EP1626752A2 - Implants medicaux revetus de maniere biocompatible - Google Patents

Implants medicaux revetus de maniere biocompatible

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Publication number
EP1626752A2
EP1626752A2 EP04731916A EP04731916A EP1626752A2 EP 1626752 A2 EP1626752 A2 EP 1626752A2 EP 04731916 A EP04731916 A EP 04731916A EP 04731916 A EP04731916 A EP 04731916A EP 1626752 A2 EP1626752 A2 EP 1626752A2
Authority
EP
European Patent Office
Prior art keywords
poly
carbon
acid
coating
substances
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04731916A
Other languages
German (de)
English (en)
Inventor
Jörg RATHENOW
Andreas Ban
Jürgen Kunstmann
Bernhard Mayer
Sohéil ASGARI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cinvention AG
Original Assignee
Blue Membranes GmbH
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
Priority claimed from DE10322182A external-priority patent/DE10322182A1/de
Priority claimed from DE2003124415 external-priority patent/DE10324415A1/de
Priority claimed from DE2003133098 external-priority patent/DE10333098A1/de
Application filed by Blue Membranes GmbH filed Critical Blue Membranes GmbH
Priority to EP08104285A priority Critical patent/EP1982772A1/fr
Publication of EP1626752A2 publication Critical patent/EP1626752A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/303—Carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/084—Carbon; Graphite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers

Definitions

  • the present invention relates to implantable medical devices with biocompatible coatings and a method for their production.
  • the present invention relates to medical implantable devices coated with a carbon-containing layer, which comprises coating the device at least partially with a polymer film and heating the polymer film in an atmosphere that is essentially free of oxygen to temperatures in the range from 200 ° C. to 2500 ° C are available, wherein a " carbon-containing layer is generated on the implantable medical device.
  • Medical implants such as surgical or orthopedic screws, plates, joint prostheses, artificial heart valves, vascular prostheses, stents, as well as subcutaneously or intramuscularly implantable drug depots are made from a wide variety of materials that are selected according to their specific biochemical and mechanical properties. These materials must be suitable for permanent use in the body, do not release toxic substances and have certain mechanical and biochemical properties.
  • the metals or metal alloys and ceramic materials frequently used for stents and joint prostheses often have disadvantages with regard to their biocompatibility, especially when used continuously.
  • implants Due to chemical and / or physical irritation, implants trigger inflammatory tissue and immune reactions, among other things, so that there are intolerance reactions in the sense of chronic inflammatory reactions with defense and rejection reactions, excessive scar formation or tissue breakdown, which in extreme cases must lead to the implant must be removed and replaced or additional therapeutic interventions of an invasive or non-invasive nature are indicated.
  • a lack of compatibility with the surrounding tissue leads, for example, to high restenosis rates in coronary stents, because on the one hand the tima of the vascular wall tends to cause inflammation-related macrophage reactions with scarring, and on the other hand both the direct surface properties and the pathologically changed vascular wall in the area of the stent lead to aggregation of platelets on the vascular implant itself, as well as on flammable vascular walls. Both mechanisms maintain a mutually influencing inflammation and intolerance process, which in 20-30% of the patients treated with interventional stents leads to a re-narrowing of the coronary artery that requires treatment.
  • US Pat. No. 5,891,507 describes methods for coating the surface of metal stents with silicone, polytetrafluoroethylene and biological materials such as heparin or growth factors which increase the biocompatibility of the metal stents.
  • carbon-based layers In addition to plastic layers, carbon-based layers have proven to be particularly advantageous.
  • DE 199 51 477 discloses coronary stents with a coating made of amorphous silicon carbide, which improves the biocompatibility of the
  • pyrolytic carbon under PVD or CVD conditions requires the careful selection of suitable gaseous or vaporizable carbon precursors, which are then often deposited on the implant at high temperatures, sometimes under plasma conditions, in an inert gas or high vacuum atmosphere.
  • Another disadvantage of the methods of the prior art is that due to different thermal expansion coefficients of materials from which the implants are made and the applied CVD layers, the layer is often only poorly adhered to the implant, which leads to flaking , Cracks and deterioration of the surface quality, which adversely affect the usability of the implants.
  • Another object of the present invention is to provide implantable medical devices provided with carbon-containing coatings, which have increased biocompatibility or biocompatibility.
  • Another object of the present invention is to provide biocompatible coated medical implants, the coating of which enables the application of medicinally active substances to or into the implant surface.
  • Yet another object of the present invention is to provide coated medical implants which can release applied pharmacologically active substances in a targeted and, if necessary, controlled manner after the implant has been inserted into the human body.
  • Another object of the invention is to provide implantable drug depots with a coating that can control the release of drugs from the depot.
  • carbon-containing layers on implantable medical devices of the most varied types can be produced in a simple and reproducible manner by first coating the device at least partially with a polymer film, which is then coated in an essentially oxygen-free atmosphere at high temperatures is carbonized or pyrolyzed. It is preferred that the resulting carbon-containing layer (s) are subsequently loaded with active substances, microorganisms or living cells.
  • biodegradable or resorbable polymers or non-biodegradable or resorbable polymers can be at least partially coated.
  • the method according to the invention for producing biocompatible coatings on implantable medical devices comprises the following steps: a) at least partially coating the medical device with a polymer film by means of a suitable coating or application method; b) heating the polymer film in an atmosphere that is essentially free of oxygen, at temperatures in the range from 200 ° C. to 2500 ° C., to produce a carbon-containing layer on the medical device.
  • partial thermal decomposition or coking becomes more carbon-containing under carbonization or pyrolysis
  • starting compounds which are usually oligomeric or polymeric materials based on hydrocarbons, which, after carbonization, depending on the selected temperature and pressure conditions and the type of polymeric material used, leave carbon-containing layers with a structure ranging from amorphous to highly ordered crystalline graphite-like structures , as well as their porosity and surface properties can be adjusted exactly.
  • the method according to the invention can be used not only for coating implantable medical devices, but in its most general aspect also generally for producing carbon-containing coatings on substrates of any kind.
  • the statements made below with regard to implants as a substrate therefore apply without exception to other substrates for other purposes.
  • biocompatible carbon-containing coatings can be applied to implantable medical devices.
  • implantable medical device and “implant” are used synonymously below and include medical or therapeutic implants such as vascular endoprostheses, intraluminal endoprostheses, stents, coronary stents, peripheral stents, surgical or orthopedic implants for temporary purposes such as surgical screws, plates , Nails and other fasteners, permanent surgical or orthopedic implants such as bone or joint prostheses, for example artificial hip or knee joints, joint socket inserts, screws, plates, nails, implantable orthopedic fixation aids, vertebral body substitutes, as well as artificial hearts and parts thereof, artificial heart valves, pacemaker housing, electrodes , subcutaneous and / or intramuscularly usable implants, drug depots and microchips, and the like.
