WO2008002632A2 - Carbon coating on an implantable device - Google Patents

Carbon coating on an implantable device Download PDF

Info

Publication number
WO2008002632A2
WO2008002632A2 PCT/US2007/014981 US2007014981W WO2008002632A2 WO 2008002632 A2 WO2008002632 A2 WO 2008002632A2 US 2007014981 W US2007014981 W US 2007014981W WO 2008002632 A2 WO2008002632 A2 WO 2008002632A2
Authority
WO
WIPO (PCT)
Prior art keywords
prc
trc
carbon coating
implantable device
rapamycin
Prior art date
Application number
PCT/US2007/014981
Other languages
French (fr)
Other versions
WO2008002632A3 (en
Inventor
Ni Ding
Gene Michal
Stephen D. Pacetti
Original Assignee
Abbott Cardiovascular Systems Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Abbott Cardiovascular Systems Inc. filed Critical Abbott Cardiovascular Systems Inc.
Publication of WO2008002632A2 publication Critical patent/WO2008002632A2/en
Publication of WO2008002632A3 publication Critical patent/WO2008002632A3/en

Links

Classifications

    • 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
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L31/084Carbon; Graphite
    • 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606Coatings

Definitions

  • This invention generally relates to covalent attachment of biologically active agents to a carbon coated stent. DESCRIPTION OF THE BACKGROUND
  • Blood vessel occlusions are commonly treated by mechanically enhancing blood flow in the affected vessels, such as by employing a stent.
  • Stents are used not only for mechanical intervention but also as vehicles for providing biological therapy.
  • the stent can be coated with a biocompatible polymeric coating.
  • the biocompatible polymeric coating can function either as a permeable layer or a carrier to allow a controlled delivery of the agent.
  • Polymeric coatings placed onto the stent serve to act both as the drug reservoir and to control the release of the drug.
  • One of the commercially available polymer coated products is stents manufactured by Boston Scientific.
  • U.S. Patent Nos. 5,869,127; 6,099,563; 6,179,817; and 6,197,051, assigned to Boston Scientific Corporation describe various compositions for coating medical devices. These compositions provide to stents described therein an enhanced biocompatibility and may optionally include a bioactive agent.
  • U.S. Patent No. 6,231,590 to Scimed Life Systems, Inc. describes a coating composition, which includes a bioactive agent, a collagenous material, or a collagenous coating optionally containing or coated with other bioactive agents.
  • Subacute thrombosis and neointimal hyperplasia are considered to be the leading complications after stenting.
  • Various factors are believed to be involved in the process. Methods for reducing thrombosis and restenosis have been previously proposed. However, those methods are less satisfactory for reducing late thrombosis and/or restenosis associated with stenting.
  • the embodiments disclosed herein address the above described problems.
  • SUMMARY OF THE INVENTION The present invention describes a method for forming a carbon coating on an implantable device.
  • the carbon coating includes a bioactive agent attached thereto.
  • a bioactive agent e.g., SODm, pegylated active agent and/or heparin
  • carbon can address more than one factor leading to neointimal hyperplasia or subacute thrombosis and may thus reduce early or late thrombosis, and restenosis. Therefore, when the bioactive agent is removed by the body after implantation, the underlying carbon surface can still provide high degree of biocompatibility.
  • the carbon coating generally includes two to four covalently linked carbon (C), hydrogen (H), silicon (Si), and oxygen (O) atoms.
  • a bioactive agent can be attached to the carbon coating without surface modification of the carbon coating.
  • a carbon coating can be exposed to a photo-reactive chemical (PRC) or a thermo-reactive chemical (TRC), which includes at least one reactive group.
  • PRC photo-reactive chemical
  • TRC thermo-reactive chemical
  • a light or heat can then be applied to the carbon coating and the PRC or TRC.
  • the PRC or TRC can then generate radicals which can extract hydrogen radicals from the carbon surface to allow the PRC or TRC to covalently link to the carbon coating surface.
  • a bioactive agent can then be covalently attached to the PRC or TRC via the at least one reactive group.
  • the attachment of the bioactive agent to the PRC or TRC can be carried out prior to attaching the PRC or TRC to the carbon coating so as to form a carbon coating having bioactive agents attached thereto via the PRC or TRC.
  • Any bioactive agent can be attached to a carbon coating according to the method described herein.
  • An implantable device bearing such a carbon coating can be used to treat, prevent, or ameliorate a disorder in a human being by implanting in the human being
  • the disorder can be, e.g., atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.
  • the present invention describes a method for forming a carbon coating on an implantable device.
  • the carbon coating includes a bioactive agent attached thereto.
  • Combination of a bioactive agent e.g., SODm, pegylated active agent and/or heparin
  • carbon can address more than one factor leading to neointimal hyperplasia or subacute thrombosis and may thus reduce early or late thrombosis, and restenosis. Therefore, when the bioactive agent is removed by the body after implantation, the underlying carbon surface can still provide high degree of biocompatibility.
  • the carbon coating generally includes two to four covalently linked carbon (C), hydrogen (H), silicon (Si), and oxygen (O) atoms.
  • a bioactive agent can be attached to the carbon coating without surface modification of the carbon coating.
  • a carbon coating can be exposed to a photo-reactive chemical (PRC) or a thermo-reactive chemical (TRC), which includes at least one reactive group.
  • PRC photo-reactive chemical
  • TRC thermo-reactive chemical
  • a light or heat can then be applied to the carbon coating and the PRC or TRC.
  • the PRC or TRC can then generate radicals which can extract hydrogen radicals from the carbon surface to allow the PRC or TRC to covalently link to the carbon coating surface.
  • a bioactive agent can then be covalently attached to the PRC or TRC via the at least one reactive group.
  • the attachment of the bioactive agent to the PRC or TRC can be carried out prior to attaching the PRC or TRC to the carbon coating so as to form a carbon coating having bioactive agents attached thereto via the PRC or TRC.
  • Any bioactive agent can be attached to a carbon coating according to the method described herein.
  • An implantable device bearing such a carbon coating can be used to treat, prevent, or ameliorate a disorder in a human being by implanting in the human being (e.g., a patient) an implantable device described herein.
  • the disorder can be, e.g., atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.
  • Carbon coating A carbon coating can be deposited via plasma assisted chemical vapor deposition (CVD) from ART, Inc. This coating has good adhesion and mechanical properties as a stent coating.
  • An ART carbon coating can contain four covalently linked carbon (C), hydrogen (H), silicon (Si), and oxygen (O) atoms.
  • the coating comprises a diamond-like material having an interpenetrating network, one of which is rich in carbon while the other is rich in silicon.
  • Another example is diamond-like carbon coating, which may contain only two elements, i.e. carbon and hydrogen.
  • the carbon coating can include other elements or materials such as a metal element(s) such as iron (Fe), silver (Ag), gold (Au), Magnesium (Mg), calcium (Ca), potassium (K), or sodium (Na), titanium, zirconium, niobium, tantalum, and hafnium, metal compound (s) such as titanium nitride, titanium carbonitride, titanium carbide, and/or other non-metal elements such as nitrogen, phosphorus, or boron.
  • a metal element(s) such as iron (Fe), silver (Ag), gold (Au), Magnesium (Mg), calcium (Ca), potassium (K), or sodium (Na), titanium, zirconium, niobium, tantalum, and hafnium
  • metal compound (s) such as titanium nitride, titanium carbonitride, titanium carbide, and/or other non-metal elements such as nitrogen, phosphorus, or boron.
  • the carbon coating can further include a ceramic material.
  • the carbon coating can be formed by established methods. For example, a chemical vapor deposition process can be used to form a diamond-like coating is known in the literature (Handbook of Chemical Vapor Deposition- Principles, Technology and Application, 2 nd edition by Hugh O. Pierson, Noyes Publication.
  • bioactive agent refers to an agent the presence of which elicits a desirable biological response in a tissue to which the agent is exposed in a mammal, e.g., a patient.
  • the bioactive agent can be, e.g., a drug, polymer, protein, peptide or a drug.
  • bioactive agent is used interchangeably with "drug.”
  • the bioactive agents can be SODm, heparin, polyethylene glycol/oxide, sialic acid, hyaluronic acid, polyethylene glycol/oxide- attached bioactive agents, synthetic peptides and natural proteins, nitric oxide donor molecules or combinations of thereof.
  • SOD refers to endogeneous superoxide dismutase enzyme.
  • SODm refers to mimetics of the SOD enzyme.
  • mimetics are sometimes referred to as and used interchangeably with the term “mimics.”
  • SOD can have important effects on vascular pathophysiology.
  • SODl -deficient mice have been found to produce more superoxide than their wild-type controls and have decreased endothelium-dependent and -independent vasodilation.
  • SODl overexpression in mice causes a decrease in vascular smooth muscle cell (VSMC) proliferation in response to endothelial growth factor (EGF) but no change in the aortic hypertrophic response to Angiotensin IL
  • VSMC vascular smooth muscle cell
  • EGF endothelial growth factor
  • SOD2 deficiency is lethal in mice, and although partial SOD2 deficiency has been shown to cause an increase in atherosclerotic lesion formation at arterial branch points, there was no effect on vasomotor responses to serotonin, PGF2a, or acetylcholine at baseline or after inhibition of SODl and SOD3 with diethyldithiocarbamate.
  • the second most abundant SOD isoform in blood vessels is SOD3, which is predominantly produced by VSMCs, but because its location in the interstitium between ECs and VSMCs it is thought to be essential for endothelial-dependent vasodilation by protecting NO as it diffuses from the ECs to the VSMCs.
  • the bioactive agent can be a polymer, or polymeric conjugate of a bioactive agent, that imparts a favorable biological property or properties to the carbon coating.
  • a bioactive agent can be a polymer, or polymeric conjugate of a bioactive agent, that imparts a favorable biological property or properties to the carbon coating.
  • Such polymers, or polymer conjugates can be, e.g., polyethylene glycol (PEG) or polyethylene oxide (PEO), polyethylene glycol/oxide derivative, sodium hyaluronate and its derivatives, sialic acid, synthetic peptides or natural proteins, synthetic or natural polysaccharides, aloe derived pectin (DelSite Inc.), recombinant human gelatin (Fibrogen), etc.
  • heparin includes sodium heparin, low molecular weight heparins, heparin derivative, heparinoids, or fragments of these.
  • the bioactive agents described above can also be pegylated active agents.
  • Pegylated bioactive agents are active agents modified or otherwise derivatized with poly(ethylene glycol).
  • the term pegylated bioactive agent are also referred as “pegylated drug” or “pegylated active agent”.
  • bioactive agent or drug described herein can specifically exclude any one or more of the above listed agents or drug.
  • attachment of the bioactive agents to the carbon coating can be induced via photo activation.
  • photo-reactive chemical(s) PRC
  • PRC photo-reactive chemical
  • the PRC contains chemically reactive groups, bioactive agents, such as SODm and/or heparin, can be bound to the PRC.
  • a desired biological agent can be covalently grafted to the carbon surface.
  • thermo-reactive chemical(s) can extract hydrogen on the surface in the form of C-H or Si-H bonds, and covalently couple directly to the surface.
  • bioactive agents such as SODm and/or heparin
  • PRCs include, but are not limited to, the ones from the benzophenone family, i.e.
  • benzophenone tetracarboxylic dianhydride benzoylbenzoic acid, benzoyl benzoyl chloride, 4-benzoylbenzoic acid N- hydroxysuccinimide ester, benzoyl benzoyl amine, or from azide family, i.e. substituted phenyl azide and substituted acyl azide.
  • TRCs include, but are not limited to acyl peroxide (e.g. acetyl and benzoyl peroxides), akyl peroxide (e.g. cumyl and t-butyl peroxide), hydroperoxide (e.g. t-butyl and cumyl hydroperoxide), perester (e.g. t- butyl perbenzoate), azo compound (e.g. Azobisisobutylonitrile (AIBN)), and disulfides
  • acyl peroxide e.g. acetyl and benzoyl peroxides
  • akyl peroxide e.g. cumyl and t-butyl peroxide
  • hydroperoxide e.g. t-butyl and cumyl hydroperoxide
  • perester e.g. t- butyl
  • the hydrogen extraction can be initiated by light, e.g. ultraviolet (UV), exposure of the PRC entity or thermal exposure of the TRC entity.
  • UV ultraviolet
  • the derivatives of PRC and TRC compounds contain the chemical reactive groups as a coupling agent.
  • the coupling reaction between PRC or TRC to the biologically active agent will be dependent on the specific structure of the PRC or TRC molecule but can be readily carried out by an ordinary artisan.
  • an amine functional group on SODm can react with an anhydride or acyl chloride of substituted benzophenone.
  • the PRC or TRC can be coupled to the carbon surface first and then coupled with the biological agent, or vice versa.
  • reactive group on PRC or TRC include, but are not limited to, an acid group (e.g., carboxylic group, sulfonic acid group, phosphoric acid group, phosphonic acid group, sulfuric acid group), hydroxyl group, amino group, thiol group, aldehyde, keto, acetal, etc.
  • the bioactive agents either include or can be made to include a reactive group such as an acid group (e.g., carboxylic group, sulfonic acid group, ⁇ phosphoric acid group, phosphonic acid group, sulfuric acid group), hydroxyl group, amino group, thiol group, aldehyde, keto, acetal, etc.
  • Attachment of the bioactive agent to the carbon coating can then be readily achieved by reaction between the reactive group on the PRC or TRC and the reactive group on the bioactive agent.
  • the carboxylic acid group of the PRC or TRC molecule can form an ester bond with a drug molecule via an established procedure in the art of organic synthesis.
  • the attachment the bioactive agent to the PRC or TRC via a carboxylic acid group can be achieved according to Scheme 1 as described below.
  • R represents a drug molecule or a derivative thereof.
  • X represents a leaving group attached to the drug molecule.
  • X can be OH, a halo group, mesylate or tosyl group, and any other groups capable of leaving the drug molecule in forming the drug/PRC ester bond.
  • PRC can also be TRC.
  • the attachment can be achieved via a hydroxyl group in the PRC molecule and a carboxylic acid in R, as shown in Scheme 2.
  • R represents a drug molecule or a derivative thereof.
  • X represents a leaving group attached to the drug molecule.
  • X can be OH, a halo group, an imidazole group, an o-Acylurea group, an NHS or Sulfo NHS group, and any other groups capable of leaving the drug molecule in forming the drug/PRC ester bond.
  • mesylate or tosylate can be leaving groups since they can be used to derivatize - OH functional materials.
  • PRC can also be TRC.
  • the PRC or TRC can be derivatized on the stent to have a good leaving group (e.g., imidazole via reaction with carbonyl di-imidazole), and this can subsequently react with a hydroxyl or amine group on the drug or bioactive polymer.
  • a good leaving group e.g., imidazole via reaction with carbonyl di-imidazole
  • the attachment described herein can be achieved via forming an imine Schiff base by PRC-CHO or TRC-CHO with an amine-containing drug (Scheme 3) or vice versa.
  • the aldehyde group of PRC-CHO can react with the amine group of an amine-containing drug to form an imine Schiff base, which is hydrolytically unstable and can release the amine-containing drug under in vivo conditions.
  • An alternative strategy for attaching a bioactive agent can be carried out by the reaction of the amino group of PRC-NH 2 or TRC-NH 2 with a keto group on the drug molecule to form an imine Schiff base linkage.
  • the stabilization of the Schiff base can be achieved by hydro genation using for example, the reducing agent Sodium cyanoborohydride.
  • the attachment described herein can be achieved via forming an acetal or hemi-acetal by PRC-CHO or TRC-CHO with a hydroxyl group or hydroxyl groups on a drug (Scheme 4) ior vice versa.
  • the acetal or hemi-acetal can undergo hydrolysis under in vivo conditions to release the bioactive agent.
  • the aldehyde group of PRC-CHO on the carbon coating can react with hydroxyl group or groups on a drug to form a prodrug with an acetal linkage or hemi-acetal linkage.
  • the hydroxyl group or groups can react with an aldehyde or keto group on a drug to form a prodrug with an acetal linkage or hemi-acetal linkage.
  • the attachment of the bioactive agent to the PRC or TRC can be carried out prior to attaching the PRC or TRC to the carbon coating so as to form a carbon coating having bioactive agents attached thereto via the PRC or TRC.
  • the chemistry for achieving this is the same as described above.
  • the bioactive agent can include other agents that are not listed above.
  • Such other bioactive agents can be any bioactive agent, which is a therapeutic, prophylactic, or diagnostic agent. These agents can have antiproliferative or anti-inflammmatory properties or can have other properties such as antineoplastic, antiplatelet, anti-coagulant, anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic, and antioxidant.
  • the agents can be cystostatic agents, agents that promote the healing of the endothelium such as NO releasing or generating agents, agents that attract endothelial progenitor cells, or agents that promote the attachment, migration and proliferation of endothelial cells (e.g., natriuretic peptide such as CNP, ANP or BNP peptide or an RGD or cRGD peptide), while quenching smooth muscle cell proliferation.
  • suitable therapeutic and prophylactic agents include synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities.
  • bioactive agent examples include antibodies, receptor ligands, enzymes, adhesion peptides, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator, antigens for immunization, hormones and growth factors, oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy.
  • anti-proliferative agents include rapamycin and its functional or structural derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), and its functional or structural derivatives, paclitaxel and its functional and structural derivatives.
  • Examples of rapamycin derivatives include 40-epi-(Nl-tetrazolyl)-rapamycin (ABT-578), 40-O-(3-hydroxy)propyl-rapamycin, 40-C>-[2-(2-hydroxy)ethoxy]ethyl- rapamycin, and 40-0-tetrazole-rapamycin.
  • Examples of paclitaxel derivatives include docetaxel.
  • Examples of antineoplastics and/or antimitotics include methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin ® from Pharmacia & Upjohn, Peapack N.
  • antiplatelets examples include hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg- chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein ⁇ b/HIa platelet membrane receptor antagonist antibody, recombinant hirudin, thrombin inhibitors such as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name
  • anti-inflammatory agents including steroidal and non- steroidal anti-inflammatory agents include tacrolimus, dexamethasone, clobetasol, or combinations thereof.
  • cytostatic substances include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten ® and Capozide ® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil ® and Prinzide ® from Merck & Co., Inc., Whitehouse Station, NJ).
  • An example of an antiallergic agent is permirolast potassium.
  • Other therapeutic substances or agents which may be appropriate include alpha-interferon, pimecrolimus, imatinib mesylate, midostaurin, bioactive RGD, and genetically engineered endothelial cells.
  • the foregoing substances can also be used in the form of prodrugs or co-drugs thereof.
  • the foregoing substances also include metabolites thereof and/or prodrugs of the metabolites.
  • the foregoing substances are listed by way of example and are not meant to be limiting. Other active agents which are currently available or that may be developed in the future are equally applicable.
  • bioactive agents described above can also be pegylated bioactive agents.
  • pegylated bioactive agents can be pegylated sirolimus, pegylated everolimus, pegylated zotarolimus, pegylated paclitaxel, pegylated proteins, pegylated peptides, etc.
  • the bioactive agent or drug described herein can specifically exclude any one or more of the above listed agents or drug.
  • the dosage or concentration of the bioactive agent required to produce a favorable therapeutic effect should be less than the level at which the bioactive agent produces toxic effects and greater than the level at which non-therapeutic results are obtained.
  • the dosage or concentration of the bioactive agent can depend upon factors such as the particular circumstances of the patient, the nature of the trauma, the nature of the therapy desired, the time over which the ingredient administered resides at the vascular site, and if other active agents are employed, the nature and type of the substance or combination of substances.
  • Therapeutic effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies. Standard pharmacological test procedures to determine dosages are understood by one of ordinary skill in the art.
  • an implantable device may be any suitable medical substrate that can be implanted in a human or veterinary patient.
  • implantable devices include self-expandable stents, balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts), heart valve prostheses, cerebrospinal fluid shunts, pacemaker electrodes, catheters, and endocardial leads (e.g., FINELEN ⁇ and ENDOTAK, available from Abbott Vascular, Santa Clara, CA), anastomotic devices and connectors, orthopedic implants such as screws, spinal implants, electro-stimulatory devices.
  • the underlying structure of the device can be of virtually any design.
  • the device can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum- iridium alloy, gold, magnesium, or combinations thereof.
  • ELGILOY cobalt chromium alloy
  • stainless steel 316L
  • high nitrogen stainless steel e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum- iridium alloy, gold, magnesium, or combinations thereof.
  • BIODUR 108 cobalt chrome alloy L-605
  • MP35N nickel-titanium alloy
  • platinum- iridium alloy gold, magnesium, or combinations
  • MP35N consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum.
  • MP20N consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
  • Devices made from bioabsorbable or biostable polymers could also be used with the embodiments of the present invention. .
  • the bioactive agents can be released from a carbon coating described herein on a medical device (e.g., stent) during delivery and (in the case of a stent) expansion of the device, or thereafter, and released at a desired rate and for a predetermined duration of time at the site of implantation.
  • a medical device e.g., stent
  • the medical device is a stent.
  • the stent described herein is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, esophagus, trachea/bronchi and other biological passageways.
  • a stent having the above-described coating is particularly useful for treating diseased regions of blood vessels caused by lipid deposition, monocyte or macrophage infiltration, or dysfunctional endothelium or a combination thereof, or occluded regions of blood vessels caused by abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis, and restenosis.
  • Stents may be placed in a wide array of blood vessels, both arteries and veins. Representative examples of sites include the iliac, femoral, popliteal, renal, carotid and coronary arteries.
  • an angiogram is first performed to determine the appropriate positioning for stent therapy.
  • An angiogram is typically accomplished by injecting a radiopaque contrast agent through a catheter inserted into an artery or vein as an x-ray is taken.
  • a guidewire is then advanced through the lesion or proposed site of treatment.
  • Over the guidewire is passed a delivery catheter which allows a stent in its collapsed configuration to be inserted into the passageway.
  • the delivery catheter is inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering the catheter through the vascular system under fluoroscopic guidance.
  • a stent having the above-described features may then be expanded at the desired area of treatment.
  • a post- insertion angiogram may also be utilized to confirm appropriate positioning.

