformality, which were considered the goal and advantages of using ALD for thin films.
• the self-limiting growth mechanism of the precursors is determined by the chemisorptions on the surface and where flux is large enough, the chemisorption layer is saturated, the excess precursor can be purged and conformality and trench filling occurs. Thus surfaces are smooth without nanorough features.
• ALD atomic layer deposition
• Bioactive anatase titania layers were build up on the substrates and form hydroxyapatite when immersed in phosphate buffered saline (PBS) for several days in vitro.
• PBS phosphate buffered saline
• a disadvantage of the coatings is lack of adhesion of the hydroxyapatite to the ALD deposited smooth, conformal surfaces.
• titanium thin films deposited from a radiofrequency generated plasma can be micropatterned onto quartz substrates. These surfaces reduce the generation of reactive oxygen species.
• ALD techniques have been employed to surface engineer already nanostructured surfaces.
• Various nanotubular surfaces can be conformally coated using ALD titania, for example, titania to provide a nanstructured surface that covers all accessible surfaces.
• Conformal surface coatings for underlying nano materials, including nanowires, nanolaminates and nanopore materials are known.
• Surface microstructure is an important consideration in the design of many types of devices, including defined purpose implants. Surfaces serve many purposes and functions; for example, smooth biocompatible internal surfaces on coronary artery stents tend to discourage cell adhesion, which can inhibit or block blood flow. On the other hand, irregular surfaces modified by physical means such as etching or nanostructuring, have been investigated as scaffolds for attracting different cell types, a desirable function for bone implants where new bond growth is important in the healing process.
• Medical devices are typically fabricated from polymers or metals, although only some materials are sufficiently biocompatible to be used as implants in orthopedic or surgical applications. Titanium is relatively unique because it shows little bio-incompatibility, due at least in part to formation of an oxide layer (Le., titanium dioxide) on its outer surface.
• Stents are small tubes placed in a blood vessel to maintain patency; Le., to hold the vessel open so blood flow is not blocked. Coronary artery stents are typically metal, or a metal mesh framework, which over the years have been used extensively in heart patients. Unfortunately, bare metal stents are foreign to the body and tend to cause an immune response. The stent itself may induce rapid cell proliferation over its surface leading to scar tissue formation.
• Coronary artery stents are typically composed of metal and many have been developed with various coatings on the stent surface.
• the coatings not only protect the body from exposure to the metal but are also designed to release various drugs intended to inhibit or at least delay reclosing of the blood vessel in which the stent was placed.
• Multilayer coatings can be used, with one or more layers containing a drug or therapeutic agent, although thick coatings can lead to sloughing or provide foci for restenosis from surface cracks or other imperfections.
• Drug eluting layers when used in coronary stents most frequently contain immunosuppressive compounds, although anti-thrombogenic agents, anti-cancer agents and anti-stenosis drugs have also been used.
• Well-known and studied immunosuppressive drugs include cyclosporin A, rapamycin, daclizumab, demethomycin, and the like.
• Protective coatings are used to modify surfaces in order to protect the underlying substrate; for example, stents have been coated with various polymer films, which not only add a protective layer to the base substrate but also act as a matrix or immobilization scaffold for different types of drugs.
• Protective films are often used to coat a metal matrix, which is typically stainless steel or titanium. The films themselves may serve dual functions as a protective hydrophilic surface and as a time-release matrix for therapeutic drugs.
• ALD atomic layer deposition
• Drug eluting stents have shown marked improvements in preventing the blood clots associated with stent thrombosis or "target lesion revascularization".
• Two models of drug eluting stents are currently used.
• the CYPHER stent (Cordis) releases rapamycin, which has both immunosuppressive and antiproliferative properties. It is sold under the name Sirolimus and is used primarily as an immunosuppressive drug to prevent organ transplant rejection.
• the drug is produced by Streptomyces hygroscopicus and has the effect of blocking certain stages in the cell cycle G — S transition.
• the CYPHER stent is fabricated from stainless steel and is coated with a polymer that acts as a time-release carrier for the drug rapamycin.