  • medical or therapeutic implants such as vascular endoprostheses, intraluminal endoprostheses, stents, coronary stents, peripheral stents, surgical or orthopedic implants for temporary purposes such as surgical screws, plates , Nails and other fasteners, permanent surgical or orthopedic implants such as bone
  • the implants which can be coated biocompatible with the method of the present invention can consist of almost any, preferably essentially temperature-stable, materials, in particular of all materials from which implants are manufactured.
  • Examples include amorphous and / or (partially) crystalline carbon
  • Full carbon material, porous carbon, graphite, carbon composite materials, carbon fibers, ceramics such as.
  • materials can be coated that are only converted to their final shape under the carbonization conditions. Examples of this are moldings made of paper, fiber materials and polymeric materials which, after coating with the polymer film, are converted together with the latter into coated carbon implants.
  • the production of coated implants is fundamentally also possible starting from ceramic precursors of the implant, such as ceramic green bodies, which, after coating with the polymer film, can be cured or sintered together with the carbonization of the polymer film to their final application form.
  • ceramic precursors of the implant such as ceramic green bodies
  • ceramic green bodies which, after coating with the polymer film, can be cured or sintered together with the carbonization of the polymer film to their final application form.
  • commercially available or conventional ceramics boron nitride, silicon carbide, etc.
  • nanocrystalline green bodies made of zirconium oxide and alpha- or gamma-Al 2 O 3
  • pressed amorphous nanoscale ALOOH airgel which result in nanoporous carbon-coated moldings at temperatures of about 500 - 2000 °, but preferably about 800 ° C are used, coatings with porosities of about 10 - 100 nm can be obtained.
  • Preferred areas of application for this are, for example, full implants for reconstruction of joints that have improved bio
  • the method according to the invention solves the problem of delamination of coated ceramic implants, which tend to abrasion of secondarily applied coatings under biomechanical torsional tensile and elongation loads.
  • the implantable medical devices that can be coated according to the invention can have almost any external shape; the invention
  • the implants can be completely or partially coated with a polymer film, which is then carbonized to form a carbon-containing layer.
  • the medical implants to be coated comprise stents, in particular metal stents.
  • stents in particular metal stents.
  • carbon-based or carbon-containing surface coatings on stents made of stainless steel, platinum-containing radiopaque steel alloys, so-called PERSS (platinum enhanced radiopaque stainless steel alloys), cobalt alloys, titanium alloys, high-melting alloys, for example based on niobium can be made in a simple and advantageous manner. Tantalum, tungsten and molybdenum, precious metal alloys, nitinol alloys, as well as magnesium alloys and mixtures of the aforementioned.
  • Preferred implants in the context of the present invention are stents made of stainless steel, in particular Fe-18Cr-14Ni-2.5Mo ("316LVM” ASTM F138), Fe-21Cr-10Ni-3.5Mn-2.5Mo (ASTM F 1586), Fe-22Cr -13Ni-5Mn (ASTM F 1314), Fe-23Mn-21Cr-1Mo-IN (Nickel Stainless Steel); from cobalt alloys such as Co-20Cr-15W-10Ni ("L605" ASTM F90), Co-20Cr-35Ni-10Mo ("MP35N” ASTM F 562), Co-20Cr-16Ni-16Fe-7Mo ("Phynox” ASTM F 1058); Examples of preferred titanium alloys are CP Titanium (ASTM F 67, Grade 1), Ti-6A1-4V (Alpha beta ASTM F 136), Ti-6Al-7Nb (alpha / beta ASTM F1295), Ti-15Mo (beta grade ASTM F2066) ; Stents made of precious metal alloy
  • the implants are coated at least partially on one of their outer surfaces, in preferred applications on their entire outer surface with one or more polymer film layers.
  • the polymer film can be in the form of a polymer film which can be applied to the implant or can also be glued on by means of suitable processes, for example by film shrinking processes.
  • Thermoplastic polymer films can be applied to most substrates, particularly in the heated state, in a substantially adherent manner.
  • the polymer film can also comprise a coating of the implant with lacquers, polymeric or partially polymeric paints, dip coatings, spray coatings or coatings from polymer solutions or suspensions, as well as laminated polymer layers.
  • Preferred coatings can be obtained by superficial parylenization of the substrates.
  • the substrates are first treated with paracyclophane at elevated temperature, usually about 600 ° C., a polymer film made of poly (p-xylylene) being formed on the surface of the substrates. This can be convert to carbon in a subsequent carbonization or pyrolysis step.
  • the parylene and carbonization steps are repeated several times.
  • polymer films are polymer foam systems, for example phenol foams, polyolefin foams, polystyrene foams, polyurethane foams, fluoropolymer foams, which can be converted into porous carbon layers in a subsequent carbonization or pyrolysis step.
  • polymer foam systems for example phenol foams, polyolefin foams, polystyrene foams, polyurethane foams, fluoropolymer foams, which can be converted into porous carbon layers in a subsequent carbonization or pyrolysis step.
  • polymers films in the form of foils, lacquers, polymeric coatings, dip coatings, spray coatings or coatings and laminated polymer layers for example homo- or copolymers of aliphatic or aromatic polyolefins such as polyethylene, polypropylene, polybutene, polyisobutene, polypentene; polybutadiene; Polyvinyls such as polyvinyl chloride or polyvinyl alcohol, poly (meth) acrylic acid, polyacrylic cyanoacrylate; Polyacrylonitrile, polyamide, polyester, polyurethane, polystyrene, polytetrafluoroethylene; Polymers such as collagen, albumin, gelatin, hyaluronic acid, starch, celluloses such as
  • Polyethylene terephthalate polymalate acid, polytartronic acid, polyanhydrides.
  • Polyphosphazenes polyamino acids; Polyethylene vinyl acetate, silicones; Poly (ester-urethanes), poly (ether-urethanes), poly (ester-ureas), polyethers such as polyethylene oxide, polypropylene oxide, Pluronics, polytetramethylene glycol; Polyvinylpyrrolidone, poly (vinyl acetate phatalate), and their copolymers, mixtures and combinations of these homo- or copolymers can be used.
  • Suitable paint-based polymer films are particularly preferred, for example films or coatings which are produced from a one- or two-component paint and which have a binder base made from alkyd resin, chlorinated rubber, epoxy resin, formaldehyde resin, (meth) acrylate resin, phenolic resin, alkylphenol resin, amm resin, melanin resin, oil-based , Nitro base, vinyl ester resin, Novolac ® epoxy resins, polyester, polyurethane, tar, tar-like materials, tar pitch, bitumen, starch, cellulose, shellac, waxes, organic materials from renewable raw materials or combinations thereof.