Abstract

A carbon coating on a stent having a bioactive agent covalently attached thereto and methods of making the same are described.

Description

CARBON COATING ON AN IMPLANTABLE DEVICE
FIELD OF THE INVENTION
This invention generally relates to covalent attachment of biologically active agents to a carbon coated stent. DESCRIPTION OF THE BACKGROUND
Blood vessel occlusions are commonly treated by mechanically enhancing blood flow in the affected vessels, such as by employing a stent. Stents are used not only for mechanical intervention but also as vehicles for providing biological therapy. To effect a controlled delivery of an active agent in stent medication, the stent can be coated with a biocompatible polymeric coating. The biocompatible polymeric coating can function either as a permeable layer or a carrier to allow a controlled delivery of the agent. Although stents work well mechanically, the chronic issues of restenosis and, to a lesser extent, stent thrombosis remain. Pharmacological therapy in the form of a drug delivery stent appears to be a feasible means to tackle these issues. Polymeric coatings placed onto the stent serve to act both as the drug reservoir and to control the release of the drug. One of the commercially available polymer coated products is stents manufactured by Boston Scientific. For example, U.S. Patent Nos. 5,869,127; 6,099,563; 6,179,817; and 6,197,051, assigned to Boston Scientific Corporation, describe various compositions for coating medical devices. These compositions provide to stents described therein an enhanced biocompatibility and may optionally include a bioactive agent. U.S. Patent No. 6,231,590 to Scimed Life Systems, Inc., describes a coating composition, which includes a bioactive agent, a collagenous material, or a collagenous coating optionally containing or coated with other bioactive agents. Subacute thrombosis and neointimal hyperplasia are considered to be the leading complications after stenting. Various factors are believed to be involved in the process. Methods for reducing thrombosis and restenosis have been previously proposed. However, those methods are less satisfactory for reducing late thrombosis and/or restenosis associated with stenting.
Therefore, there is a need for a coating on a stent that provides for reduction of early and late thrombosis and/or restenosis.
The embodiments disclosed herein address the above described problems. SUMMARY OF THE INVENTION The present invention describes a method for forming a carbon coating on an implantable device. The carbon coating includes a bioactive agent attached thereto. Combination of a bioactive agent (e.g., SODm, pegylated active agent and/or heparin) and carbon can address more than one factor leading to neointimal hyperplasia or subacute thrombosis and may thus reduce early or late thrombosis, and restenosis. Therefore, when the bioactive agent is removed by the body after implantation, the underlying carbon surface can still provide high degree of biocompatibility.
As used herein, the carbon coating generally includes two to four covalently linked carbon (C), hydrogen (H), silicon (Si), and oxygen (O) atoms.
In some embodiments, a bioactive agent can be attached to the carbon coating without surface modification of the carbon coating. For example, a carbon coating can be exposed to a photo-reactive chemical (PRC) or a thermo-reactive chemical (TRC), which includes at least one reactive group. A light or heat can then be applied to the carbon coating and the PRC or TRC. The PRC or TRC can then generate radicals which can extract hydrogen radicals from the carbon surface to allow the PRC or TRC to covalently link to the carbon coating surface. A bioactive agent can then be covalently attached to the PRC or TRC via the at least one reactive group.
In some embodiments, the attachment of the bioactive agent to the PRC or TRC can be carried out prior to attaching the PRC or TRC to the carbon coating so as to form a carbon coating having bioactive agents attached thereto via the PRC or TRC.
Any bioactive agent can be attached to a carbon coating according to the method described herein. An implantable device bearing such a carbon coating can be used to treat, prevent, or ameliorate a disorder in a human being by implanting in the human being
(e.g., a patient) an implantable device described herein. The disorder can be, e.g., atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.
DETAILED DESCRIPTION The present invention describes a method for forming a carbon coating on an implantable device. The carbon coating includes a bioactive agent attached thereto.
Combination of a bioactive agent (e.g., SODm, pegylated active agent and/or heparin) and carbon can address more than one factor leading to neointimal hyperplasia or subacute thrombosis and may thus reduce early or late thrombosis, and restenosis. Therefore, when the bioactive agent is removed by the body after implantation, the underlying carbon surface can still provide high degree of biocompatibility.
As used herein, the carbon coating generally includes two to four covalently linked carbon (C), hydrogen (H), silicon (Si), and oxygen (O) atoms. hi some embodiments, a bioactive agent can be attached to the carbon coating without surface modification of the carbon coating. For example, a carbon coating can be exposed to a photo-reactive chemical (PRC) or a thermo-reactive chemical (TRC), which includes at least one reactive group. A light or heat can then be applied to the carbon coating and the PRC or TRC. The PRC or TRC can then generate radicals which can extract hydrogen radicals from the carbon surface to allow the PRC or TRC to covalently link to the carbon coating surface. A bioactive agent can then be covalently attached to the PRC or TRC via the at least one reactive group.
In some embodiments, the attachment of the bioactive agent to the PRC or TRC can be carried out prior to attaching the PRC or TRC to the carbon coating so as to form a carbon coating having bioactive agents attached thereto via the PRC or TRC. Any bioactive agent can be attached to a carbon coating according to the method described herein. An implantable device bearing such a carbon coating can be used to treat, prevent, or ameliorate a disorder in a human being by implanting in the human being (e.g., a patient) an implantable device described herein. The disorder can be, e.g., atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.
Carbon coating A carbon coating can be deposited via plasma assisted chemical vapor deposition (CVD) from ART, Inc. This coating has good adhesion and mechanical properties as a stent coating. An ART carbon coating can contain four covalently linked carbon (C), hydrogen (H), silicon (Si), and oxygen (O) atoms. The coating comprises a diamond-like material having an interpenetrating network, one of which is rich in carbon while the other is rich in silicon. Another example is diamond-like carbon coating, which may contain only two elements, i.e. carbon and hydrogen. In some embodiments, the carbon coating can include other elements or materials such as a metal element(s) such as iron (Fe), silver (Ag), gold (Au), Magnesium (Mg), calcium (Ca), potassium (K), or sodium (Na), titanium, zirconium, niobium, tantalum, and hafnium, metal compound (s) such as titanium nitride, titanium carbonitride, titanium carbide, and/or other non-metal elements such as nitrogen, phosphorus, or boron.
In some embodiments, the carbon coating can further include a ceramic material. The carbon coating can be formed by established methods. For example, a chemical vapor deposition process can be used to form a diamond-like coating is known in the literature (Handbook of Chemical Vapor Deposition- Principles, Technology and Application, 2nd edition by Hugh O. Pierson, Noyes Publication.
Bioactive Agents
As used herein, the term bioactive agent refers to an agent the presence of which elicits a desirable biological response in a tissue to which the agent is exposed in a mammal, e.g., a patient. The bioactive agent can be, e.g., a drug, polymer, protein, peptide or a drug. In some embodiments, the term "bioactive agent" is used interchangeably with "drug."
In some embodiments, the bioactive agents can be SODm, heparin, polyethylene glycol/oxide, sialic acid, hyaluronic acid, polyethylene glycol/oxide- attached bioactive agents, synthetic peptides and natural proteins, nitric oxide donor molecules or combinations of thereof.
The term "SOD" refers to endogeneous superoxide dismutase enzyme. SODm refers to mimetics of the SOD enzyme. The term "mimetic" is sometimes referred to as and used interchangeably with the term "mimics."
SOD can have important effects on vascular pathophysiology. For example, SODl -deficient mice have been found to produce more superoxide than their wild-type controls and have decreased endothelium-dependent and -independent vasodilation. SODl overexpression in mice causes a decrease in vascular smooth muscle cell (VSMC) proliferation in response to endothelial growth factor (EGF) but no change in the aortic hypertrophic response to Angiotensin IL A separate study with mice overexpressing SODl on the apoE"7" background showed no significant effect on aortic atherosclerotic lesion area. Total SOD2 deficiency is lethal in mice, and although partial SOD2 deficiency has been shown to cause an increase in atherosclerotic lesion formation at arterial branch points, there was no effect on vasomotor responses to serotonin, PGF2a, or acetylcholine at baseline or after inhibition of SODl and SOD3 with diethyldithiocarbamate. The second most abundant SOD isoform in blood vessels is SOD3, which is predominantly produced by VSMCs, but because its location in the interstitium between ECs and VSMCs it is thought to be essential for endothelial-dependent vasodilation by protecting NO as it diffuses from the ECs to the VSMCs. These differences in the regulation of vascular tone or in the formation of atherosclerotic lesions indicate the potential importance of the subcellular localization of antioxidant systems in the modulation of local oxidant signaling.
SODm includes any compounds that provides for functions similar to those of SOD. Such examples of SODm include peptide mimetics of SOD. Another example of SODm is a manganese-based, low molecular weight (MW = 543) SOD complex with the structure illustrated below.
Figure imgf000007_0001
In some embodiments, the bioactive agent can be a polymer, or polymeric conjugate of a bioactive agent, that imparts a favorable biological property or properties to the carbon coating. Such polymers, or polymer conjugates, can be, e.g., polyethylene glycol (PEG) or polyethylene oxide (PEO), polyethylene glycol/oxide derivative, sodium hyaluronate and its derivatives, sialic acid, synthetic peptides or natural proteins, synthetic or natural polysaccharides, aloe derived pectin (DelSite Inc.), recombinant human gelatin (Fibrogen), etc.
As used herein, the term heparin includes sodium heparin, low molecular weight heparins, heparin derivative, heparinoids, or fragments of these. The bioactive agents described above can also be pegylated active agents.
Pegylated bioactive agents are active agents modified or otherwise derivatized with poly(ethylene glycol). The term pegylated bioactive agent are also referred as "pegylated drug" or "pegylated active agent".
In some embodiments, the bioactive agent or drug described herein can specifically exclude any one or more of the above listed agents or drug.
Attaching bioactive agents
In some embodiments, attachment of the bioactive agents to the carbon coating can be induced via photo activation. For example, photo-reactive chemical(s) (PRC) can extract hydrogen on the surface in the form of C-H or Si-H bonds, and covalently couple directly to the surface. If the PRC contains chemically reactive groups, bioactive agents, such as SODm and/or heparin, can be bound to the PRC. As a result, a desired biological agent can be covalently grafted to the carbon surface.
In some embodiments, attachment of the bioactive agents to the carbon coating can be induced via thermal activation. For example, thermo-reactive chemical(s) (TRC) can extract hydrogen on the surface in the form of C-H or Si-H bonds, and covalently couple directly to the surface. If the TRC contains chemically reactive groups, bioactive agents, such as SODm and/or heparin, can be bound to the PRC. As a result, a desired biological agent can be covalently grafted to the carbon surface. Examples of PRCs include, but are not limited to, the ones from the benzophenone family, i.e. benzophenone tetracarboxylic dianhydride, benzoylbenzoic acid, benzoyl benzoyl chloride, 4-benzoylbenzoic acid N- hydroxysuccinimide ester, benzoyl benzoyl amine, or from azide family, i.e. substituted phenyl azide and substituted acyl azide.
TRC typically involves the compounds possessing O-O, S-S, N-O, N=N bonds. Examples of TRCs include, but are not limited to acyl peroxide (e.g. acetyl and benzoyl peroxides), akyl peroxide (e.g. cumyl and t-butyl peroxide), hydroperoxide (e.g. t-butyl and cumyl hydroperoxide), perester (e.g. t- butyl perbenzoate), azo compound (e.g. Azobisisobutylonitrile (AIBN)), and disulfides
The hydrogen extraction can be initiated by light, e.g. ultraviolet (UV), exposure of the PRC entity or thermal exposure of the TRC entity. The derivatives of PRC and TRC compounds contain the chemical reactive groups as a coupling agent. The coupling reaction between PRC or TRC to the biologically active agent will be dependent on the specific structure of the PRC or TRC molecule but can be readily carried out by an ordinary artisan. For example, an amine functional group on SODm can react with an anhydride or acyl chloride of substituted benzophenone. The PRC or TRC can be coupled to the carbon surface first and then coupled with the biological agent, or vice versa.
For example, some examples of reactive group on PRC or TRC include, but are not limited to, an acid group (e.g., carboxylic group, sulfonic acid group, phosphoric acid group, phosphonic acid group, sulfuric acid group), hydroxyl group, amino group, thiol group, aldehyde, keto, acetal, etc. The bioactive agents either include or can be made to include a reactive group such as an acid group (e.g., carboxylic group, sulfonic acid group, δ phosphoric acid group, phosphonic acid group, sulfuric acid group), hydroxyl group, amino group, thiol group, aldehyde, keto, acetal, etc.
Attachment of the bioactive agent to the carbon coating can then be readily achieved by reaction between the reactive group on the PRC or TRC and the reactive group on the bioactive agent. For example, the carboxylic acid group of the PRC or TRC molecule can form an ester bond with a drug molecule via an established procedure in the art of organic synthesis. Generally, the attachment the bioactive agent to the PRC or TRC via a carboxylic acid group can be achieved according to Scheme 1 as described below.
O carbon carbon coating *ΛA. PRC C OH + RX (ΛΠ- PRC- coating -OR
Scheme 1
In Scheme 1, R represents a drug molecule or a derivative thereof. X represents a leaving group attached to the drug molecule. For example, X can be OH, a halo group, mesylate or tosyl group, and any other groups capable of leaving the drug molecule in forming the drug/PRC ester bond. PRC can also be TRC. Alternatively, the attachment can be achieved via a hydroxyl group in the PRC molecule and a carboxylic acid in R, as shown in Scheme 2.
PRC OH + RCOX carbon IΛTL coating
Figure imgf000010_0001
Figure imgf000010_0002
Scheme 2
In Scheme 2, R represents a drug molecule or a derivative thereof. X represents a leaving group attached to the drug molecule. For example, X can be OH, a halo group, an imidazole group, an o-Acylurea group, an NHS or Sulfo NHS group,, and any other groups capable of leaving the drug molecule in forming the drug/PRC ester bond. For example, mesylate or tosylate can be leaving groups since they can be used to derivatize - OH functional materials. PRC can also be TRC. In alternate embodiments, the PRC or TRC can be derivatized on the stent to have a good leaving group (e.g., imidazole via reaction with carbonyl di-imidazole), and this can subsequently react with a hydroxyl or amine group on the drug or bioactive polymer.
In some other embodiments, the attachment described herein can be achieved via forming an imine Schiff base by PRC-CHO or TRC-CHO with an amine-containing drug (Scheme 3) or vice versa. As shown in Scheme 3, the aldehyde group of PRC-CHO can react with the amine group of an amine-containing drug to form an imine Schiff base, which is hydrolytically unstable and can release the amine-containing drug under in vivo conditions. An alternative strategy for attaching a bioactive agent can be carried out by the reaction of the amino group of PRC-NH2 or TRC-NH2 with a keto group on the drug molecule to form an imine Schiff base linkage. In some embodiments, the stabilization of the Schiff base can be achieved by hydro genation using for example, the reducing agent Sodium cyanoborohydride.
PRC CHO + NH2-DnIg ► Carbon IΛΛJ PRC CH=NH-Drug coating
Figure imgf000011_0001
imine Schiff base Scheme 3
Again, in Scheme 3, PRC can be replaced with TRC.
In still some other embodiments, the attachment described herein can be achieved via forming an acetal or hemi-acetal by PRC-CHO or TRC-CHO with a hydroxyl group or hydroxyl groups on a drug (Scheme 4) ior vice versa. The acetal or hemi-acetal can undergo hydrolysis under in vivo conditions to release the bioactive agent. As shown in Scheme 4, the aldehyde group of PRC-CHO on the carbon coating can react with hydroxyl group or groups on a drug to form a prodrug with an acetal linkage or hemi-acetal linkage. Alternatively, the hydroxyl group or groups can react with an aldehyde or keto group on a drug to form a prodrug with an acetal linkage or hemi-acetal linkage.
Carbon coating
Figure imgf000012_0001
Scheme 4
Other methods of attaching the bioactive agent to the carbon coating are well documented and readily appreciable by an ordinary artisan (see, for example, Larock, Comprehensive Organic Transformations : A Guide to Functional Group Preparations, John Wiley & Sons, Inc., Copyright 1999).
In some embodiments, the attachment of the bioactive agent to the PRC or TRC can be carried out prior to attaching the PRC or TRC to the carbon coating so as to form a carbon coating having bioactive agents attached thereto via the PRC or TRC. The chemistry for achieving this is the same as described above.
Other bioactive agents
The bioactive agent can include other agents that are not listed above. Such other bioactive agents can be any bioactive agent, which is a therapeutic, prophylactic, or diagnostic agent. These agents can have antiproliferative or anti-inflammmatory properties or can have other properties such as antineoplastic, antiplatelet, anti-coagulant, anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic, and antioxidant. The agents can be cystostatic agents, agents that promote the healing of the endothelium such as NO releasing or generating agents, agents that attract endothelial progenitor cells, or agents that promote the attachment, migration and proliferation of endothelial cells (e.g., natriuretic peptide such as CNP, ANP or BNP peptide or an RGD or cRGD peptide), while quenching smooth muscle cell proliferation. Examples of suitable therapeutic and prophylactic agents include synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities. Some other examples of the bioactive agent include antibodies, receptor ligands, enzymes, adhesion peptides, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator, antigens for immunization, hormones and growth factors, oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy. Examples of anti-proliferative agents include rapamycin and its functional or structural derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), and its functional or structural derivatives, paclitaxel and its functional and structural derivatives. Examples of rapamycin derivatives include 40-epi-(Nl-tetrazolyl)-rapamycin (ABT-578), 40-O-(3-hydroxy)propyl-rapamycin, 40-C>-[2-(2-hydroxy)ethoxy]ethyl- rapamycin, and 40-0-tetrazole-rapamycin. Examples of paclitaxel derivatives include docetaxel. Examples of antineoplastics and/or antimitotics include methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn, Peapack N. J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg- chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein πb/HIa platelet membrane receptor antagonist antibody, recombinant hirudin, thrombin inhibitors such as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station, NJ), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxide donors, super oxide dismutases, super oxide dismutase mimetic, 4-amino-2,2,6,6-tetramethylpiperidine-l-oxyl (4-amino-TEMPO), estradiol, anticancer agents, dietary supplements such as various vitamins, and a combination thereof. Examples of anti-inflammatory agents including steroidal and non- steroidal anti-inflammatory agents include tacrolimus, dexamethasone, clobetasol, or combinations thereof. Examples of cytostatic substances include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc., Whitehouse Station, NJ). An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, pimecrolimus, imatinib mesylate, midostaurin, bioactive RGD, and genetically engineered endothelial cells. The foregoing substances can also be used in the form of prodrugs or co-drugs thereof. The foregoing substances also include metabolites thereof and/or prodrugs of the metabolites. The foregoing substances are listed by way of example and are not meant to be limiting. Other active agents which are currently available or that may be developed in the future are equally applicable.
The bioactive agents described above can also be pegylated bioactive agents. Examples of such pegylated bioactive agents can be pegylated sirolimus, pegylated everolimus, pegylated zotarolimus, pegylated paclitaxel, pegylated proteins, pegylated peptides, etc.
In some embodiments, the bioactive agent or drug described herein can specifically exclude any one or more of the above listed agents or drug. The dosage or concentration of the bioactive agent required to produce a favorable therapeutic effect should be less than the level at which the bioactive agent produces toxic effects and greater than the level at which non-therapeutic results are obtained. The dosage or concentration of the bioactive agent can depend upon factors such as the particular circumstances of the patient, the nature of the trauma, the nature of the therapy desired, the time over which the ingredient administered resides at the vascular site, and if other active agents are employed, the nature and type of the substance or combination of substances. Therapeutic effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies. Standard pharmacological test procedures to determine dosages are understood by one of ordinary skill in the art.
Examples of Implantable Device
As used herein, an implantable device may be any suitable medical substrate that can be implanted in a human or veterinary patient. Examples of such implantable devices include self-expandable stents, balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts), heart valve prostheses, cerebrospinal fluid shunts, pacemaker electrodes, catheters, and endocardial leads (e.g., FINELENΕ and ENDOTAK, available from Abbott Vascular, Santa Clara, CA), anastomotic devices and connectors, orthopedic implants such as screws, spinal implants, electro-stimulatory devices. The underlying structure of the device can be of virtually any design. The device can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N," "MP20N," ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum- iridium alloy, gold, magnesium, or combinations thereof. "MP35N" and "MP20N" are trade names for alloys of cobalt, nickel, chromium and molybdenum available from
Standard Press Steel Co., Jenkintown, PA. "MP35N" consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. "MP20N" consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devices made from bioabsorbable or biostable polymers could also be used with the embodiments of the present invention. . Method of Use
In accordance with embodiments of the invention, the bioactive agents can be released from a carbon coating described herein on a medical device (e.g., stent) during delivery and (in the case of a stent) expansion of the device, or thereafter, and released at a desired rate and for a predetermined duration of time at the site of implantation. Preferably, the medical device is a stent. The stent described herein is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, esophagus, trachea/bronchi and other biological passageways. A stent having the above-described coating is particularly useful for treating diseased regions of blood vessels caused by lipid deposition, monocyte or macrophage infiltration, or dysfunctional endothelium or a combination thereof, or occluded regions of blood vessels caused by abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis, and restenosis. Stents may be placed in a wide array of blood vessels, both arteries and veins. Representative examples of sites include the iliac, femoral, popliteal, renal, carotid and coronary arteries. For implantation of a stent, an angiogram is first performed to determine the appropriate positioning for stent therapy. An angiogram is typically accomplished by injecting a radiopaque contrast agent through a catheter inserted into an artery or vein as an x-ray is taken. A guidewire is then advanced through the lesion or proposed site of treatment. Over the guidewire is passed a delivery catheter which allows a stent in its collapsed configuration to be inserted into the passageway. The delivery catheter is inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering the catheter through the vascular system under fluoroscopic guidance. A stent having the above-described features may then be expanded at the desired area of treatment. A post- insertion angiogram may also be utilized to confirm appropriate positioning.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.