• the TAXUSTM Stent (Boston Scientific, Boston, MA) releases paclitaxel, which, like rapamycin, is an antiproliferative drug used primarily in cancer therapies. Paclitaxel interacts with microtubles so that the cell cannot undergo mitosis.
• the TAXUSTM Stent also utilizes a polymer drug carrier coated over a stainless steel substrate.
• the drugs selected for use as drug-releasing coatings are often imbedded in or associated with a polymer matrix, which is co-coated on the stent surface.
• a polymer matrix which is co-coated on the stent surface.
• Commonly used polymers are polyester lactides, polyvinyl alcohol, and cellulose.
• One example is a metal stent coated with a tripolide dispersed within a polymer matrix.
• Another example is an intravascular stent with a drug releasing coating composed of an immunosuppressive agent in a poly-dl-lactide polymer with a micro thick polymer undercoating on the stent.
• Polylactide polymers have also been used to prepare macrocyclic triene immunosuppressive coatings over a polymer underlayer. Not all polymers are biocompatible and some will not effectively coat the metals commonly used for fabricating stents and other medical implants.
• Stent design has also been investigated, including various shapes for improved coating adherence and drug delivery. Development of more flexible materials such as metal mesh has improved stent function and in vivo adaptability. Stent structures that can be coated with varying thicknesses in different segments of the stent have been designed.
• stents are subject to failure, due to development of inflammation at the implantation site or more commonly to restenosis of the artery.
• Metals such as tantalum and cobalt alloy based stents are under investigation as bare metal stents, although current thinking is that drug eluting stents are preferable because they minimize re-blockage in artery linings to a greater extent than bare-metal stents, particularly when used for FDA approved situations; i.e., "on-label”.
• the invention is based on using a modification of atomic layer deposition (ALD) techniques to create nonconformal, porous nanostructured metal films on a wide range of substrates.
• ALD atomic layer deposition
• APD atomic plasma
• the new method produces films with mesh- like lattices punctured with pinhole and pore imperfections.
• the APD surfaces are useful as scaffolds for cell attachment, controlled release of bioactive agents and as protective coatings.
• ALD atomic layer deposition
• ALD atomic plasma
• APD provides a nanorough, porous nonconformal surface films using a cyclic sequential introduction and purging of precursors.
• the APD surfaces are nanoporous, nonconformal, thin films, which have traditionally been considered undesirable side products of ALD procedures.
• the present invention discloses a method for obtaining nonconformal nanostructured thin coatings using APD.
• conditions are adjusted so that, in contrast to typical ALD manufacturing procedures, nonconformal, amorphous deposits on substrate surfaces are produced.
• Nonconformal films can be produced on metal, polymer, ceramic and silicon substrates.
• APD deposited metal oxide surfaces are amorphous, nonconformal and porous with a typical net-like appearance.
• porous thin films produced by the described method are ideal scaffolds for cell attachment due to the nanostructure features. Such porous surfaces are also ideal as matrices for drug or other bioactive molecules, with applications for in vivo time release applications. Controlled deposition steps and proper substrate selection allows preparation of APD films that attract many types of cells.
• the described APD method is exemplified with production of nonconformal titania and alumina surface deposited films, but may be used to provide films from other metal precursors; e.g., SiO 2 , CdS, B 2 O 3 , V 2 O 5 , HfO 2 , ZrO 2 , ZnO and Pd.
• APD deposited silver oxide is contemplated to provide advantages not only as a thin adherent coating but also as providing antimicrobial properties on elution from the underlying substrate surface.
• the APD surfaces can be deposited from a variety of metal oxides, metals, or combinations of metals and/or metal oxides.
• APD films are distinguished from ALD (atomic layer deposition films) in that deposited titania or alumina is neither crystalline nor uniform.
• the present invention demonstrates that the surface properties of APD deposited films are different from ALD deposited films and are suitable for surface coatings on implant devices, scaffolds for cell adhesion and matrices for bioactive molecules and controlled release.