  • a binder base made from alkyd resin, chlorinated rubber, epoxy resin, formaldehyde resin, (meth) acrylate resin, phenolic resin, alkylphenol resin, amm resin, melanin resin, oil-based , Nitro base, vinyl ester resin, Novolac ® epoxy resins, polyester, polyurethane, tar, tar-
  • Varnishes based on phenolic and / or melamine resins which may or may not be completely or partially epoxidized, are particularly preferred, e.g. B. commercially available enamel varnishes, and one- or two-component varnishes based on optionally epoxidized aromatic hydrocarbon resins.
  • the implant which are then carbonized together.
  • targeted gradient coatings can be applied to the implant, for example with variable porosity or adsorption profiles within the coatings.
  • the step sequence of polymer film coating and carbonization can be repeated once and possibly several times in order to obtain carbon-containing multilayer coatings on the implant.
  • the polymer films or substrates can be pre-structured or modified using additives. Suitable aftertreatment steps as described below can also be carried out after each or after individual step sequences Carbonization of the method according to the invention can be applied, such as an oxidative treatment of individual layers.
  • the polymer film can be equipped with additives which influence the carbonization behavior of the film and / or the macroscopic properties of the carbon-based substrate coating resulting from the process.
  • suitable additives are fillers, pore formers, metals, metal compounds, alloys and metal powders, extenders, lubricants, lubricants, etc.
  • inorganic additives or fillers are examples of inorganic additives or fillers.
  • catalytically active transition metals such as copper, gold and silver, titanium, zirconium, hafnium, vanadium, Niobium, tantalum, chromium, molybdenum, tungsten, manganese, rhenium, iron, cobalt, nickel, rut
  • Such additives in the polymer film can be used, for example, to modify and adjust the biological, mechanical and thermal properties of the films and of the resulting carbon coatings.
  • the thermal expansion coefficient of the carbon layer can be adjusted to that of a ceramic substrate, so that the applied carbon-based coating adheres firmly, even with large temperature differences.
  • the person skilled in the art becomes familiar with simple routine experiments select a suitable combination of polymer film and additive in order to obtain the desired adhesion and expansion properties of the carbon-containing layer for each implant material.
  • Polymer, glass or other fibers take place in a woven or non-woven form, which leads to a significant increase in the elasticity of the coating.
  • the biocompatibility of the layers obtained can also be changed and additionally increased by a suitable choice of additives in the polymer film.
  • epoxy resins phenolic resin, tar, tar pitch, bitumen, rubber, polychloro
  • coated substrates by incorporating the abovementioned additives into the polymer film, there is the possibility of improving the adhesion of the applied layer to the substrate, for example by applying silanes, polyaniline or porous titanium layers, and, if appropriate, the thermal expansion coefficient of the outer Adapt layer to that of the substrate, so that these coated substrates are more resistant to breaks in and flaking of the coating.
  • These coatings are therefore more durable and long-term stable in concrete use than conventional products of this type.
  • metals and metal salts in particular also noble metals and transition metals, makes it possible to adapt the chemical, biological and adsorptive properties of the resulting carbon-based coatings to the desired requirements, so that the resulting coating can also be equipped with heterogeneous catalytic properties for special applications, for example can.
  • metals and metal salts in particular also noble metals and transition metals
  • the resulting coating can also be equipped with heterogeneous catalytic properties for special applications, for example can.
  • silicon, titanium, zirconium or tantalum salts during the carbonization, the corresponding metal carbide phases can be formed which, among other things, increase the oxidation resistance of the layer.
  • the polymer films used in the process according to the invention have the advantage that they can easily be produced in almost any dimension or are commercially available. Polymer films and varnishes are readily available, inexpensive and easy to apply to implants of all kinds and shapes.
  • the polymer films used according to the invention can be structured in a suitable manner before pyrolysis or carbonization by folding, embossing, punching, printing, extruding, gathering, injection molding and the like, before or after they are applied to the implant. In this way, certain structures of regular or irregular type can be built into the carbon coating produced by the method according to the invention. APPLICATION OF THE POLYMER FILM
  • the polymer films which can be used according to the invention from coatings in the form of lacquers or coatings can be obtained from the liquid, pasty or pasty state, for example by painting, brushing, painting, knife coating, spin coating, dispersion or thin-film coating, extruding, casting, dipping, spraying, printing or also as hot melts, from the solid state by means of powder coating, spraying on sprayable particles, flame spraying, sintering or the like according to methods known per se onto the implant. If necessary, the polymeric material can be dissolved or suspended in suitable solvents for this purpose.
  • the lamination of suitably shaped substrates with suitable polymer materials or foils is also a method according to the invention for coating the implant with a polymer film.
  • the polymer film is applied as a liquid polymer or polymer solution in a suitable solvent or solvent mixture, optionally with subsequent drying.
  • suitable solvents include, for example, methanol, ethanol, N-propanol, isopropanol, butoxydiglycol, butoxyethanol, butoxyisopropanol, butoxypropanol, n-butyl alcohol, t-butyl alcohol, butylene glycol, butyl octanol, diethylene glycol, dimethoxydiglycol, dimethyl ether, dipropylene glycol, ethoxydethanol glycol.
  • Preferred solvents include one or more organic solvents from the group consisting of ethanol, isopropanol, propanol, dipropylene glycol methyl ether and butoxyisopropanol (1,2-propylene glycol n-butyl ether), tetrahydrofuran, phenol, benzene, toluene, xylene, preferably ethanol, isopropanol, n Propanol and / or dipropylene glycol methyl ether, in particular isopropanol and / or propanol.
  • organic solvents from the group consisting of ethanol, isopropanol, propanol, dipropylene glycol methyl ether and butoxyisopropanol (1,2-propylene glycol n-butyl ether), tetrahydrofuran, phenol, benzene, toluene, xylene, preferably ethanol, isopropanol, n Propanol
  • the implantable medical devices can also be coated several times with a plurality of polymer films made of the same polymers of the same or different film thickness or different polymers of the same or different film thickness.
  • a plurality of polymer films made of the same polymers of the same or different film thickness or different polymers of the same or different film thickness.
  • deeper porous layers can be combined with overlying narrow-pored layers, which can suitably delay the release of active substances deposited in the more porous layer.
  • the polymer film applied to the implant is optionally dried and then subjected to pyrolytic decomposition under carbonization conditions.
  • the polymer film (s) coated on the implant is heated, i.e. Carbonized in an essentially oxygen-free atmosphere at elevated temperature.
  • the temperature of the carbonization step is preferably in the range from 200 ° C. to 2500 ° C. and is chosen by the person skilled in the art depending on the specific temperature-dependent properties of the polymer films and implants used.