Claims

CLAIMS We claim:
1. A method, comprising: providing an implantable comprising a carbon coating that comprises covalently linked carbon (C), and hydrogen (H); exposing the carbon coating to a photo-reactive chemical (PRC) or a thermo- reactive chemical (TRC) wherein the PRC or TRC comprises at least a reactive group; applying a light to the carbon coating exposed to the PRC or heat to the carbon coating exposed to TRC to cause the PRC or TRC to attach to the carbon coating; and attaching a bioactive agent to the PRC or TRC via the reactive group via covalent bonding.
2. The method of claim 1, wherein the carbon coating further comprises covalently linked silicon (Si) and oxygen (O) atoms.
3. The method of claim 1, wherein the light is ultraviolet.
4. The method of claim 1, wherein the light is visible.
5. The method of claim 1, wherein the PRC is a compound in the benzophenone family or a compound in the azide family.
6. The method of claim 3, wherein the PRC is selected from group consisting of benzophenone tetracarboxylic dianhydride, benzoylbenzoic acid, benzoyl benzoyl chloride, 4-benzoylbenzoic acid N-hydroxysuccinimide ester, benzoyl benzoyl amine, substituted phenyl azide and substituted acyl azide.
7. The method of claim 1, wherein the TRC is selected from acyl peroxide , akyl peroxide, hydroperoxide, perester, azo compounds, and disulfides.
8. The method of claim 7, wherein the TRC is selected from acetyl or benzoyl peroxides, cumyl or t-butyl peroxide, t-butyl or cumyl hydroperoxide, t- butyl perbenzoate, or azobisisobutylonitrile (AIBN)-
9. The method of claim 1, wherein the carbon coating further comprises a metal or a ceramic.
10. The method of claim 1, wherein the bioactive agent is superoxide dismutase (SOD), super oxide dismutase mimetics (SODm), heparin, polyethylene glycol/oxide, polyethylene glycol/oxide derivative, sodium hyaluronate and its derivatives, sialic acid, synthetic peptides or natural proteins, synthetic or natural polysaccharides, aloe derived pectin (DelSite Inc.), recombinant human gelatin (Fibrogen), nitric oxide donor molecules or combinations of thereof.
11. The method of claim 1 , wherein the bioactive agent is selected from paclitaxel, docetaxel, estradiol, 4-amino-2,2,6,6-tetrarnethylpiperidine-l-oxyl (4-amino- TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2- hydroxy)ethyl-rapamycin (everolimus), 40-0-(3-hydroxy)propyl-rapamycin, 40-<9-[2-(2- hydroxy)ethoxy]ethyl-rapamycin, and 40-0-tetrazole-rapamycin, 40-epi-(Nl-tetrazolyl)- rapamycin (ABT-578), clobetasol, pimecrolimus, imatinib mesylate, midostaurin, prodrugs thereof, co-drugs thereof, pegylated drug thereof, and a combination thereof.
12. The method of claim 1, wherein the implantable device is a stent.
13. The method of claim 1, wherein the implantable device is a bioabsorbable stent.
14. A method, comprising: providing an implantable comprising a carbon coating that comprises covalently linked carbon (C), and hydrogen (H); attaching a bioactive agent to a photo-reactive chemical (PRC) or a thermo-reactive chemical (TRC) via a reactive group via covalent bonding where the PRC or TRC comprises at least one reactive group; exposing the carbon coating to the PRC or TRC with the bioactive agent attached thereto; and applying a light to the carbon coating exposed to the PRC or heat to the carbon coating exposed to TRC to cause the PRC or TRC to attach to the carbon coating.
15. The method of claim 14, wherein the carbon coating further comprises covalently linked silicon (Si) and oxygen (O) atoms.
16. The method of claim 14, wherein the light is ultraviolet.
17. The method of claim 14, wherein the light is visible.
18. The method of claim 14, wherein the PRC is a compound in the benzophenone family or a compound in the azide family.
19. The method of claim 16, wherein the PRC is selected from group consisting of benzophenone tetracarboxylic dianhydride, benzoylbenzoic acid, benzoyl benzoyl chloride, 4-benzoylbenzoic acid N-hydroxysuccinimide ester, benzoyl benzoyl amine, substituted phenyl azide and substituted acyl azide.
20. The method of claim 14, wherein the TRC is selected from acyl peroxide , akyl peroxide, hydroperoxide, perester, azo compounds, and disulfides.
21. The method of claim 20, wherein the TRC is selected from acetyl or benzoyl peroxides, cumyl or t-butyl peroxide, t-butyl or cumyl hydroperoxide, t- butyl perbenzoate, or azobisisobutylonitrile (AIBN).
22. The method of claim 14, wherein the carbon coating further comprises a metal or a ceramic.
23. The method of claim 14, wherein the bioactive agent is superoxide dismutase (SOD), super oxide dismutase mimetics (SODm), heparin, polyethylene glycol/oxide, polyethylene glycol/oxide derivative, sodium hyaluronate and its derivatives, sialic acid, synthetic peptides or natural proteins, synthetic or natural polysaccharides, aloe derived pectin (DelSite Inc.), recombinant human gelatin (Fibrogen), nitric oxide donor molecules or combinations of thereof.
24. The method of claim 14, wherein the bioactive agent is selected from paclitaxel, docetaxel, estradiol, 4-amino-2,2,6,6-tetramethylpiperidine-l-oxyl (4-amino- TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2- hydroxy)ethyl-rapamycin (everolimus), 40-0-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2- hydroxy)ethoxy]ethyl-rapamycin, and 40-0-tetrazole-rapamycin, 40-epi-(Nl-tetrazolyl)- rapamycin (ABT-578), clobetasol, pimecrolimus, imatinib mesylate, midostaurin, prodrugs thereof, co-drugs thereof, pegylated drug thereof, and a combination thereof.
25. The method of claim 14, wherein the implantable device is a stent.
26. The method of claim 14, wherein the implantable device is a bioabsorbable stent.
27. An implantable device comprising a carbon coating and a bioactive agent attached thereto, wherein the bioactive agent is covalently attached to a photo-reactive chemical (PRC) or a thermo-reactive chemical (TRC), which is in turn covalently attached directly to the carbon coating, and wherein the carbon coating comprises covalently linked carbon (C), and hydrogen (H) atoms.
28. The implantable device of claim 27, wherein the carbon coating further comprises covalently linked silicon (Si) and oxygen (O) atoms.
29. The implantable device of claim 27, wherein the PRC is ultraviolet reactive.
30. The implantable device of claim 27, wherein the PRC is visible light reactive.
31. The implantable device of claim 27, wherein the bioactive agent is attached to the PRC or TRC via at least one reactive group.
32. The implantable device of claim 27, wherein the PRC is a compound in the benzophenone family or a compound in the azidβ family.
33. The implantable device of claim 32, wherein the PRC is selected from group consisting of benzophenone tetracarboxylic dianhydride, benzoylbenzoic acid, benzoyl benzoyl chloride, 4-benzoylbenzoic acid N-hydroxysuccinimide ester, benzoyl benzoyl amine, substituted phenyl azide and substituted acyl azide.
34. The implantable device of claim 27, wherein the TRC is selected from acyl peroxide , akyl peroxide, hydroperoxide, perester, azo compounds, and disulfides.
35. The implantable device of claim 27, wherein the TRC is selected from acetyl or benzoyl peroxides, cumyl or t-butyl peroxide, t-butyl or cumyl hydroperoxide, t- butyl perbenzoate, or azobisisobutylonitrile (AIBN).
36. The implantable device of claim 27, wherein the carbon coating further comprises a metal or a ceramic.
37. The implantable device of claim 27, wherein the bioactive agent is superoxide dismutase (SOD), super oxide dismutase mimetics (SODm), heparin, polyethylene glycol/oxide, polyethylene glycol/oxide derivative, sodium hyaluronate and its derivatives, sialic acid, synthetic peptides or natural proteins, synthetic or natural polysaccharides, aloe derived pectin (DelSite Inc.), recombinant human gelatin (Fibrogen), nitric oxide donor molecules or combinations of thereof.
38. The implantable device of claim 27, wherein the bioactive agent is selected from paclitaxel, docetaxel, estradiol, 4-amino-2,2,6,6-tetramethylpiperidine-l-oxyl (4-amino- TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-<9-(2- hydroxy)ethyl-rapamycin (everolimus), 40-0-(3-hydroxy)propyl-rapamycin, 40-0-[2-(2- hydroxy)ethoxy]ethyl-rapamycin, and 40-0-tetrazole-rapamycin, 40-epi-(Nl-tetrazolyl)- rapamycin (ABT-578), clobetasol, pimecrolimus, imatinib mesylate, midostaurin, prodrugs thereof, co-drugs thereof, pegylated drug thereof, and combinations thereof.
39. The implantable device of claim 27 , wherein the implantable device is a stent.
40. The implantable device of claim 27, wherein the implantable device is a bioabsorbable stent.
41. A method of treating or preventing a disorder, comprising implanting in a human being an implantable device according to claim 27, wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.
42. A method of treating or preventing a disorder, comprising implanting in a human being an implantable device according to claim 38, wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.
PCT/US2007/014981 2006-06-27 2007-06-25 Carbon coating on an implantable device WO2008002632A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US81722906P 2006-06-27 2006-06-27
US60/817,229 2006-06-27
US11/820,560 2007-06-19
US11/820,560 US8128688B2 (en) 2006-06-27 2007-06-19 Carbon coating on an implantable device

Publications (2)

Publication Number Publication Date
WO2008002632A2 true WO2008002632A2 (en) 2008-01-03
WO2008002632A3 WO2008002632A3 (en) 2008-07-10

Family

ID=38713421

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/014981 WO2008002632A2 (en) 2006-06-27 2007-06-25 Carbon coating on an implantable device

Country Status (2)

Country Link
US (1) US8128688B2 (en)
WO (1) WO2008002632A2 (en)

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8394446B2 (en) 2005-07-25 2013-03-12 Abbott Cardiovascular Systems Inc. Methods of providing antioxidants to implantable medical devices
US7785647B2 (en) * 2005-07-25 2010-08-31 Advanced Cardiovascular Systems, Inc. Methods of providing antioxidants to a drug containing product
US8642093B2 (en) * 2007-10-30 2014-02-04 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US20090112197A1 (en) * 2007-10-30 2009-04-30 Searete Llc Devices configured to facilitate release of nitric oxide
US8221690B2 (en) 2007-10-30 2012-07-17 The Invention Science Fund I, Llc Systems and devices that utilize photolyzable nitric oxide donors
US20090048666A1 (en) * 2007-08-14 2009-02-19 Boston Scientific Scimed, Inc. Medical devices having porous carbon adhesion layers
US8349262B2 (en) 2007-10-30 2013-01-08 The Invention Science Fund I, Llc Nitric oxide permeable housings
US10080823B2 (en) * 2007-10-30 2018-09-25 Gearbox Llc Substrates for nitric oxide releasing devices
US20110182970A1 (en) * 2007-10-30 2011-07-28 Hyde Roderick A Nitric oxide sensors and systems
US8877508B2 (en) 2007-10-30 2014-11-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
CN102292053A (en) 2008-09-29 2011-12-21 卡迪尔克阀门技术公司 Heart valve
WO2010040009A1 (en) 2008-10-01 2010-04-08 Cardiaq Valve Technologies, Inc. Delivery system for vascular implant
WO2010090767A2 (en) * 2009-02-09 2010-08-12 St. Jude Medical, Inc. Enhancing biocompatibility of a medical device
EP4119098A1 (en) 2009-04-15 2023-01-18 Edwards Lifesciences CardiAQ LLC Vascular implant and delivery system
ES2355784B1 (en) * 2009-09-21 2012-02-03 Universitat De Valencia SOD MIMETIC METALLIC COMPLEXES
US8579964B2 (en) 2010-05-05 2013-11-12 Neovasc Inc. Transcatheter mitral valve prosthesis
US9308087B2 (en) 2011-04-28 2016-04-12 Neovasc Tiara Inc. Sequentially deployed transcatheter mitral valve prosthesis
US9554897B2 (en) 2011-04-28 2017-01-31 Neovasc Tiara Inc. Methods and apparatus for engaging a valve prosthesis with tissue
US9345573B2 (en) 2012-05-30 2016-05-24 Neovasc Tiara Inc. Methods and apparatus for loading a prosthesis onto a delivery system
US10583002B2 (en) 2013-03-11 2020-03-10 Neovasc Tiara Inc. Prosthetic valve with anti-pivoting mechanism
US9681951B2 (en) 2013-03-14 2017-06-20 Edwards Lifesciences Cardiaq Llc Prosthesis with outer skirt and anchors
US9572665B2 (en) 2013-04-04 2017-02-21 Neovasc Tiara Inc. Methods and apparatus for delivering a prosthetic valve to a beating heart
EP2994174A1 (en) 2013-05-06 2016-03-16 Abbott Cardiovascular Systems Inc. A hollow stent filled with a therapeutic agent formulation
ES2543850B1 (en) * 2014-02-24 2016-06-16 Universitat De Valencia Use of SOD mimetic metal complexes as food agents and as cosmetics
GB2559988B (en) 2017-02-23 2020-05-13 Cook Medical Technologies Llc Regulation/modification of stent contact surface for polymer free drug coating