• the present invention utilizes relatively low temperature deposition conditions to produce thin nanoporous surface growth, in contrast to other vapor depositions which are conducted at much higher temperatures. Porous, amorphous surface films are cyclically deposited in thin layers, best described as monolayers.
• Amorphous APD titania strongly attracts osteoblast, endothelial, gingival fibroblast and periodontal fibroblast cells.
• the cells exhibit both increased proliferation and adherence compared to substrates lacking the APD coatings.
• Increased cell adhesion is observed on amorphous APD titania on titanium substrates compared to adhesion on smooth titanium or other substrates such as polymers.
• APD titania films appear to have different properties from conventionally deposited thin crystalline TiO 2 films. Titania films are typically deposited as epitaxial TiO 2 thin films with directional hydroxyl groups as a conformal film on single crystalline silicon wafers or titanium 1 or 2. The APD surfaces are noncrystalline and adhere strongly to the underlying substrate. ADP titania or alumina films do not slough or peel, in contrast to the significant flaking of surface coatings such as hydroxyapatite formed on deposited anatase TiO 2 (Heinrichs, et al., 2008).
• the invention is directed to thin, porous metal oxide surface films that serve as time variable release coatings.
• a controlled number of atomic layers of a metal oxide, illustrated with titanium oxide, can be deposited over a biomolecule, such as a drug, using the new APD process. Thickness of the APD film can be adjusted to control elution rate of the underlying drug attached or adhered to a substrate surface.
• Controlled drug release APD films are particularly suitable for drug-eluting stents.
• atomic plasma deposited layers of a metal oxide can be applied over a drug attached or adhering to a stent surface.
• the deposition is on an atomic scale such that each deposition can be considered in effect as a monolayer.
• a greater number of deposited layers increasingly hinders elution of a surface-attached drug, thus allowing customization of time release.
• the number of APD deposited coatings over drug-coated substrates has a distinct effect on drug release. Bare metal substrates, on which drug is deposited, show relatively rapid elution. Multiple alumina or titania APD top coats slow elution initially by at least several hours. The number of cycled layers, or monolayers, appears to have a controlling effect, with 10 layers having little effect on normal elution, while an increasing number of layers, on the order of 100s, show a definite effect in slowing elution.
• Nanostructured substrate surfaces are formed when materials are deposited from high energy plasmas by nanoplasma deposition (NPD), where the deposited materials, e.g., titanium, are metals. Biomaterials, including drugs and proteins, can be efficiently deposited, becoming firmly attached to underlying nanosurfaced metal substrates.
• the nanorough surfaces may be particularly useful on implant surfaces which act as matrices for biomolecule loading. This nanorough surface is preferably less than 100 nm thick.
• a substrate is overlaid with a biomolecule eluting surface constructed of two or three layers, which can be described as a biolayer and a porous top coating or, where there are three layers, a nanorough surface, a biolayer, and a porous top coating, respectively.
• the layers may be formed on any substrate material including metals, polymers or ceramics, and are ideal for use on materials commonly used for medical implants, which are typically stainless steel, titanium, chromium cobalt or any of a variety of ceramics or polymers.
• biomolecule eluting surfaces can be utilized in order to achieve the desired elution profiles.
• the biolayer need not be limited to a single type of compound or biomolecule, nor do the compounds need to be bioactive.
• Coated drug surfaces are of particular interest in view of the wide range of therapeutic agents available to address adverse interactions encountered with medical implants. Currently popular drugs for use in arterial stents, for example, include anti-thrombotic and immunosuppressive agents. Other specialized implants may benefit from anti-microbial agents or antiflammatory drug coatings.
• a particularly advantageous feature of the APD method is the ability to deposit a relatively thin biolayer underlying the barrier layer.
• Many stents are multicoated with a protective polymer layer (the barrier layer over the substrate) followed by one or more layers (the biolayer) of polymer-attached or emeshed drug.
• Such multilayers add thickness to the lumen of a coated stent, which may exacerbate sloughing and contribute to manufacturing cost and quality control.