  • Preferred generally usable temperatures for the carbonization step of the process according to the invention are from 200 ° C. to about 1200 ° C. With some
  • Embodiments are preferred temperatures in the range of 250 ° C to 700 ° C.
  • the temperature is selected depending on the properties of the materials used so that the polymer film is essentially completely converted to a carbon-containing solid at the lowest possible temperature.
  • the porosity, strength and stiffness of the material and other properties can be set in a targeted manner by suitable selection or control of the pyrolysis temperature.
  • the type and structure of the deposited carbon-containing layer can be set or varied in a targeted manner with the method according to the invention. For example, when using pure hydrocarbon-based polymer films in an oxygen-free atmosphere at temperatures up to approx. 1000 ° C Deposition of essentially amorphous carbon, whereas highly crystalline graphite structures are obtained at temperatures above 2000 ° C. In the range between these two temperatures, partially crystalline carbon-containing layers of different densities and porosities can be obtained.
  • foamed polymer films for example foamed polyurethanes, which, when carbonized, allow relatively porous carbon layers with pore sizes in the lower millimeter range to be obtained.
  • the thickness of the deposited polymer film and the selected temperature and pressure conditions during pyrolysis can vary the layer thickness of the deposited carbon-containing layer within wide limits, from carbon monolayers to almost invisible layers in the nanometer range up to lacquer layer thicknesses of 10 to 40 micrometers dry layer, right up to to thicker depot layer thicknesses in the millimeter to centimeter range.
  • the latter is particularly preferred in the case of implants made of full carbon materials, in particular in the case of bone implants.
  • molecular sieve-like depot layers with specifically controllable pore sizes and sieving properties can be obtained, which enable the covalent, adsorbent or absorbent or electrostatic connection of active substances or surface modifications.
  • Porosity is preferably generated in the layers according to the invention on implants by treatment methods as described in DE 103 35 131 and PCT / EP04 / 00077, the disclosures of which are hereby fully incorporated.
  • the atmosphere in the carbonization step of the method according to the invention is essentially free of oxygen, preferably with O 2 contents below 10 ppm, particularly preferably below 1 ppm.
  • Nitrogen and / or argon are preferred.
  • the carbonization is usually carried out at normal pressure in the presence of inert gases such as those mentioned above. If necessary, however, higher inert gas pressures can also be used advantageously. In some embodiments of the method according to the invention, the carbonization can also take place under reduced pressure or in a vacuum.
  • the carbonization step will preferably take place in a batch process in suitable furnaces, but can also be carried out in continuous furnace processes, which may also be preferred.
  • the possibly structured, pretreated polymer film-coated implants are fed to the furnace on one side and emerge again at the other end of the furnace.
  • the polymer film-coated implant can rest in the oven on a perforated plate, a sieve or the like, so that negative pressure can be applied through the polymer film during pyrolysis or carbonization. This not only enables simple fixation of the implants in the furnace, but also suction and optimal flow through the films or assemblies with inert gas during the pyrolysis and / or carbonization.
  • the furnace can be divided into individual segments by means of appropriate inert gas locks, in which one or more pyrolysis or carbonization steps are carried out in succession, if necessary with different pyrolysis or carbonization steps. Conditions such as different temperature levels, different inert gases or vacuum can be carried out.
  • after-treatment steps such as after-activation by reduction or oxidation or impregnation with metal salt solutions etc. can also be carried out in corresponding segments of the furnace.
  • the carbonization can also be carried out in a closed furnace, which is particularly preferred when the pyrolysis and / or carbonization is to be carried out in vacuo.
  • a decrease in weight of the polymer film of approximately 5% to 95%, preferably approximately 40% to 90%, in particular 50% to 70%, usually occurs, depending on the starting material used and pretreatment.
  • the carbon-based coating produced according to the invention on the implants or substrates generally has, depending on the starting material, amount and type of filler materials, a carbon content of at least 1% by weight, preferably at least 25%, optionally also at least 60% and particularly preferably at least 75%. Coatings which are particularly preferred according to the invention have a carbon content of at least 50% by weight.
  • the physical and chemical properties of the carbon-based coating after pyrolysis or carbonization are further modified by suitable aftertreatment steps and adapted to the intended use in each case.
  • suitable aftertreatments are, for example, reducing or oxidative aftertreatment steps in which the coating is treated with suitable reducing agents and / or oxidizing agents such as hydrogen, carbon dioxide, nitrogen oxides such as N 2 O, water vapor, oxygen, air, nitric acid and the like and, if appropriate, mixtures thereof.
  • the post-treatment steps can optionally be carried out at elevated temperature, but below the pyrolysis temperature, for example from 40 ° C. to 1000 ° C., preferably 70 ° C. to 900 ° C., particularly preferably 100 ° C. to 850 ° C., particularly preferably 200 ° C. to 800 ° C. ° C and in particular be carried out at about 700 ° C.
  • the coating produced according to the invention is modified reductively or oxidatively, or with a combination of these post-treatment steps at room temperature.
  • the surface properties of the coatings produced according to the invention can be specifically influenced or changed by oxidative or reductive treatment, or else the incorporation of additives, fillers or functional materials.
  • oxidative or reductive treatment or else the incorporation of additives, fillers or functional materials.
  • inorganic nanoparticles or nanocomposites such as layered silicates
  • Surface properties of the coating can be hydrophilized or hydrophobized.
  • the coatings produced according to the invention can also be retrofitted with biocompatible surfaces by incorporation of suitable additives and used as a drug carrier or depot.
  • suitable additives for example, drugs or enzymes can be introduced into the material, the former possibly being released in a controlled manner by means of suitable retardation and / or selective permeation properties of the coatings.
  • the coating on the implant can also be suitably modified using the method according to the invention, for example by varying the pore sizes by means of suitable oxidative or reductive post-treatment steps, such as oxidation in air at elevated temperature, boiling in oxidizing acids, alkalis, or mixing in volatile constituents which occur during the Carbonization is completely broken down and pores are left in the carbon-containing layer.
  • the carbonized coating can optionally also be subjected to a further optional process step, a so-called CVD process (chemical vapor deposition, chemical vapor deposition) or CVI process (chemical vapor infiltration) in order to further modify the surface or pore structure and its properties.
  • CVD process chemical vapor deposition, chemical vapor deposition
  • CVI process chemical vapor infiltration
  • the carbonized coating is treated with suitable, carbon-releasing precursor gases at high temperatures.
  • Other elements can also be deposited with it, for example silicon. Such methods have long been known in the prior art.
  • saturated and unsaturated hydrocarbons with sufficient volatility under CVD conditions are suitable as carbon-releasing precursors.