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2654345A1 (en) * 1989-09-05 1991-05-17 Hamann Sylvie Biocompatible covering consisting of a carbon powder
EP0556940A1 (en) * 1986-02-24 1993-08-25 Robert E. Fischell Intravascular stent
US5869127A (en) * 1995-02-22 1999-02-09 Boston Scientific Corporation Method of providing a substrate with a bio-active/biocompatible coating
US6254634B1 (en) * 1998-06-10 2001-07-03 Surmodics, Inc. Coating compositions
US20030187496A1 (en) * 2000-07-28 2003-10-02 Kirk Matthew P Intravascular stent with expandable coating
WO2003086496A1 (en) * 2002-04-16 2003-10-23 Lothar Sellin Medical implant, preferably a stent, and method for producing the same
WO2006060836A1 (en) * 2004-12-07 2006-06-15 Rho-Best Coating Hartstoffbeschichtungs Gmbh Biological surfaces
EP1754684A1 (en) * 2004-03-30 2007-02-21 Toyo Advanced Technologies Co., Ltd. Method for treating surface of base, surface-treated base, material for medical use and instrument for medical use

Family Cites Families (370)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2732410A (en) * 1956-01-24 Process for preparing tetrafluoro
US2737249A (en) * 1954-05-14 1956-03-06 Pinkel Isadore Irving Crash-fire ignition source inerting system
US3076507A (en) * 1958-05-16 1963-02-05 William G Sweetman Chemical cutting method and apparatus for use in wells
US3174550A (en) * 1961-08-22 1965-03-23 Jet Set Ltd Method and apparatus for rendering aviation fuel from a flowable to a non-flowable state
US3372208A (en) * 1964-03-20 1968-03-05 Dow Chemical Co Flame resistant epoxy resins containing phosphorus and a halogen
US3476463A (en) 1965-05-11 1969-11-04 Perkin Elmer Corp Coherent light optical system yielding an output beam of desired intensity distribution at a desired equiphase surface
GB1237035A (en) 1969-08-20 1971-06-30 Tsi Travmatologii I Ortopedii Magnesium-base alloy for use in bone surgery
US3637022A (en) * 1969-10-30 1972-01-25 Marathon Oil Co Use of high water content oil-external micellar solutions for extinguishing fires
US3900632A (en) 1970-02-27 1975-08-19 Kimberly Clark Co Laminate of tissue and random laid continuous filament web
US3839743A (en) 1972-04-21 1974-10-08 A Schwarcz Method for maintaining the normal integrity of blood
US4104410A (en) 1973-12-21 1978-08-01 Malecki George J Processing of green vegetables for color retention in canning
DE2623907C3 (en) * 1976-05-28 1980-01-31 Emil Pester Platinen- U. Apparatefabrik, 8941 Wolfertschwenden Tensioning device
US4110497A (en) 1976-07-02 1978-08-29 Snyder Manufacturing Co., Ltd. Striped laminate and method and apparatus for making same
GB1565004A (en) * 1977-04-18 1980-04-16 Weatherford Dmc Chemical cutting appratus and method for use in wells
JPS6037735B2 (en) * 1978-10-18 1985-08-28 住友電気工業株式会社 Artificial blood vessel
DE2928007A1 (en) 1979-07-11 1981-01-15 Riess Guido Dr BONE IMPLANT BODY FOR PROSTHESES AND BONE CONNECTORS AND METHOD FOR THE PRODUCTION THEREOF
US4346028A (en) 1979-12-14 1982-08-24 Monsanto Company Asbestiform crystalline calcium sodium or lithium phosphate, preparation and compositions
DE3019996A1 (en) 1980-05-24 1981-12-03 Institute für Textil- und Faserforschung Stuttgart, 7410 Reutlingen HOHLORGAN
US4428430A (en) * 1981-01-13 1984-01-31 Gearhart Industries, Inc. Chemical method and apparatus for perforating drill collars
US4494601A (en) * 1981-09-14 1985-01-22 Gearhart Industries, Inc. Downhole chemical cutting tool
US4902289A (en) * 1982-04-19 1990-02-20 Massachusetts Institute Of Technology Multilayer bioreplaceable blood vessel prosthesis
US4517687A (en) 1982-09-15 1985-05-21 Meadox Medicals, Inc. Synthetic woven double-velour graft
US4656083A (en) 1983-08-01 1987-04-07 Washington Research Foundation Plasma gas discharge treatment for improving the biocompatibility of biomaterials
US4594407A (en) 1983-09-20 1986-06-10 Allied Corporation Prosthetic devices derived from krebs-cycle dicarboxylic acids and diols
US5197977A (en) * 1984-01-30 1993-03-30 Meadox Medicals, Inc. Drug delivery collagen-impregnated synthetic vascular graft
US4633873A (en) * 1984-04-26 1987-01-06 American Cyanamid Company Surgical repair mesh
US4596574A (en) 1984-05-14 1986-06-24 The Regents Of The University Of California Biodegradable porous ceramic delivery system for bone morphogenetic protein
US4886870A (en) 1984-05-21 1989-12-12 Massachusetts Institute Of Technology Bioerodible articles useful as implants and prostheses having predictable degradation rates
CH671337A5 (en) 1984-06-19 1989-08-31 Ceskoslovenska Akademie Ved
US4879135A (en) 1984-07-23 1989-11-07 University Of Medicine And Dentistry Of New Jersey Drug bonded prosthesis and process for producing same
IT1186142B (en) * 1984-12-05 1987-11-18 Medinvent Sa TRANSLUMINAL IMPLANTATION DEVICE
US4718907A (en) * 1985-06-20 1988-01-12 Atrium Medical Corporation Vascular prosthesis having fluorinated coating with varying F/C ratio
US4818559A (en) 1985-08-08 1989-04-04 Sumitomo Chemical Company, Limited Method for producing endosseous implants
US4733665C2 (en) 1985-11-07 2002-01-29 Expandable Grafts Partnership Expandable intraluminal graft and method and apparatus for implanting an expandable intraluminal graft
US5061281A (en) 1985-12-17 1991-10-29 Allied-Signal Inc. Bioresorbable polymers and implantation devices thereof
US4743252A (en) 1986-01-13 1988-05-10 Corvita Corporation Composite grafts
US4878906A (en) 1986-03-25 1989-11-07 Servetus Partnership Endoprosthesis for repairing a damaged vessel
EP0241838B1 (en) 1986-04-07 1992-04-15 Agency Of Industrial Science And Technology Antithrombogenic material
US4740207A (en) 1986-09-10 1988-04-26 Kreamer Jeffry W Intralumenal graft
US4723549A (en) * 1986-09-18 1988-02-09 Wholey Mark H Method and apparatus for dilating blood vessels
US4722335A (en) * 1986-10-20 1988-02-02 Vilasi Joseph A Expandable endotracheal tube
US4800882A (en) * 1987-03-13 1989-01-31 Cook Incorporated Endovascular stent and delivery system
US4816339A (en) * 1987-04-28 1989-03-28 Baxter International Inc. Multi-layered poly(tetrafluoroethylene)/elastomer materials useful for in vivo implantation
US5527337A (en) 1987-06-25 1996-06-18 Duke University Bioabsorbable stent and method of making the same
US5059211A (en) 1987-06-25 1991-10-22 Duke University Absorbable vascular stent
US5082575A (en) * 1987-09-29 1992-01-21 Shin-Etsu Handotai Company, Ltd. Method for fire-extinguishment on hardly extinguishable burning materials
US4886062A (en) 1987-10-19 1989-12-12 Medtronic, Inc. Intravascular radially expandable stent and method of implant
US4877030A (en) 1988-02-02 1989-10-31 Andreas Beck Device for the widening of blood vessels
US5192311A (en) * 1988-04-25 1993-03-09 Angeion Corporation Medical implant and method of making
US4994298A (en) * 1988-06-07 1991-02-19 Biogold Inc. Method of making a biocompatible prosthesis
US5502158A (en) 1988-08-08 1996-03-26 Ecopol, Llc Degradable polymer composition
US5328471A (en) 1990-02-26 1994-07-12 Endoluminal Therapeutics, Inc. Method and apparatus for treatment of focal disease in hollow tubular organs and other tissue lumens
US5019090A (en) 1988-09-01 1991-05-28 Corvita Corporation Radially expandable endoprosthesis and the like
CA1322628C (en) 1988-10-04 1993-10-05 Richard A. Schatz Expandable intraluminal graft
US5085629A (en) * 1988-10-06 1992-02-04 Medical Engineering Corporation Biodegradable stent
US4977901A (en) 1988-11-23 1990-12-18 Minnesota Mining And Manufacturing Company Article having non-crosslinked crystallized polymer coatings
CH678393A5 (en) 1989-01-26 1991-09-13 Ulrich Prof Dr Med Sigwart
DE69030811T2 (en) 1989-01-27 1997-10-02 Au Membrane & Biotech Res Inst RECEPTOR MEMBRANES AND SELECTIVE CONTROL OF THE ION FLOW BY IONOPHORES
US5163958A (en) 1989-02-02 1992-11-17 Cordis Corporation Carbon coated tubular endoprosthesis
US5289831A (en) * 1989-03-09 1994-03-01 Vance Products Incorporated Surface-treated stent, catheter, cannula, and the like
NZ228382A (en) 1989-03-17 1992-08-26 Carter Holt Harvey Plastic Pro Drug administering coil-like device for insertion in body cavity of animal
US5108755A (en) 1989-04-27 1992-04-28 Sri International Biodegradable composites for internal medical use
US5100429A (en) * 1989-04-28 1992-03-31 C. R. Bard, Inc. Endovascular stent and delivery system
US4990158A (en) 1989-05-10 1991-02-05 United States Surgical Corporation Synthetic semiabsorbable tubular prosthesis
ATE130519T1 (en) 1989-06-09 1995-12-15 Boehringer Ingelheim Kg ABSORBABLE MOLDED BODY AND METHOD FOR THE PRODUCTION THEREOF.
US5084065A (en) * 1989-07-10 1992-01-28 Corvita Corporation Reinforced graft assembly
US5084190A (en) * 1989-11-14 1992-01-28 E. I. Du Pont De Nemours And Company Fire extinguishing composition and process
US5093013A (en) * 1989-12-11 1992-03-03 Halocarbon Products Corporation Ozone friendly fire-extinguishing agents
US5971954A (en) 1990-01-10 1999-10-26 Rochester Medical Corporation Method of making catheter
ATE120377T1 (en) 1990-02-08 1995-04-15 Howmedica INFLATABLE DILATATOR.
US5545208A (en) 1990-02-28 1996-08-13 Medtronic, Inc. Intralumenal drug eluting prosthesis
US5156623A (en) 1990-04-16 1992-10-20 Olympus Optical Co., Ltd. Sustained release material and method of manufacturing the same
US5123917A (en) 1990-04-27 1992-06-23 Lee Peter Y Expandable intraluminal vascular graft
US5290271A (en) * 1990-05-14 1994-03-01 Jernberg Gary R Surgical implant and method for controlled release of chemotherapeutic agents
US5279594A (en) * 1990-05-23 1994-01-18 Jackson Richard R Intubation devices with local anesthetic effect for medical use
US6060451A (en) 1990-06-15 2000-05-09 The National Research Council Of Canada Thrombin inhibitors based on the amino acid sequence of hirudin
US5236447A (en) 1990-06-29 1993-08-17 Nissho Corporation Artificial tubular organ
US5342395A (en) 1990-07-06 1994-08-30 American Cyanamid Co. Absorbable surgical repair devices
US5112457A (en) 1990-07-23 1992-05-12 Case Western Reserve University Process for producing hydroxylated plasma-polymerized films and the use of the films for enhancing the compatiblity of biomedical implants
US5080177A (en) * 1990-07-26 1992-01-14 Great Lakes Chemical Corporation Fire extinguishing methods utilizing 1-bromo-1,1,2,2-tetra-fluoroethane
US5455040A (en) 1990-07-26 1995-10-03 Case Western Reserve University Anticoagulant plasma polymer-modified substrate
IL99296A (en) 1990-08-28 1995-12-08 Meadox Medicals Inc Self-supporting woven vascular graft and its preparation
DE69114505T2 (en) * 1990-08-28 1996-04-18 Meadox Medicals Inc SELF-SUPPORTING WOVEN VESSEL TRANSPLANT.
US5258020A (en) * 1990-09-14 1993-11-02 Michael Froix Method of using expandable polymeric stent with memory
US5108417A (en) 1990-09-14 1992-04-28 Interface Biomedical Laboratories Corp. Anti-turbulent, anti-thrombogenic intravascular stent
US5163952A (en) 1990-09-14 1992-11-17 Michael Froix Expandable polymeric stent with memory and delivery apparatus and method
DE69116130T2 (en) 1990-10-18 1996-05-15 Ho Young Song SELF-EXPANDING, ENDOVASCULAR DILATATOR
US5104410A (en) 1990-10-22 1992-04-14 Intermedics Orthopedics, Inc Surgical implant having multiple layers of sintered porous coating and method