• the thin APD coatings over a biolayer can impart a distinct advantage for medical implants.
• the top layer over multilayer biocoatings can be an APD deposited film of a metal oxide such as titania or alumina.
• APD deposited layers function to some extent as a protective layer, but mainly act as a time release control for the underlying bioactive molecules comprising the biolayer.
• a set number of depositions; Le. monolayers, will control the amount of drug elution, such as rapamycin, from near 100% elution within 2 hr for untreated surfaces to a much slower release over a period of 12 hours with 150 APD deposited titania layers.
• Underlying surfaces i.e., the substrates to which biomolecules are attached or in contact with, can have distinct functions and features.
• a nanorough substrate surface if used, can be a thin NPD deposited material such as any of a number of metals, ranging from 1 to up to 100 nm thick, depending on desired substrate coverage and roughness. Coatings up to 500 nm may be useful, but generally thicker coatings or layers on the order of several hundred nm appear to be most practical for implant devices.
• a biolayer on the substrate can be deposited by MPD to obtain a select coverage or activity.
• Biolayers may be any of several molecular types, including metals, proteins and many organic molecules. The procedure is described and exemplified in U.S. Pat. No. 7,250,195 (2007). The biolayer may also be applied using ink-jet printing, spin coating, dip-coating and similar methods well-known in the art.
• a top or final APD layer can be used to form a porous surface and can be deposited to a thickness appropriate for a desired elution rate of one or more biomolecules. The overall top layer is thin, less than 1 nanometer to several hundred nanometers thick depending on the elution rate desired.
• Titania is nontoxic and is not associated with an immune response.
• the base substrate can be selected from a metal, ceramic or polymer including copolymers, biocompatible polymers such as polylactic acid and dissolvable polymers, depending on intended use.
• a biomolecule or other agent can be attached to or coated over gold or silicon in applications such as biosensors.
• Typical substrate materials used in devices such as orthopedic implants, dental implants, catheters and indwelling permanent or long-term devices include metals and plastics.
• Stainless steel, titanium and cobalt chromium stents are of particular interest in view of widespread use in heart vessel replacements.
• An additional advantage of APD titania top layers, as discussed, is that release of bioactive materials from substrate surfaces can be tailored to the properties of the underlying biomolecule.
• titania and alumina are exemplary of metal oxides that can be APD deposited, other metals are expected to exhibit similar properties.
• Alumina APD films exhibit properties similar to titania.
• Other metals such as hafnium, indium, platinum, gold, and silver can be produced as thin surface films with analogous properties.
• FIG. 1 illustrates the arrangement of a substrate (1) coated with a biomolecule (2) and overlaid with APD deposited titanium oxide (3) that allows elution of the biomolecule.
• FIG. 2 illustrates a biomolecule-eluting system with repeating layers of biomolecule and coating on a substrate surface (1); layers of biomolecule (2a and 2b) overlaid with an APD titanium oxide film (3a and 3b) over each layer of drug.
• FIG. 3 is a graph showing an elution profile for rapamycin deposited on a substrate covered with APD titania, in the arrangement illustrated in FIG. 1.
• X represents the control without the APD titanium oxide coating film over the rapamyxin; •, A, ⁇ , and represent APD deposited titania surface films of thicknesses 25 nm, 50 nm and 75 nm respectively.
• FIG. 4 is a graph showing a rapamycin elution profile from the multilayer system illustrated in FIG. 2.
• X is the control with only the drug applied to the substrate;
• O corresponds to elution of the drug applied in two layers, the first layer 2a covered with a 30 nm thick APD titanium oxide film 3a and the second layer 2b covered with a 35 nm thick APD titanium oxide film 3b.
• FIG. 5 is a graph showing osteoblast cell adhesion on APD amorphous titania coated on 316L stainless steel after 4 hr and 3 days incubation; SSl is coated with amorphous titania about 5 nm thick; SS2 about 8 nm thick; SS3 about 12 nm thick and SS4 about 15 nm thick; C is stainless steel control without an APD titanium coating; *indicates standard deviation.