  • Examples include methane, ethane, ethylene, acetylene, linear and branched alkanes, alkenes and alkynes with carbon numbers of Ci - C 20 , aromatic hydrocarbons such as benzene, naphthalene etc., as well as mono- and poly-alkyl, alkenyl and alkynyl-substituted aromatics such as for example toluene, xylene, cresol, styrene, parylene etc.
  • BC1 3 , NH 3 , silanes such as SiH, tetraethoxysilane can be used as ceramic precursors
  • TEOS dichlorodimethylsilane
  • DDS dichlorodimethylsilane
  • MDS methyltrichlorosilane
  • TDADB trichlorosilyldichloroborane
  • HDMSO hexadichloromethylsilyloxide
  • A1C1 3 TiCl 3 or mixtures thereof.
  • the compounds mentioned split off hydrocarbon fragments or carbon or ceramic precursors, which are essentially uniformly distributed in the pore system of the pyrolyzed coating, modify the pore structure there and thus lead to an essentially homogeneous pore size and pore distribution.
  • pores in the carbon-containing layer on the implant can be specifically reduced, right up to the complete closure / sealing of the pores. This allows the sorptive properties as well as the mechanical properties of the implant surface to be tailored.
  • CND of silanes or siloxanes makes it possible, for example, to modify the carbon-containing implant coatings by formation of carbide or oxycarbide in an oxidation-resistant manner.
  • the implants coated according to the invention can additionally be coated or modified using sputtering methods.
  • carbon, silicon or metals or metal compounds from suitable sputtering targets can be applied by methods known per se. Examples of these are Ti, Zr, Ta, W, Mo, Cr, Cu, which are included in the carbonaceous
  • Layers can be dusted, the corresponding carbides generally forming.
  • the surface properties of the coated implant can be modified by means of ion implantation. So by implanting Nitrogen nitride, carbonitride or oxynitride phases with embedded transition metals are formed, which significantly increases the chemical resistance and mechanical resistance of the carbon-containing implant coatings.
  • the ion implantation of carbon can be used to increase the mechanical strength of the coatings as well as to densify porous layers.
  • implant coatings produced according to the invention for example in order to coat surface-coated implants such as e.g. To make stents or orthopedic implants usable for the absorption of lipophilic active substances.
  • biodegradable or resorbable polymers such as collagen, albumin, gelatin,
  • Hyaluronic acid, starch celluloses such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose phthalate; Casein, Dextrans, Polysaccharides, Fibrinogen, Poly (D, L-Lactide), Poly (D, L-Lactide-Co-Glycolide), Poly (Glycolide), Poly (Hydroxybutylate), Poly (Alkylcarbonate), Poly (Orthoester), Polyester, poly (hydroxyvaleric acid), polydioxanones, poly (ethylene terephthalates), poly (malate acid), poly (tartronic acid), polyanhydrides.
  • celluloses such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose phthalate
  • Casein Dextrans, Polysaccharides, Fibrinogen, Poly (D, L-Lactide), Poly (D, L-Lactide-Co-Glycolide
  • polyphosphazenes poly (amino acids), and their copolymers or non-biodegradable or resorbable polymers at least partially.
  • Anionic, cationic or amphoteric coatings such as e.g. Alginate, carrageenan, carboxymethyl cellulose; Chitosan, poly-L-lysine; and / or phosphorylcholine.
  • the coated implant can undergo further chemical or physical after carbonization and / or after treatment steps that may have taken place Surface modifications are subjected. Cleaning steps to remove any residues and contaminants can also be provided here. Acids, in particular oxidizing acids, or solvents can be used for this, boiling out in acids or solvents is preferred.
  • the implants coated according to the invention can be sterilized using customary methods, for example by autoclaving, ethylene oxide sterilization or gamma radiation.
  • Pyrolytic carbon itself which is produced according to the invention from polymer films, is generally a highly biocompatible material which can be used in medical applications such as, for example, the outer coating of implants.
  • the biocompatibility of the implants coated according to the invention can also be influenced or changed in a targeted manner by incorporating additives, fillers, proteins or functional materials and / or medicaments into the polymer films before or after carbonization, as mentioned above. As a result, rejection phenomena in the body can be reduced or completely eliminated in the case of implants produced according to the invention.
  • carbon-coated medical implants produced according to the invention can be used for the controlled release of active substances from the substrate into the external environment by specifically adjusting the porosity of the applied carbon layer.
  • Preferred coatings are porous, in particular nanoporous.
  • medical implants, in particular also stents can be used as drug carriers with a depot effect, wherein the carbon-based coating of the implant can be used as a release-regulating membrane.
  • Drugs can also be applied to the biocompatible coatings. This is particularly useful where active substances cannot be applied directly in or on the implant, such as with metals.
  • the coatings produced according to the invention can be loaded with medicinal substances or drugs in a further process step, or can also be provided with markers, contrast agents for localizing coated implants in the body, for example also with therapeutic or diagnostic amounts of radioactive emitters.
  • the carbon-based coatings according to the invention are particularly suitable for the latter since, in contrast to polymer layers, they are not deteriorated or attacked by radioactive radiation.
  • the implants coated according to the invention prove to be particularly long-term stable, since the carbon-based coatings can be adjusted to be sufficiently elastic and flexible in addition to their high strength, so that they can follow the movements of the implant, in particular in the case of highly stressed joints, without the danger there is cracking or peeling of the layer.
  • the porosity of coatings applied to implants according to the invention can in particular also be adapted by means of aftertreatment with oxidizing agents, for example activation at elevated temperature in oxygen or oxygen-containing atmospheres or application of strongly oxidizing acids such as concentrated nitric acid and the like, such that the carbon-containing surface on the implant becomes ingrown Body tissue enables and promotes.
  • oxidizing agents for example activation at elevated temperature in oxygen or oxygen-containing atmospheres or application of strongly oxidizing acids such as concentrated nitric acid and the like, such that the carbon-containing surface on the implant becomes ingrown Body tissue enables and promotes.
  • Suitable layers for this purpose are macroporous, with a pore size of 0.1 ⁇ m to 100 ⁇ m, preferably l ⁇ m to 400 ⁇ m.
  • the appropriate porosity can also be achieved by appropriate pre-structuring of the implant or the polymer film to be influenced. Suitable measures for this are e.g. B. embossing, punching, perforating, foaming of
  • the implants coated according to the invention in a biocompatible manner can be loaded with active substances, including microorganisms or living cells.
  • active substances including microorganisms or living cells.
  • the loading with active ingredients can be in or on the carbon-containing coating by means of suitable sorptive methods such as
  • Adsorption, absorption, physisorption, chemisorption take place, in the simplest case by impregnation of the carbon-containing coating with active substance solutions, active substance dispersions or active substance suspensions in suitable solvents.