US5163951A (en) 1990-12-27 1992-11-17 Corvita Corporation Mesh composite graft
JP3199124B2 (en) 1990-12-28 2001-08-13 株式会社ニデック Laser ablation equipment
CS277367B6 (en) 1990-12-29 1993-01-13 Krajicek Milan Three-layered vascular prosthesis
EP0525210A4 (en) * 1991-02-20 1993-07-28 Tdk Corporation Composite bio-implant and production method therefor
SE9100610D0 (en) 1991-03-04 1991-03-04 Procordia Ortech Ab BIORESORBABLE MATERIAL FOR MEDICAL USE
WO1992015342A1 (en) 1991-03-08 1992-09-17 Keiji Igaki Stent for vessel, structure of holding said stent, and device for mounting said stent
US5383925A (en) * 1992-09-14 1995-01-24 Meadox Medicals, Inc. Three-dimensional braided soft tissue prosthesis
SE9101752D0 (en) * 1991-06-10 1991-06-10 Procordia Ortech Ab METHOD OF PRODUCING A MICROSTRUCTURE IN A BIORESORBABLE ELEMENT
US5356433A (en) 1991-08-13 1994-10-18 Cordis Corporation Biocompatible metal surfaces
US6515009B1 (en) * 1991-09-27 2003-02-04 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5811447A (en) 1993-01-28 1998-09-22 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5500013A (en) 1991-10-04 1996-03-19 Scimed Life Systems, Inc. Biodegradable drug delivery vascular stent
US5234457A (en) 1991-10-09 1993-08-10 Boston Scientific Corporation Impregnated stent
US5282860A (en) * 1991-10-16 1994-02-01 Olympus Optical Co., Ltd. Stent tube for medical use
US5545408A (en) 1991-10-21 1996-08-13 Peptide Technology Limited Biocompatible implant for the timing of ovulation in mares
US5167614A (en) 1991-10-29 1992-12-01 Medical Engineering Corporation Prostatic stent
US5756476A (en) 1992-01-14 1998-05-26 The United States Of America As Represented By The Department Of Health And Human Services Inhibition of cell proliferation using antisense oligonucleotides
CA2087132A1 (en) * 1992-01-31 1993-08-01 Michael S. Williams Stent capable of attachment within a body lumen
US5573934A (en) * 1992-04-20 1996-11-12 Board Of Regents, The University Of Texas System Gels for encapsulation of biological materials
DE69332950T2 (en) 1992-03-31 2004-05-13 Boston Scientific Corp., Natick BLOOD VESSEL FILTER
DE4222380A1 (en) 1992-07-08 1994-01-13 Ernst Peter Prof Dr M Strecker Endoprosthesis implantable percutaneously in a patient's body
US5306294A (en) 1992-08-05 1994-04-26 Ultrasonic Sensing And Monitoring Systems, Inc. Stent construction of rolled configuration
US5514379A (en) 1992-08-07 1996-05-07 The General Hospital Corporation Hydrogel compositions and methods of use
CA2103846A1 (en) 1992-08-13 1994-02-14 Patricia-Ann Truter Hydrogel composition and methods of making it
US5853408A (en) 1992-08-20 1998-12-29 Advanced Cardiovascular Systems, Inc. In-vivo modification of the mechanical properties of surgical devices
US5342621A (en) 1992-09-15 1994-08-30 Advanced Cardiovascular Systems, Inc. Antithrombogenic surface
US5770609A (en) 1993-01-28 1998-06-23 Neorx Corporation Prevention and treatment of cardiovascular pathologies
US5830461A (en) 1992-11-25 1998-11-03 University Of Pittsburgh Of The Commonwealth System Of Higher Education Methods for promoting wound healing and treating transplant-associated vasculopathy
US5342348A (en) 1992-12-04 1994-08-30 Kaplan Aaron V Method and device for treating and enlarging body lumens
US5380976A (en) * 1992-12-11 1995-01-10 Hypertherm, Inc. Process for high quality plasma arc and laser cutting of stainless steel and aluminum
EP0604022A1 (en) 1992-12-22 1994-06-29 Advanced Cardiovascular Systems, Inc. Multilayered biodegradable stent and method for its manufacture
US5443458A (en) 1992-12-22 1995-08-22 Advanced Cardiovascular Systems, Inc. Multilayered biodegradable stent and method of manufacture
US5981568A (en) 1993-01-28 1999-11-09 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
JP3583801B2 (en) 1993-03-03 2004-11-04 ボストン サイエンティフィック リミテッド Luminal stents and implants
FI92465C (en) 1993-04-14 1994-11-25 Risto Tapani Lehtinen A method for handling endo-osteal materials
US5441515A (en) 1993-04-23 1995-08-15 Advanced Cardiovascular Systems, Inc. Ratcheting stent
US5464650A (en) 1993-04-26 1995-11-07 Medtronic, Inc. Intravascular stent and method
US5994341A (en) * 1993-07-19 1999-11-30 Angiogenesis Technologies, Inc. Anti-angiogenic Compositions and methods for the treatment of arthritis
EG20321A (en) 1993-07-21 1998-10-31 Otsuka Pharma Co Ltd Medical material and process for producing the same
DE69330132T2 (en) 1993-07-23 2001-11-15 Cook Inc FLEXIBLE STENT WITH A CONFIGURATION MOLDED FROM A MATERIAL SHEET
US5565215A (en) 1993-07-23 1996-10-15 Massachusettes Institute Of Technology Biodegradable injectable particles for imaging
DK0716610T3 (en) 1993-08-26 2006-09-04 Genetics Inst Llc Human bone morphogenetic proteins for use in neural regeneration
DK0659389T3 (en) 1993-10-20 1999-02-15 Schneider Europ Ag endoprosthesis
US5723004A (en) 1993-10-21 1998-03-03 Corvita Corporation Expandable supportive endoluminal grafts
US5389106A (en) * 1993-10-29 1995-02-14 Numed, Inc. Impermeable expandable intravascular stent
US5599301A (en) * 1993-11-22 1997-02-04 Advanced Cardiovascular Systems, Inc. Motor control system for an automatic catheter inflation system
SE501288C2 (en) 1993-11-30 1995-01-09 Corimed Gmbh Process for preparing ceramic implant material, preferably hydroxylapatite having ceramic implant material
US5626611A (en) 1994-02-10 1997-05-06 United States Surgical Corporation Composite bioabsorbable materials and surgical articles made therefrom
US5556413A (en) * 1994-03-11 1996-09-17 Advanced Cardiovascular Systems, Inc. Coiled stent with locking ends
CA2190121A1 (en) 1994-03-15 1995-09-21 Edith Mathiowitz Polymeric gene delivery system
AU704549B2 (en) 1994-03-18 1999-04-29 Lynx Therapeutics, Inc. Oligonucleotide N3'-P5' phosphoramidates: synthesis and compounds; hybridization and nuclease resistance properties
US5726297A (en) * 1994-03-18 1998-03-10 Lynx Therapeutics, Inc. Oligodeoxyribonucleotide N3' P5' phosphoramidates
US5599922A (en) * 1994-03-18 1997-02-04 Lynx Therapeutics, Inc. Oligonucleotide N3'-P5' phosphoramidates: hybridization and nuclease resistance properties
US5656186A (en) 1994-04-08 1997-08-12 The Regents Of The University Of Michigan Method for controlling configuration of laser induced breakdown and ablation
US5399666A (en) * 1994-04-21 1995-03-21 E. I. Du Pont De Nemours And Company Easily degradable star-block copolymers
US5693085A (en) 1994-04-29 1997-12-02 Scimed Life Systems, Inc. Stent with collagen
US5629077A (en) 1994-06-27 1997-05-13 Advanced Cardiovascular Systems, Inc. Biodegradable mesh and film stent
US5670558A (en) 1994-07-07 1997-09-23 Terumo Kabushiki Kaisha Medical instruments that exhibit surface lubricity when wetted
US5554120A (en) 1994-07-25 1996-09-10 Advanced Cardiovascular Systems, Inc. Polymer blends for use in making medical devices including catheters and balloons for dilatation catheters
US5817327A (en) * 1994-07-27 1998-10-06 The Trustees Of The University Of Pennsylvania Incorporation of biologically active molecules into bioactive glasses
DE4429380C1 (en) * 1994-08-15 1996-04-25 Biotronik Mess & Therapieg Method for producing a non-collapsing intravascular vascular prosthesis (stent)
US6015429A (en) 1994-09-08 2000-01-18 Gore Enterprise Holdings, Inc. Procedures for introducing stents and stent-grafts
US5593403A (en) * 1994-09-14 1997-01-14 Scimed Life Systems Inc. Method for modifying a stent in an implanted site
US5578073A (en) 1994-09-16 1996-11-26 Ramot Of Tel Aviv University Thromboresistant surface treatment for biomaterials
US5649977A (en) 1994-09-22 1997-07-22 Advanced Cardiovascular Systems, Inc. Metal reinforced polymer stent
EP0785774B1 (en) 1994-10-12 2001-01-31 Focal, Inc. Targeted delivery via biodegradable polymers
US5765682A (en) 1994-10-13 1998-06-16 Menlo Care, Inc. Restrictive package for expandable or shape memory medical devices and method of preventing premature change of same
IL115755A0 (en) 1994-10-27 1996-01-19 Medinol Ltd X-ray visible stent
US5836964A (en) 1996-10-30 1998-11-17 Medinol Ltd. Stent fabrication method
US5707385A (en) * 1994-11-16 1998-01-13 Advanced Cardiovascular Systems, Inc. Drug loaded elastic membrane and method for delivery
CA2301351C (en) 1994-11-28 2002-01-22 Advanced Cardiovascular Systems, Inc. Method and apparatus for direct laser cutting of metal stents
US5637113A (en) 1994-12-13 1997-06-10 Advanced Cardiovascular Systems, Inc. Polymer film for wrapping a stent structure
US5919570A (en) 1995-02-01 1999-07-06 Schneider Inc. Slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with a poly(N-vinylpyrrolidone) polymer hydrogel, coated polymer and metal substrate materials, and coated medical devices
US6017577A (en) 1995-02-01 2000-01-25 Schneider (Usa) Inc. Slippery, tenaciously adhering hydrophilic polyurethane hydrogel coatings, coated polymer substrate materials, and coated medical devices
US6179817B1 (en) * 1995-02-22 2001-01-30 Boston Scientific Corporation Hybrid coating for medical devices
US5876743A (en) 1995-03-21 1999-03-02 Den-Mat Corporation Biocompatible adhesion in tissue repair
US5605696A (en) * 1995-03-30 1997-02-25 Advanced Cardiovascular Systems, Inc. Drug loaded polymeric material and method of manufacture
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
US5837313A (en) 1995-04-19 1998-11-17 Schneider (Usa) Inc Drug release stent coating process
US6120536A (en) 1995-04-19 2000-09-19 Schneider (Usa) Inc. Medical devices with long term non-thrombogenic coatings
JP2795824B2 (en) * 1995-05-12 1998-09-10 オオタ株式会社 Surface treatment method for titanium-based implant and biocompatible titanium-based implant
US5603722A (en) * 1995-06-06 1997-02-18 Quanam Medical Corporation Intravascular stent
US5954744A (en) 1995-06-06 1999-09-21 Quanam Medical Corporation Intravascular stent
CA2178541C (en) * 1995-06-07 2009-11-24 Neal E. Fearnot Implantable medical device
US5609629A (en) 1995-06-07 1997-03-11 Med Institute, Inc. Coated implantable medical device
US6129761A (en) 1995-06-07 2000-10-10 Reprogenesis, Inc. Injectable hydrogel compositions
US5820917A (en) * 1995-06-07 1998-10-13 Medtronic, Inc. Blood-contacting medical device and method
US5591199A (en) 1995-06-07 1997-01-07 Porter; Christopher H. Curable fiber composite stent and delivery system
US5667767A (en) 1995-07-27 1997-09-16 Micro Therapeutics, Inc. Compositions for use in embolizing blood vessels
GB9611437D0 (en) 1995-08-03 1996-08-07 Secr Defence Biomaterial
EP0765913B1 (en) 1995-09-29 2002-08-28 Dainippon Ink And Chemicals, Inc. Process for the preparation of lactic acid-based polyester compositions
US5830879A (en) 1995-10-02 1998-11-03 St. Elizabeth's Medical Center Of Boston, Inc. Treatment of vascular injury using vascular endothelial growth factor
US5736152A (en) 1995-10-27 1998-04-07 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US5607442A (en) * 1995-11-13 1997-03-04 Isostent, Inc. Stent with improved radiopacity and appearance characteristics
US6048964A (en) 1995-12-12 2000-04-11 Stryker Corporation Compositions and therapeutic methods using morphogenic proteins and stimulatory factors