• FIG. 6 is a graph showing endothelial cell adhesion on APD amorphous titania coated on titanium grade 1 after 3 days; Ti-I coating is about 5 nm thick; Ti-2 coating is about 10 nm
• Ti-3 coating is about 20 nm thick;
• Ti-4 is about 40 nm thick;
• Ti-5 is about 60 nm thick;
• Ti-6 is about 80 nm thick; C is a control without the APD titanium surface coating; *indicates standard deviation.
• FIG. 7 is an AFM image of atomic plasma deposited alumina on a silicon substrate.
• FIG. 8 is an AFM image of atomic plasma deposited titania on a silicon substrate.
• FIG. 9 is an AFM image of a typical smooth surface with an ALD titania coating.
• FIG. 10 is an AFM image of APD deposited titania showing the nanorough surface.
• FIG. 11 shows several metal parts coated with APD deposited titania with surfaces varying from curved to flat.
• the present invention utilizes an atomic plasma deposition (APD) technique to produce nanoscale thickness films on surfaces.
• the films are produced using a modified plasma deposition technique (APD) to achieve surfaces ranging from sub-nanometer thicknesses up to hundreds of nanometers.
• APD atomic plasma deposition
• the APD process produces thin films that are amorphous rather than crystalline and which have a porous character, making them ideal for time-release applications, cell adhesion matrices and protective coatings.
• the APD process as described is distinguishable from ALD, MLD, IPD, NPD and
• Atomic layer deposition is used to create conformal, pinhole free thin films typically used in the electronics and solar cell industries. The process is defined by two sequential, self-limiting surface reactions.
• MLD Molecular Layer Deposition
• IPD Ionic Plasma Deposition
• the ionized plasma particles so generated are deposited on a substrate which acts as an anode.
• Nanoplasma deposition utilizes an ionized gas produced by a DC current in order to deposit the ionized species onto a selected substrate surface.
• the thickness of films and coatings produced in this manner can be controlled but deposition is not uniform. This results in a nanorough surface.
• MPD or molecular plasma deposition also utilizes a plasma, but produces the plasma from solutions or suspensions of materials introduced between the high voltage cathode and substrate anode, set up in a manner similar to IPD.
• the APD method of the present invention is performed under sub-optimal conditions such that deposited films are grown via two sequential reactions resulting in porous or mesh- like surfaces. Pinhole and pore imperfections in these surfaces are shown in FIG. 1 and FIG. 2.
• the films are amorphous and do not conform to the substrate surface, instead forming an adherent, yet nanorough surface as deposition occurs.
• APD differs from ALD and MLD in using sub-optimal depositions so that there are imperfections such as pinholes and pores incorporated into a thinn film, thereby creating a mesh-like structure. Two sequential surface reactions are performed.
• the APD method for producing nanoscale thin films utilizes a chemical process that sequentially promotes a chemical reaction on a substrate surface between an organometallic compound and an oxygen source. Nonconformal, porous surfaces are formed, using intermittent, cyclic deposition of nanolayers to form films ranging from sub-nanometer thicknesses up to hundreds of nanometers in thickness.
• Virtually any type of substrate can be selected; for example stainless steel, titanium, titanium alloy, magnesium alloy, cobalt alloy, ceramics, silicon, glass or polymers, including biocompatible and dissolvable polymers.
• Nanophase single or multiple layer time release coatings over drugs attached to metal surfaces are described.
• the coatings are deposited over a drug attached to a porous metal substrate using an atomic plasma deposition procedure. Porosity of the substrate and the number of APD deposited layers controls drug release when the attached drug is exposed to an aqueous medium.
• the invention provides methods for preparing nanoporous surfaces over immobilized or otherwise attached molecules on an underlying surface.
• the APD deposited metal oxide serves to protect the underlying biomolecule while not preventing elution of the biomolecule.