  • Covalent or non-covalent attachment of active substances in or on the carbon-containing coating can also be a preferred option here, depending on the active substance used and its chemical properties.
  • active ingredients can be occluded in pores.
  • the drug loading can be temporary, i.e. H. the active ingredient can after
  • Implantation of the medical device are released, or the
  • Active ingredient is permanently immobilized in or on the carbon-containing layer.
  • active substances are essentially immobilized permanently on or in the coating.
  • Active substances are inorganic substances, for example hydroxyapatite (HAP), fluoroapatite, tricalcium phosphate (TCP), zinc; and / or organic substances such as peptides, proteins, carbohydrates such as mono-, oligo- and polysaccharides, lipids, phospholipids, steroids, lipoproteins, glycoproteins, glycolipids, proteoglycans, DNA, RNA, signal peptides or antibodies or antibody fragments, bioresorbable polymers, eg polylactonic acid, chitosan, and pharmacologically active substances or mixtures of substances, combinations of these and the like.
  • HAP hydroxyapatite
  • TCP tricalcium phosphate
  • zinc zinc
  • organic substances such as peptides, proteins, carbohydrates such as mono-, oligo- and polysaccharides, lipids, phospholipids, steroids, lipoproteins, glycoproteins,
  • the release of the applied active substances after implantation of the medical device in the body is provided.
  • the coated implants can be used for therapeutic purposes, the active substances applied to the implant being successively released locally at the place of use of the implant.
  • Active substances which can be used in dynamic active substance loads for the release of active substances are, for example, hydroxylapatite (HAP), fluoroapatite, tricalcium phosphate (TCP), zinc; and / or organic substances such as peptides, proteins, carbohydrates such as mono-, oligo- and polysaccharides, lipids, phospholipids, steroids, lipoproteins, glycoproteins, glycolipids, proteoglycans, DNA, RNA, signal peptides or antibodies or antibody fragments, bioresorbable polymers, e.g. Polylactonic acid, chitosan, and the like, and pharmacologically active substances or mixtures of substances.
  • HAP hydroxylapatite
  • TCP tricalcium phosphate
  • zinc zinc
  • organic substances such as peptides, proteins, carbohydrates such as mono-, oligo- and polysaccharides, lipids, phospholipids, steroids, lipoproteins, glycoproteins, glycolipids, proteo
  • Suitable pharmacologically active substances or substance mixtures for the static and / or dynamic loading of implantable medical devices coated according to the invention include active substances or
  • Active substance combinations which are selected from heparin, synthetic heparin analogs (eg Fondaparinux), hirudin, antithrombin III, drotrecogin alpha; Fibrinolytics such as old plase, plasmin, lysokinases, factor Xlla, prourokinase, urokinase, anistreplase, streptokinase; Antiplatelet agents such as acetylsalicylic acid, ticlopidine, clopidogrel, abciximab, dextrans; corticosteroids such as Alclometasone, Amcinonide, Augmented Betamethasone, Beclomethasone, Betamethasone, Budesonide, Cortisone, Clobetasol, Clocortolone, Desonide, Desoximetasone, Dexamethasone, Flucinolone, Fluocinonide, Flurandrenolid, Halide, Halide, Halide
  • Triamcinolone So-called Non-Steroidal A ⁇ ti-hiflammatory Dmgs such as Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, lbuprofen, Indomethacin, Ketoprofen, Ketorolac, Meclofenamate, Mefenamic Acid, Meloxicam, Nabumetoxamate, Napoloxamoxinoxamate, Napoloxinoxamate, Napoloxamate, Napoloxinoxamate, Napoloxamate, Napoloxinoxamate rofecoxib; Cytostatics like alkaloids and podophyllum toxins like vinblastine,
  • Alkylating agents such as nitrosoureas, nitrogen mustard analogs; cytotoxic antibiotics such as daunorubicin, doxombicin and other anthracyclines and related substances, bleomycin, mitomycin; Antimetabolites such as folic acid, purine or pyrimidine analogs; Paclitaxel, docetaxel, sirolimus; Platinum compounds such as carboplatin, cisplatin or oxaliplatin; Amsacrine, irinotecan, hnatinib, topotecan, hiterferon-alpha 2a, interferon-alpha 2b, hydroxycarbamide, miltefosine, pentostatin, porfimer, aldesleukin, bexarotene, tretinoin; Antiandrogens, and anti-estrogens; Antiarrhythmics, in particular class I antiarrhythmics such as quinidine-type antiarrhythmics, for example quin
  • Anticalins® Stem cells, endothelial progenitor cells (EPC); Digitalis glycosides like Acetyl digoxin / metildigoxin, digitoxin, digoxin; Cardiac glycosides such as ouabain, Proscillaridin; Antihypertensives such as centrally acting anti-adrenergic substances, for example methyldopa, hnidazoline receptor agonists; Calcium channel blockers of the dihydropyridine type such as nifedipine, nitrendipine; ACE inhibitors: quinaprilat, cilazapril, moexipril, trandolapril, spirapril, imidapril, trandolapril; Angiotensin II antagonists: candesartan cilexetil, valsartan, telmisartan, olmesartan medoxomil, eprosartan; peripherally active alpha
  • BMPs bone mo ⁇ hogenetic proteins
  • rhBMP-2 Re
  • EGF epidermal growth factor
  • PDGF platelet-derived growth factor
  • FGFs fibroblast growth factors
  • TGF-a transforming growth factor-a
  • Epo insulin-like Growth Factor-I
  • IGF-I insulin-like Growth Factor-I
  • IGF-II insulin-like Growth Factor-I
  • IGF-II insulin-like Growth Factor-I
  • IGF-II insulin-like Growth Factor-I
  • IGF-II insulin-like Growth Factor-I
  • IGF-II insulin-like Growth Factor-I
  • IGF-II Insulin-Like Growth Factor-II
  • IGF-II Interleukin-1
  • IL-2 Interleukin-2
  • IL-6 Interleukin-6
  • IL-8 Interleukin-8
  • Tumor Necrosis Factor-a Tumor Necrosis Factor-a
  • TNF-b Tumor Necro
  • vascular endoprostheses intraluminal endoprostheses
  • stents coronary stents
  • intravascular stents peripheral stents and the like.
  • the activation of the carbon-containing coating for example with air at elevated temperature, can increase the hydrophilicity of the coating, which further increases the biocompatibility.
  • stents provided with a carbon-containing layer are loaded with pharmacologically active substances or mixtures of substances by the method according to the invention.