DK2111876T3 (en) 1995-12-18 2011-12-12 Angiodevice Internat Gmbh Crosslinked polymer preparations and methods for their use
ATE290832T1 (en) 1996-01-05 2005-04-15 Medtronic Inc EXPANDABLE ENDOLUMINAL PROSTHESES
US6150630A (en) 1996-01-11 2000-11-21 The Regents Of The University Of California Laser machining of explosives
EP1011889B1 (en) 1996-01-30 2002-10-30 Medtronic, Inc. Articles for and methods of making stents
JP2000509014A (en) 1996-03-11 2000-07-18 フォーカル,インコーポレイテッド Polymer delivery of radionuclides and radiopharmaceuticals
US6071266A (en) 1996-04-26 2000-06-06 Kelley; Donald W. Lubricious medical devices
US6241760B1 (en) 1996-04-26 2001-06-05 G. David Jang Intravascular stent
US6592617B2 (en) 1996-04-30 2003-07-15 Boston Scientific Scimed, Inc. Three-dimensional braided covered stent
US5733326A (en) 1996-05-28 1998-03-31 Cordis Corporation Composite material endoprosthesis
US5670161A (en) 1996-05-28 1997-09-23 Healy; Kevin E. Biodegradable stent
US5874165A (en) * 1996-06-03 1999-02-23 Gore Enterprise Holdings, Inc. Materials and method for the immobilization of bioactive species onto polymeric subtrates
US5914182A (en) 1996-06-03 1999-06-22 Gore Hybrid Technologies, Inc. Materials and methods for the immobilization of bioactive species onto polymeric substrates
US5830178A (en) 1996-10-11 1998-11-03 Micro Therapeutics, Inc. Methods for embolizing vascular sites with an emboilizing composition comprising dimethylsulfoxide
US5800516A (en) 1996-08-08 1998-09-01 Cordis Corporation Deployable and retrievable shape memory stent/tube and method
US6344271B1 (en) 1998-11-06 2002-02-05 Nanoenergy Corporation Materials and products using nanostructured non-stoichiometric substances
US5855618A (en) * 1996-09-13 1999-01-05 Meadox Medicals, Inc. Polyurethanes grafted with polyethylene oxide chains containing covalently bonded heparin
US5807404A (en) * 1996-09-19 1998-09-15 Medinol Ltd. Stent with variable features to optimize support and method of making such stent
US6387121B1 (en) 1996-10-21 2002-05-14 Inflow Dynamics Inc. Vascular and endoluminal stents with improved coatings
EP0842729A1 (en) 1996-10-21 1998-05-20 Arterial Vascular Engineering, Inc. Method and apparatus for laser processing of intravascular devices
US5868781A (en) * 1996-10-22 1999-02-09 Scimed Life Systems, Inc. Locking stent
US5833651A (en) 1996-11-08 1998-11-10 Medtronic, Inc. Therapeutic intraluminal stents
US5877263A (en) 1996-11-25 1999-03-02 Meadox Medicals, Inc. Process for preparing polymer coatings grafted with polyethylene oxide chains containing covalently bonded bio-active agents
US5741881A (en) 1996-11-25 1998-04-21 Meadox Medicals, Inc. Process for preparing covalently bound-heparin containing polyurethane-peo-heparin coating compositions
US5728751A (en) * 1996-11-25 1998-03-17 Meadox Medicals, Inc. Bonding bio-active materials to substrate surfaces
IT1289728B1 (en) 1996-12-10 1998-10-16 Sorin Biomedica Cardio Spa SYSTEM AND EQUIPMENT DEVICE THAT INCLUDES IT
US5980972A (en) 1996-12-20 1999-11-09 Schneider (Usa) Inc Method of applying drug-release coatings
US5906759A (en) 1996-12-26 1999-05-25 Medinol Ltd. Stent forming apparatus with stent deforming blades
IT1291001B1 (en) 1997-01-09 1998-12-14 Sorin Biomedica Cardio Spa ANGIOPLASTIC STENT AND ITS PRODUCTION PROCESS
US5733330A (en) 1997-01-13 1998-03-31 Advanced Cardiovascular Systems, Inc. Balloon-expandable, crush-resistant locking stent
US6159951A (en) 1997-02-13 2000-12-12 Ribozyme Pharmaceuticals Inc. 2'-O-amino-containing nucleoside analogs and polynucleotides
US6582472B2 (en) 1997-02-26 2003-06-24 Applied Medical Resources Corporation Kinetic stent
US6210715B1 (en) 1997-04-01 2001-04-03 Cap Biotechnology, Inc. Calcium phosphate microcarriers and microspheres
US5874101A (en) * 1997-04-14 1999-02-23 Usbiomaterials Corp. Bioactive-gel compositions and methods
US6240616B1 (en) 1997-04-15 2001-06-05 Advanced Cardiovascular Systems, Inc. Method of manufacturing a medicated porous metal prosthesis
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
FI103715B (en) 1997-04-21 1999-08-31 Vivoxid Oy New composite and its use
US5879697A (en) 1997-04-30 1999-03-09 Schneider Usa Inc Drug-releasing coatings for medical devices
US5741327A (en) 1997-05-06 1998-04-21 Global Therapeutics, Inc. Surgical stent featuring radiopaque markers
US6610764B1 (en) 1997-05-12 2003-08-26 Metabolix, Inc. Polyhydroxyalkanoate compositions having controlled degradation rates
US6303901B1 (en) 1997-05-20 2001-10-16 The Regents Of The University Of California Method to reduce damage to backing plate
US5891192A (en) 1997-05-22 1999-04-06 The Regents Of The University Of California Ion-implanted protein-coated intralumenal implants
US6056993A (en) 1997-05-30 2000-05-02 Schneider (Usa) Inc. Porous protheses and methods for making the same wherein the protheses are formed by spraying water soluble and water insoluble fibers onto a rotating mandrel
CA2294917C (en) 1997-06-18 2009-01-06 Boston Scientific Corporation Polycarbonate-polyurethane dispersions for thrombo-resistant coatings
US6110483A (en) 1997-06-23 2000-08-29 Sts Biopolymers, Inc. Adherent, flexible hydrogel and medicated coatings
JP3844848B2 (en) 1997-06-24 2006-11-15 三菱電機株式会社 Laser processing machine
DE19731021A1 (en) 1997-07-18 1999-01-21 Meyer Joerg In vivo degradable metallic implant
US5980928A (en) 1997-07-29 1999-11-09 Terry; Paul B. Implant for preventing conjunctivitis in cattle
US6245103B1 (en) 1997-08-01 2001-06-12 Schneider (Usa) Inc Bioabsorbable self-expanding stent
US6174330B1 (en) 1997-08-01 2001-01-16 Schneider (Usa) Inc Bioabsorbable marker having radiopaque constituents
US5980564A (en) 1997-08-01 1999-11-09 Schneider (Usa) Inc. Bioabsorbable implantable endoprosthesis with reservoir
US6340367B1 (en) 1997-08-01 2002-01-22 Boston Scientific Scimed, Inc. Radiopaque markers and methods of using the same
US6121027A (en) 1997-08-15 2000-09-19 Surmodics, Inc. Polybifunctional reagent having a polymeric backbone and photoreactive moieties and bioactive groups
US6117979A (en) 1997-08-18 2000-09-12 Medtronic, Inc. Process for making a bioprosthetic device and implants produced therefrom
US6129928A (en) 1997-09-05 2000-10-10 Icet, Inc. Biomimetic calcium phosphate implant coatings and methods for making the same
US6284333B1 (en) 1997-09-10 2001-09-04 Scimed Life Systems, Inc. Medical devices made from polymer blends containing low melting temperature liquid crystal polymers
US6010445A (en) * 1997-09-11 2000-01-04 Implant Sciences Corporation Radioactive medical device and process
WO1999016871A2 (en) 1997-09-22 1999-04-08 Max-Planck-Gesellschaft Zur Forderung Der Wissensc Nucleic acid catalysts with endonuclease activity
DE69838256T2 (en) 1997-09-24 2008-05-15 Med Institute, Inc., West Lafayette RADIAL EXPANDABLE STENT
US6042606A (en) 1997-09-29 2000-03-28 Cook Incorporated Radially expandable non-axially contracting surgical stent
US5976182A (en) 1997-10-03 1999-11-02 Advanced Cardiovascular Systems, Inc. Balloon-expandable, crush-resistant locking stent and method of loading the same
DE19745294A1 (en) 1997-10-14 1999-04-15 Biotronik Mess & Therapieg Process for the production of fine-structured medical technology implants
US7128737B1 (en) 1997-10-22 2006-10-31 Carl Zeiss Meditec Ag Object figuring device
DE29724852U1 (en) 1997-10-22 2005-01-13 Carl Zeiss Meditec Ag Pulsed laser beam system figuring all types of optical surfaces, especially the cornea
DE19746882A1 (en) 1997-10-23 1999-04-29 Angiomed Ag Expandable stent for tubular anatomical structures such as bile-ducts
US6015541A (en) * 1997-11-03 2000-01-18 Micro Therapeutics, Inc. Radioactive embolizing compositions
DE19881727D2 (en) 1997-11-24 2001-01-04 Herbert P Jennissen Process for immobilizing mediator molecules on inorganic and metallic implant materials
US6156062A (en) 1997-12-03 2000-12-05 Ave Connaught Helically wrapped interlocking stent
US6093463A (en) 1997-12-12 2000-07-25 Intella Interventional Systems, Inc. Medical devices made from improved polymer blends
US5957975A (en) 1997-12-15 1999-09-28 The Cleveland Clinic Foundation Stent having a programmed pattern of in vivo degradation
US6626939B1 (en) 1997-12-18 2003-09-30 Boston Scientific Scimed, Inc. Stent-graft with bioabsorbable structural support
US5986169A (en) 1997-12-31 1999-11-16 Biorthex Inc. Porous nickel-titanium alloy article
WO1999034750A1 (en) * 1998-01-06 1999-07-15 Bioamide, Inc. Bioabsorbable fibers and reinforced composites produced therefrom
US6224626B1 (en) 1998-02-17 2001-05-01 Md3, Inc. Ultra-thin expandable stent
RU2215542C2 (en) 1998-02-23 2003-11-10 Массачусетс Инститьют Оф Текнолоджи Biodecomposing polymers able recovery of form
DK1062278T3 (en) 1998-02-23 2006-09-25 Mnemoscience Gmbh Polymers with shape memory
US5938697A (en) 1998-03-04 1999-08-17 Scimed Life Systems, Inc. Stent having variable properties
US6110188A (en) 1998-03-09 2000-08-29 Corvascular, Inc. Anastomosis method
US6563998B1 (en) 1999-04-15 2003-05-13 John Farah Polished polymide substrate
US6113629A (en) 1998-05-01 2000-09-05 Micrus Corporation Hydrogel for the therapeutic treatment of aneurysms
US6083258A (en) 1998-05-28 2000-07-04 Yadav; Jay S. Locking stent
US6572651B1 (en) * 1998-06-03 2003-06-03 N.V. Bekaert S.A. Stents with a diamond like coating
DE19856983A1 (en) 1998-06-25 1999-12-30 Biotronik Mess & Therapieg Implantable, bioresorbable vascular wall support, in particular coronary stent
EP0966979B1 (en) 1998-06-25 2006-03-08 Biotronik AG Implantable bioresorbable support for the vascular walls, in particular coronary stent
US6153252A (en) 1998-06-30 2000-11-28 Ethicon, Inc. Process for coating stents
WO2000023123A1 (en) 1998-10-19 2000-04-27 Synthes Ag Chur Hardenable ceramic hydraulic cement
DE19855421C2 (en) 1998-11-02 2001-09-20 Alcove Surfaces Gmbh Implant
US6187024B1 (en) 1998-11-10 2001-02-13 Target Therapeutics, Inc. Bioactive coating for vaso-occlusive devices
DE69822470T2 (en) 1998-11-12 2005-01-20 Takiron Co. Ltd. Biodegradable absorbable shape memory material
US6125523A (en) 1998-11-20 2000-10-03 Advanced Cardiovascular Systems, Inc. Stent crimping tool and method of use
US6350277B1 (en) 1999-01-15 2002-02-26 Scimed Life Systems, Inc. Stents with temporary retaining bands
ATE390902T1 (en) * 1999-01-22 2008-04-15 Gore Enterprise Holdings Inc LOW PROFILE STENT AND TRANSPLANT COMBINATION
DE60017363T2 (en) 1999-02-02 2006-03-02 Wright Medical Technology Inc., Arlington CONTROLLED RELEASE OF A COMPOSITE MATERIAL
US6187045B1 (en) 1999-02-10 2001-02-13 Thomas K. Fehring Enhanced biocompatible implants and alloys
US6183505B1 (en) * 1999-03-11 2001-02-06 Medtronic Ave, Inc. Method of stent retention to a delivery catheter balloon-braided retainers
US6066156A (en) 1999-03-11 2000-05-23 Advanced Cardiovascular Systems, Inc. Temperature activated adhesive for releasably attaching stents to balloons
US6667049B2 (en) 1999-06-14 2003-12-23 Ethicon, Inc. Relic process for producing bioresorbable ceramic tissue scaffolds
US6312459B1 (en) 1999-06-30 2001-11-06 Advanced Cardiovascular Systems, Inc. Stent design for use in small vessels