• Elution rate is determined by several factors in addition to the porosity of a thin film, including thickness of the film, the metal oxide used, species of biomolecule, and the nature and degree of biomolecule adherence to the underlying substrate.
• the fluid environment to which the APD coated material is exposed is also a factor. In most applications, it is desirable to use APD coatings over drugs appropriate for in vivo use, which are well characterized regarding activity and ability to attach to substrates.
• the thickness of APD materials can be readily controlled by cycling the deposition conditions.
• relatively thin layers in the range of 25 to about 75 nm thickness provide a range of elution profiles, indicating that it is a matter of routine to determine appropriate thickness of the porous topcoat, in this case titania, but it could also be other metals such as aluminum oxide, for a desired elution rate.
• APD surface film thickness is not the sole factor to consider in achieving a desired elution. Elution rates will necessarily depend on the chemical characteristics of the biomolecule and on the adhesion or binding of the biomolecule to the base substrate.
• the biomolecule can be covalently attached to some substrates; for example, a gold or other substrate with an activated surface. Substrates are not necessarily metal, and polymeric substrates could be combined with bioactive molecules.
• biomolecule adhesion to the matrix or substrate is a factor in the elution characteristics.
• Several methods of attaching biomolecules to a surface are known, including spraying, dipping, ink jet printing, and deposition methods such as NPD or MPD deposition.
• Adherence or binding of the biomolecule may be affected by both the substrate material itself and surface roughness. Non-covalent interactions may be enhanced on nanorough surfaces.
• Surface area can be increased by mechanical means or by laser or plasma surface exposure.
• Deposit a metal onto a substrate using NPD can be used to pickle the surface with micro or nanoparticulates, which generally increases adherence to these surfaces compared to smooth surfaces.
• the disclosed APD titania nanoporous surfaces are appropriate as protective surfaces for mitigation of potential toxic effects from certain plastics or polymers that are in contact with the body or from potentially toxic drugs.
• a toxic agent can be controllably eluted from an indwelling probe or other device in such a manner that the toxic agent is targeted to a specific location, either by positioning of the device and/or because the material itself targets to a particular organ or type of cell; e.g., a targeting vector or antibody.
• APD titania surfaces are their very thin profiles, which are resistant to sloughing. This is not only economical but also at least in the case of titania, provides a surface which consists of an inert material that is not known to be immunogenic and is nontoxic.
• Rapamycin was purchased from L.C. Laboratories (Woburn, MA) and used without further purification. Elution tests were performed in a 60% Ix phosphate buffered saline
• Osteoblasts (CRLl 1372) were purchased from American Type Culture Collection (ATCC); endothelial cells from VEC Technology (Rensselaer, NY). All substrates were sterilized under UV light overnight prior to cell attachment measurements. Human osteoblasts, population numbers 5-7) in Dulbecco's Modified Eagle Medium (Gibco) supplemented with 10% fetal bovine serum (Hyclone) and 1% penicillin/streptomycin (Hyclone) were seeded at a density of 3500 cells/cm 2 onto the substrate and then incubated under standard cell culture conditions (humidified, CO 2 /95% air environment, 34°C).
• Gibco Dulbecco's Modified Eagle Medium
• Hyclone fetal bovine serum
• Hyclone penicillin/streptomycin
• the substrates were rinsed in a phosphate buffered saline to remove any non-adherent cells. After rinsing, cells remaining attached to the substrate were fixed with formaldehyde (Aldrich), stained with Hoescht 33258 dye (Sigma), and counted under a fluorescence microscope (Leica, DM IRB). Five random fields were counted per substrate. All substrates were run in triplicate Standard t-tests were used to check statistical significance between means. Endothelial cells were incubated and counted in the same manner as the osteoblast cells.
• the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay is based on the ability of a mitochrodrial dehydrogenase enzyme from viable cells to cleave tetrazolium rings of the pale yellow MTT and form dark blue formazan crystals which are largely impermeable to cell membranes, resulting in accumulation in healthy cells. Solubilization of the cells by addition of a detergent results in the liberation of the solubilized crystals. The number of surviving cells is directly proportional to the amount of formazan product produced. Color can be quantified by colorimetric assay and read on a multiwall scanning spectrophotometer (ELISA reader).