  • the stent surfaces can be local Suppression of cell adhesion, platelet aggregation, complement activation or inflammatory tissue reactions or cell proliferation can be equipped with the following active ingredients:
  • Heparin, synthetic heparin analogs for example, fondaparinux
  • Hiradin antithrombin III
  • drotrecogin alpha fibrinolytics (alteplase, plasmin, Lysokinasen, factor XIIa, prourokinase, urokinase, anistreplase, streptokinase), platelet aggregation inhibitors (acetylsalicylic acid, ticlopidine, clopidogrel, abciximab , Dextrans), corticosteroids (Alclometasone, Amcinonide, Augmented Betamethasone, Beclomethasone, Betamethasone, Budesonide, Cortisone, Clobetasol, Clocortolone, Desonide, Deoximetasone, Dexamethasone, Flucinolone, Flocinrenideide, Halocononide, Haloconidone, Haloconidone,
  • cytostatic agents alkaloids and Podophyllumtoxine such as vinblastine, vincristine, alkylating agents such as nitrosoureas, nitrogen mustard analogs; cytotoxic antibiotics such as daunorabicin, doxorubicin and other anthracyclines and related substances, bleomycm, mitomycin; antimetabohte such as folic acid, purine or pyrimidine analogs; paclitaxel, docetaxel, sirolimus; platinum compounds such as carboplatin, cisplatin or oxaliplatin; amsacrotine, iminotonone, irinotinone, irinotferon, ir
  • the stents coated according to the invention can be loaded with: Antiarrhythmics, in particular class I antiarrhythmics (quinidine-type antiarrhythmics: quinidine, dysopyramide, ajmaline, prajmalium bitartrate, detajmium bitartrate; lidocaine-type antiarrhythmics: lidocaine, mexiletine, phenytoin, tocainide; anti-arrhythmic agents, class IC): antiarrhafenonate class IC: anti-arrhythmic agents II (beta-blockers) (metoprolol, esmolol, propranolol, metoprolol, atenolol, oxprenolol), class III antiarrhythmic drugs (amiodarone, sotalol), class IN antiarrhythmic drugs (diltiazem, verapamil, gallopamil), other antiarrhythmic drugs such as adenropa
  • cardiacs are: digitalis glycosides (acetyldigoxin / metildigoxin, digitoxin, digoxin), other cardiac glycosides (ouabain, oscillaridin).
  • antihypertensives centrally active antiadrenergic substances methyldopa, 1-midazolinrezeptoragonisten
  • Kalciumkanalblocker the dihydropyridine type such as nifedipine, nitrendipine
  • ACE-inhibitors quinaprilat, cilazapril, moexipril, trandolapril, spirapril, imidapril, trandolapril
  • angiotensin II antagonists candesartan cilexetil, valsartan , Telmisartan, olmesartan medoxomil, eprosartan
  • peripherally active alpha-receptor blockers prazosin, urapidil, doxazosin,
  • Components of the extracellular matrix, fibronectin, polylysines, ethylene vinyl acetates, inflammatory cytokines such as: TGFß, PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-a, IL-1, can be used to increase the tissue adhesion, particularly in the case of peripheral stents.
  • IL-8, IL-6, growth hormone; as well as adhesive substances such as: cyanoacrylates, beryllium, or silica are used:
  • erythropoietin growth factors
  • Hormones can also be provided in the stent coatings, such as, for example, corticotropins, gonadotropins, somatropin, thyrotrophin, desmopressin, terlipressin, oxytocin, cetrorelix, corticorelin, leuprorelin, triptorelin, gonadorelin, ganirelix, buserelin, nafarelin, and satin, as well as patinelin, gatinelin, goserelin / or octreotide.
  • corticotropins such as, for example, corticotropins, gonadotropins, somatropin, thyrotrophin, desmopressin, terlipressin, oxytocin, cetrorelix, corticorelin, leuprorelin, triptorelin, gonadorelin, ganirelix, buserelin, nafarelin, and satin, as
  • Suitable pore sizes are in the range from 0.1 to 1000 ⁇ m, preferably from 1 to 400 ⁇ m, in order to support better integration of the implants by ingrowth into the surrounding cell or bone tissue.
  • the same active substances can be used for the local suppression of cell adhesion, platelet aggregation, complement activation or inflammatory tissue reaction or cell proliferation as in the stent applications described above.
  • the following active ingredients can also be used to stimulate tissue growth, particularly in orthopedic implants for better implant integration: Bone and Cartilage Stimulating Peptides, bone morphogenetic proteins (BMPs), in particular recombinant BMPs (e.g.
  • Recombinant human BMP-2 (rhBMP-2)) Bisphosphonates (eg risedronate, pamidronate, ibandronate, zoledronic acid, clodronic acid, etidronic acid, alendronic acid, tiludronic acid), fluorides (disodium fluorophosphate, sodium fluoride); Calcitonin, dihydrotachystyrene.
  • all growth factors and cytokines such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factors (FGFs), transforming growth factors-b TGFs-b,
  • TGF-a Transforming Growth Factor-a
  • Epo Erythropoietin
  • IGF-I Insulin-Like Growth Factor-I
  • IGF-II Insulin-Like Growth Factor-II
  • IL-1 IL-1
  • IL-2 Interleukin-2
  • IL-6 h ⁇ terleukin-6
  • IL-8 Interleukin-8
  • TGF-a Tumor Necrosis Factor-a
  • TNF-b Tumor Necrosis Factor-b
  • INF-g Colony Stimulating Factors
  • substances are the monocyte chemotactic protein, fibroblast stimulating factor 1, histamine, fibrin or fibrinogen, endothelin-1, angiotensin II, collagens, bromocriptine, methylsergide, methotrexate, carbon tetrachloride, thioacetamide, ethanol.
  • implants coated according to the invention in particular stents and the like, can also be provided instead of pharmaceuticals or additionally with antibacterial-anti-infectious coatings, the following substances or mixtures of substances being usable: silver (ions), titanium dioxide, antibiotics and anti-infectives.
  • beta-lactam antibiotics / 3-lactam antibiotics: / 3-lactamase-sensitive penicillins such as benzylpenicillins (penicillin G), Phenoxymethylpenicillin (Penicillin V); 3-lactamase-resistant penicillins such as aminopenicillins such as amoxicillin, ampicillin, bacampicillin; Acylaminopenicillins such as mezlocillin, piperacillin; Carboxotypicillins, Cephalosporins (Cefazolin, Cefuroxim, Cefoxitin, Cefotiam, Cefaclor, Cefadroxil, Cefalexin, Loracarbef, Cefixim, Cefuroximaxetil, Ceftibuten, Cefpodoximproxetil, Cefpodoximproxtememon, Merefrom or Erptemrepenem).