US6177523B1 (en) * 1999-07-14 2001-01-23 Cardiotech International, Inc. Functionalized polyurethanes
AUPQ170799A0 (en) * 1999-07-20 1999-08-12 Cardiac Crc Nominees Pty Limited Shape memory polyurethane or polyurethane-urea polymers
US6569193B1 (en) 1999-07-22 2003-05-27 Advanced Cardiovascular Systems, Inc. Tapered self-expanding stent
DE19938704C1 (en) 1999-08-14 2001-10-31 Ivoclar Vivadent Ag Process for the production of reaction systems for implantation in the human and animal body as a bone substitute, which i.a. Contain calcium and phosphorus
US6479565B1 (en) 1999-08-16 2002-11-12 Harold R. Stanley Bioactive ceramic cement
US6379381B1 (en) 1999-09-03 2002-04-30 Advanced Cardiovascular Systems, Inc. Porous prosthesis and a method of depositing substances into the pores
JP4172883B2 (en) 1999-09-08 2008-10-29 Hoya株式会社 Drug sustained release carrier and method for producing drug sustained release carrier
WO2001026584A1 (en) 1999-10-14 2001-04-19 United Stenting, Inc. Stents with multilayered struts
US7226475B2 (en) 1999-11-09 2007-06-05 Boston Scientific Scimed, Inc. Stent with variable properties
DE19953771C1 (en) * 1999-11-09 2001-06-13 Coripharm Medizinprodukte Gmbh Absorbable bone implant material and method for producing the same
WO2001035928A1 (en) 1999-11-17 2001-05-25 Microchips, Inc. Microfabricated devices for the delivery of molecules into a carrier fluid
US7947069B2 (en) 1999-11-24 2011-05-24 University Of Washington Medical devices comprising small fiber biomaterials, and methods of use
US6554854B1 (en) 1999-12-10 2003-04-29 Scimed Life Systems, Inc. Process for laser joining dissimilar metals and endoluminal stent with radiopaque marker produced thereby
US6654183B2 (en) 1999-12-15 2003-11-25 International Business Machines Corporation System for converting optical beams to collimated flat-top beams
US6295168B1 (en) 1999-12-15 2001-09-25 International Business Machines Corporation Refractive optical system that converts a laser beam to a collimated flat-top beam
US6494908B1 (en) 1999-12-22 2002-12-17 Ethicon, Inc. Removable stent for body lumens
US6338739B1 (en) 1999-12-22 2002-01-15 Ethicon, Inc. Biodegradable stent
US6981987B2 (en) * 1999-12-22 2006-01-03 Ethicon, Inc. Removable stent for body lumens
US6375826B1 (en) 2000-02-14 2002-04-23 Advanced Cardiovascular Systems, Inc. Electro-polishing fixture and electrolyte solution for polishing stents and method
DE10010771C1 (en) 2000-03-04 2001-05-03 Celanese Chem Europe Gmbh Production of aliphatic carboxylic acid, e.g. n-butyric, 2-methylbutyric, n-heptanoic or isononanoic acid, by oxidizing corresponding aldehyde uses group 5-11 metal or compound as catalyst
KR100371559B1 (en) 2000-04-03 2003-02-06 주식회사 경원메디칼 Calcium phosphate artificial bone as osteoconductive and biodegradable bone substitute material
US6527801B1 (en) 2000-04-13 2003-03-04 Advanced Cardiovascular Systems, Inc. Biodegradable drug delivery material for stent
EP1153621A1 (en) 2000-05-12 2001-11-14 MERCK PATENT GmbH Biocements based on a mixture of TCP-PHA with improved compressive strength
US7394591B2 (en) 2000-05-23 2008-07-01 Imra America, Inc. Utilization of Yb: and Nd: mode-locked oscillators in solid-state short pulse laser systems
US6395326B1 (en) 2000-05-31 2002-05-28 Advanced Cardiovascular Systems, Inc. Apparatus and method for depositing a coating onto a surface of a prosthesis
IL137090A (en) 2000-06-29 2010-04-15 Pentech Medical Devices Ltd Polymeric stent
US6569191B1 (en) 2000-07-27 2003-05-27 Bionx Implants, Inc. Self-expanding stent with enhanced radial expansion and shape memory
US6574851B1 (en) 2000-07-31 2003-06-10 Advanced Cardiovascular Systems, Inc. Stent made by rotational molding or centrifugal casting and method for making the same
US6485512B1 (en) 2000-09-27 2002-11-26 Advanced Cardiovascular Systems, Inc. Two-stage light curable stent and delivery system
US6805898B1 (en) 2000-09-28 2004-10-19 Advanced Cardiovascular Systems, Inc. Surface features of an implantable medical device
US20020111590A1 (en) 2000-09-29 2002-08-15 Davila Luis A. Medical devices, drug coatings and methods for maintaining the drug coatings thereon
US6746773B2 (en) 2000-09-29 2004-06-08 Ethicon, Inc. Coatings for medical devices
US6492615B1 (en) 2000-10-12 2002-12-10 Scimed Life Systems, Inc. Laser polishing of medical devices
FR2816227B1 (en) 2000-11-09 2003-01-24 Air Liquide HIGH SPEED LASER CUTTING PROCESS WITH ADAPTED GAS
US6517888B1 (en) 2000-11-28 2003-02-11 Scimed Life Systems, Inc. Method for manufacturing a medical device having a coated portion by laser ablation
US6664335B2 (en) 2000-11-30 2003-12-16 Cardiac Pacemakers, Inc. Polyurethane elastomer article with “shape memory” and medical devices therefrom
JP3881508B2 (en) 2000-12-04 2007-02-14 株式会社ニデック Laser therapy device
US6565599B1 (en) 2000-12-28 2003-05-20 Advanced Cardiovascular Systems, Inc. Hybrid stent
US6563080B2 (en) 2001-02-15 2003-05-13 Scimed Life Systems, Inc. Laser cutting of stents and other medical devices
US6540777B2 (en) 2001-02-15 2003-04-01 Scimed Life Systems, Inc. Locking stent
US8262687B2 (en) * 2001-02-27 2012-09-11 Kyoto Medical Planning Co., Ltd. Stent holding member and stent feeding system
WO2002074480A1 (en) 2001-03-16 2002-09-26 Laser Machining, Inc. Laser ablation technique
US6764505B1 (en) 2001-04-12 2004-07-20 Advanced Cardiovascular Systems, Inc. Variable surface area stent
US6913762B2 (en) 2001-04-25 2005-07-05 Mayo Foundation For Medical Education And Research Stent having non-woven framework containing cells
EP1383504A1 (en) * 2001-04-26 2004-01-28 Control Delivery Systems, Inc. Sustained release drug delivery system containing codrugs
US8182527B2 (en) * 2001-05-07 2012-05-22 Cordis Corporation Heparin barrier coating for controlled drug release
US6679980B1 (en) * 2001-06-13 2004-01-20 Advanced Cardiovascular Systems, Inc. Apparatus for electropolishing a stent
US6521865B1 (en) * 2001-06-14 2003-02-18 Advanced Cardiovascular Systems, Inc. Pulsed fiber laser cutting system for medical implants
US6695920B1 (en) * 2001-06-27 2004-02-24 Advanced Cardiovascular Systems, Inc. Mandrel for supporting a stent and a method of using the mandrel to coat a stent
US6585755B2 (en) 2001-06-29 2003-07-01 Advanced Cardiovascular Polymeric stent suitable for imaging by MRI and fluoroscopy
US6926733B2 (en) 2001-08-02 2005-08-09 Boston Scientific Scimed, Inc. Method for enhancing sheet or tubing metal stent radiopacity
IN2014DN10834A (en) 2001-09-17 2015-09-04 Psivida Inc
JP2005503865A (en) 2001-09-28 2005-02-10 ボストン サイエンティフィック リミテッド Medical device comprising nanomaterial and treatment method using the same
US20040143180A1 (en) 2001-11-27 2004-07-22 Sheng-Ping Zhong Medical devices visible under magnetic resonance imaging
US20030105530A1 (en) 2001-12-04 2003-06-05 Inion Ltd. Biodegradable implant and method for manufacturing one
CN1241442C (en) 2001-12-14 2006-02-08 广达电脑股份有限公司 Built-in antenna module for mobile phone
US6752826B2 (en) 2001-12-14 2004-06-22 Thoratec Corporation Layered stent-graft and methods of making the same
US20030153971A1 (en) 2002-02-14 2003-08-14 Chandru Chandrasekaran Metal reinforced biodegradable intraluminal stents
US20030155328A1 (en) 2002-02-15 2003-08-21 Huth Mark C. Laser micromachining and methods and systems of same
US20030187495A1 (en) 2002-04-01 2003-10-02 Cully Edward H. Endoluminal devices, embolic filters, methods of manufacture and use
US7270675B2 (en) 2002-05-10 2007-09-18 Cordis Corporation Method of forming a tubular membrane on a structural frame
DE10222117B4 (en) 2002-05-17 2004-09-16 W&H Dentalwerk Bürmoos Gesellschaft m.b.H. Dental medical laser processing device for plasma-induced ablation
US20030236563A1 (en) 2002-06-20 2003-12-25 Dan Fifer Stent delivery catheter with retention bands
US6780261B2 (en) 2002-06-27 2004-08-24 Scimed Life Systems, Inc. Method of manufacturing an implantable stent having improved mechanical properties
US7141063B2 (en) 2002-08-06 2006-11-28 Icon Medical Corp. Stent with micro-latching hinge joints
US6818063B1 (en) 2002-09-24 2004-11-16 Advanced Cardiovascular Systems, Inc. Stent mandrel fixture and method for minimizing coating defects
US20040098090A1 (en) 2002-11-14 2004-05-20 Williams Michael S. Polymeric endoprosthesis and method of manufacture
US6696667B1 (en) * 2002-11-22 2004-02-24 Scimed Life Systems, Inc. Laser stent cutting
US7491234B2 (en) 2002-12-03 2009-02-17 Boston Scientific Scimed, Inc. Medical devices for delivery of therapeutic agents
US6899729B1 (en) 2002-12-18 2005-05-31 Advanced Cardiovascular Systems, Inc. Stent for treating vulnerable plaque
US6852946B2 (en) * 2002-12-20 2005-02-08 Caterpillar Inc Laser-induced plasma micromachining
US7455687B2 (en) 2002-12-30 2008-11-25 Advanced Cardiovascular Systems, Inc. Polymer link hybrid stent
US20040126405A1 (en) 2002-12-30 2004-07-01 Scimed Life Systems, Inc. Engineered scaffolds for promoting growth of cells
US20040143317A1 (en) 2003-01-17 2004-07-22 Stinson Jonathan S. Medical devices
US20040167610A1 (en) 2003-02-26 2004-08-26 Fleming James A. Locking stent
US7163555B2 (en) * 2003-04-08 2007-01-16 Medtronic Vascular, Inc. Drug-eluting stent for controlled drug delivery
US7635734B2 (en) * 2004-02-17 2009-12-22 The Children's Hospital Of Philadelphia Photochemical activation of surfaces for attaching biomaterial
US6846323B2 (en) * 2003-05-15 2005-01-25 Advanced Cardiovascular Systems, Inc. Intravascular stent
US20050211680A1 (en) 2003-05-23 2005-09-29 Mingwei Li Systems and methods for laser texturing of surfaces of a substrate
EP1633280A4 (en) * 2003-06-16 2011-03-16 Univ Nanyang Tech Polymeric stent and method of manufacture
US7166099B2 (en) * 2003-08-21 2007-01-23 Boston Scientific Scimed, Inc. Multilayer medical devices
US20050087520A1 (en) 2003-10-28 2005-04-28 Lixiao Wang Method and apparatus for selective ablation of coatings from medical devices
US8309112B2 (en) 2003-12-24 2012-11-13 Advanced Cardiovascular Systems, Inc. Coatings for implantable medical devices comprising hydrophilic substances and methods for fabricating the same
US20050157382A1 (en) 2004-01-07 2005-07-21 Kafka James D. Industrial directly diode-pumped ultrafast amplifier system
US8435287B2 (en) * 2004-03-30 2013-05-07 Toyo Advanced Technologies Co., Ltd. Stent and method for fabricating the same
US6943964B1 (en) 2004-06-01 2005-09-13 Southeastern Univ. Research Assn. Single element laser beam shaper
US8158904B2 (en) * 2004-08-13 2012-04-17 Boston Scientific Scimed, Inc. Method and apparatus for forming a feature in a workpiece by laser ablation with a laser beam having an adjustable intensity profile to redistribute the energy density impinging on the workpiece
US7508853B2 (en) 2004-12-07 2009-03-24 Imra, America, Inc. Yb: and Nd: mode-locked oscillators and fiber systems incorporated in solid-state short pulse laser systems
US7785647B2 (en) * 2005-07-25 2010-08-31 Advanced Cardiovascular Systems, Inc. Methods of providing antioxidants to a drug containing product
US20080286588A1 (en) * 2007-05-18 2008-11-20 Biomedflex, Llc Metallic component with wear and corrosion resistant coatings and methods therefor