• ELISA reader multiwall scanning spectrophotometer
• the MTT assay was used to quantify and check viability of the cells.
• a colorimetric procedure was employed to measure cell growth. Living cells reduced MTT which is yellow in color to formazan which is purple. The purple color was quantified using UV absorbance at 500-600 nm.
• Metal oxide films can be deposited on various substrates by atomic plasma deposition (APD).
• APD atomic plasma deposition
• titanium oxide was deposited in self limiting reactions from a reaction chamber supplied with alternating exposures of volatilized 30% hydrogen peroxide (in water) and titanium isopropoxide, using nitrogen as the carrier gas.
• the following reaction sequence was used: evacuation of reaction chamber to IxIO ⁇ * Torr; stop the evacuation during a 0.2 sec introduction of hydrogen peroxide into the closed chamber, a 10 second delay during which the vacuum is released, closing of the chamber and a 0.2 second introduction of titanium isopropoxide, then 10 sec delay during which time the chamber is evacuated and the process is repeated.
• the temperature of the reaction chamber was 160° C.
• FIG. 1 is a schematic illustration of the relative thicknesses of the rapamycin coated substrate and the overlying surface formed from the APD deposited titania.
• A, ⁇ represent APD deposited titania surface films of thicknesses 25 nm, 50 nm and 75 nm respectively with respective release of the drug over up to about 6 hr for the 25 and 50 nm thick layers and up to about 12 hr for 75 nm thick top layer.
• the rate of drug release into a PBS/methanol solution is roughly proportional to the thickness of the surface deposited material, at least for layers up to about 100 nm thick.
• Example 4- APD Titania Multilayer Films for Controlled Release [00100] A titanium oxide film was deposited over rapamycin deposited onto a cobalt chromium substrate. Rapamycin was deposited from a colloidal solution using the MPD procedure described. An APD coating of titanium oxide was deposited over the rapamycin using the APD process described in example 1 as depicted in the cross section of FIG. 1. [00101] FIG. 4 is a rapamycin elution profile for release from a cobalt chromium substrate surface with APD deposited titania on two separate layers of MPD deposited rapamycin as depicted in the cross section of FIG. 2.
• the thicknesses of the titania layers 3a and 3b were 30 and 35 nm respectively.
• the control (x) has no top coating and the drug releases almost completely within about 2 hours. With the multiple layer coatings, rapamycin in initially released fairly rapidly, but then slows significantly up to about 4.5 hr compared with the control.
• FIG. 5 is a graph showing osteoblast cell adhesion on APD amorphous titania coated on stainless steel after 4 hrs and 3 days incubation; SSl is coated with amorphous titania about 5 nm thick; SS2 substrate is coated about 8 nm thick; SS3 is coated about 12 nm thick and SS4 coated about 15 nm thick.
• C is stainless steel control without an APD titanium coating; * indicated standard deviation.
• APD deposited titania films exhibited different cell attracting characteristics depending on the particular underlying substrate.
• Polycarbonate substrates coated with thin titania films exhibited at least an order of magnitude greater adhesion for osteoblast cells than for other types of cells such as gingival and periodontal fibroblasts.
• the APD method was performed under sub-optimal conditions to deposit thin titania oxide films with mesh-like surfaces. Pinhole and pore imperfections form in these surfaces under these conditions. The amorphous films form a nanorough, porous surface as deposition occurs.
• FIG. 7 An AFM image of APD alumina on a silicon substrate is shown in FIG. 7 and of titania on a silicon substrate in FIG. 8.
• FIG. 9 is an image of a smooth titania surface while FIG. 10 illustrates the nanorough surface of APD titania.
• APD titania coatings did not chip or flake and did not peel from the substrate when subjected to a standard tape test.
• FIG. 11 shows examples of differently shaped metal parts successfully coated with highly adherent titania

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