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0556940A1 (en) * 1986-02-24 1993-08-25 Robert E. Fischell Intravascular stent
FR2654345A1 (en) * 1989-09-05 1991-05-17 Hamann Sylvie Biocompatible covering consisting of a carbon powder
US5869127A (en) * 1995-02-22 1999-02-09 Boston Scientific Corporation Method of providing a substrate with a bio-active/biocompatible coating
US6254634B1 (en) * 1998-06-10 2001-07-03 Surmodics, Inc. Coating compositions
US20030187496A1 (en) * 2000-07-28 2003-10-02 Kirk Matthew P Intravascular stent with expandable coating
WO2003086496A1 (en) * 2002-04-16 2003-10-23 Lothar Sellin Medical implant, preferably a stent, and method for producing the same
EP1754684A1 (en) * 2004-03-30 2007-02-21 Toyo Advanced Technologies Co., Ltd. Method for treating surface of base, surface-treated base, material for medical use and instrument for medical use
WO2006060836A1 (en) * 2004-12-07 2006-06-15 Rho-Best Coating Hartstoffbeschichtungs Gmbh Biological surfaces

Also Published As

Publication number Publication date
WO2008002632A3 (en) 2008-07-10
US8128688B2 (en) 2012-03-06
US20070298354A1 (en) 2007-12-27

Similar Documents

Publication Publication Date Title
US8128688B2 (en) Carbon coating on an implantable device
US9421223B2 (en) Nitric oxide generating medical devices
US20070198080A1 (en) Coatings including an antioxidant
EP2136851B1 (en) A coating of fast absorption or dissolution
US9067002B2 (en) Tailored aliphatic polyesters for stent coatings
US6994867B1 (en) Biocompatible carrier containing L-arginine
US8048441B2 (en) Nanobead releasing medical devices
US8029816B2 (en) Medical device coated with a coating containing elastin pentapeptide VGVPG
US20160263291A1 (en) Implantable device with a triblock polymer coating
US7591841B2 (en) Implantable devices for accelerated healing
US8591934B2 (en) Coatings of acrylamide-based copolymers
US20160158420A1 (en) Coatings formed from stimulus-sensitive material

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07809974

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07809974

Country of ref document: EP

Kind code of ref document: A2