  • penicillin G benzylpenicillins
  • Phenoxymethylpenicillin Penicillin V
  • 3-lactamase-resistant penicillins such
  • antibiotics are ß-lactamase Inliibitoren (sulbactam, Sultamicillintosilat), tetracyclines (doxycycline, minocycline, tetracycline, chlortetracycline, oxytetracycline), aminoglycosides (gentamicin, neomycin, streptomycin, tobramycin, amikacin, netilmicin, paromomycin, framycetin, spectinomycin), macrolide antibiotics ( Azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, josamycin), lincosamides (clindamycin, lincomycin), gyrase inhibitors (fluoroquinolones such as ciprofloxacin, ofloxacin, moxifloxacin, norfloxacin, gatoxacacin, quinolone, floxoxinoxinid, quinoxacin, quinox
  • nirustatics are aciclovir, ganciclovir, famciclovir, foscamet, inosine (dimepranol-4-acetamidobenzoate), nalganciclovir, nalaciclovir, cidofovir, brivudine.
  • antiretroviral drugs nucleoside reverse transcriptase inhibitors and derivatives: lamivudine, zalcitabine, didanosine, zidovudine, tenofovir, stavudine, abacavir, non-nucleoside reverse transcriptase inhibitors: amprenavir, indinavir, saquinavir, lopinavir, ritonavir Nelfmavir
  • other nirustatics such as amantadine, ribavirin, zanamivir, oseltamivir, lamivudine.
  • the carbon-containing layers produced according to the invention can be suitably modified in their chemical or physical properties before or after the active substance loading by means of further agents, for example in order to modify the hydrophilicity, hydrophobicity, electrical conductivity, adhesion or other surface properties.
  • further agents for example in order to modify the hydrophilicity, hydrophobicity, electrical conductivity, adhesion or other surface properties.
  • biodegradable or non-degradable polymers such as the biodegradable ones: collagens, albumin, gelatin, hyaluronic acid, starch, cellulose (methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose phthalate; further casein, dextrans, polysaccharides,
  • Fibrinogen Poly (D, L-Lactide), Poly (D, L-Lactide-Co-Glycolide), Poly (Glycolide), Poly (Hydroxybutylate), Poly (Alkylcarbonate), Poly (Orthoester), Polyester, Poly (Hydroxyvaleric Acid ), Polydioxanones, poly (ethylene terephthalates), poly (malate acid), poly (tartronic acid), polyanhydrides, polyphosphohazenes, poly (amino acids), and all their copolymers.
  • the non-biodegradable include: poly (ethylene-vinyl acetates), silicones, acrylic polymers such as polyacrylic acid, polymethylacrylic acid, polyacrylcynoacrylate; Polyethylenes, polypropylenes, polyamides, polyurethanes, poly (ester-urethanes), poly (ether-urethanes), poly (ester-ureas), polyethers such as polyethylene oxide, polypropylene oxide, Pluronics, polyTetramethylene glycol; Vinyl polymers such as polyvinyl pyrrolidones, poly (vinyl alcohols), poly (vinyl acetate phatalate).
  • polymers with anionic e.g. alginate, carrageenan, carboxymethylcellulose
  • cationic e.g. chitosan, poly-L-lysine etc.
  • both properties phosphorylcholine
  • PH-sensitive polymers are poly (acrylic acid) and derivatives, for example: homopolymers such as poly (aminocarboxylic acid), poly (acrylic acid), poly (methyl-acrylic acid) and their copolymers. This also applies to polysaccharides such as cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, cellulose acetate trimellitate and chitosan.
  • Thermosensitive polymers are, for example, poly (N-isopropylacrylamide-co-sodium-acrylate-Co-nN-alkylacrylamide), poly (N-methyl-Nn-propyl-acrylamide), poly (N-methyl-N-isopropylacrylamide), poly (Nn-propyl methacrylamide), poly (N-isopropylacrylamide), poly (N, n-diethylacrylamide), poly (N-isopropyl methacrylamide), poly (N-cyclopropylacrylamide), poly (N-ethyl acrylamide), poly (N-ethyl methacrylamide) ), Poly (N-methyl-N-ethyl acrylamide), poly (N-cyclopropylacrylamide).
  • polymers with thermal gel characteristics are hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, ethyl hydroxyethyl cellulose and Pluronics such as F-127, L-122, L-92, L-81, L-61.
  • the active substances can be adsorbed on the one hand in the pores of the carbon-containing layer (non-covalent, covalent), their release being controllable primarily by pore size and geometry. Additional modifications of the porous carbon layer by chemical modification (anionic, cationic) allow the release to be modified, for example depending on the pH. Another application is the release of active substance-containing carriers, namely microcapsules, liposomes, nanocapsules, nanoparticles, micelles, synthetic phospholipids, gas dispersions, emulsions, microemulsions, nanospheres etc., which are adsorbed in the pores of the carbon layer and then released therapeutically. By additional covalent or non-covalent modification of the
  • the pores can be occluded in the carbon layer so that biologically active substances are protected.
  • the polysaccharides, lipids, etc. already mentioned above come into question, but also the polymers mentioned.
  • physical barriers such as inert biodegradable substances (for example poly-1-lysine, fibronectin, chitosan, heparin etc.) and biologically active barriers.
  • the latter can be sterically hindering molecules that are physiologically bioactivated and allow the release of active substances or their carriers.
  • enzymes that mediate the release, activate biologically active substances or bind non-active coatings and lead to exposure of active substances. All mechanisms and properties listed specifically are to be applied both to the primary carbon layer produced according to the invention and to layers additionally applied thereon.
  • the implants coated according to the invention can also be loaded with living cells or microorganisms. These can settle in suitably porous carbon-containing layers, whereby the implant colonized in this way can then be provided with a suitable membrane coating which is permeable to nutrients and active substances produced by the cells or microorganisms, but not to the cells themselves.
  • implants can be produced which contain insulin-producing cells which, after implantation in the body, produce and release insulin depending on the glucose level in the environment.
  • Example 1 Carbon A carbon material coated according to the invention was produced as follows: A polymer film was applied to a paper with 38 g / m 2 basis weight by coating the paper several times with a doctor blade with a commercially available epoxidized phenolic resin lacquer and drying it at room temperature. Dry weight 125g / m 2 . Pyrolysis at 800 ° C for 48 hours under nitrogen with a shrinkage of 20% and a weight loss of 57% gives an asymmetrically constructed carbon sheet with the following dimensions: total thickness 50 microns, with 10 microns of a dense carbon-containing layer according to the invention on an open-pore carbon support with a 40 micron thickness formed from the paper in situ under the pyrolysis conditions. The absorption capacity of the coated carbon material was up to 18 g ethanol / m 2 .
  • Example 2 Glass Duroplan® glass is a 15 min. Subjected to ultrasonic cleaning in a surfactant-containing water bath, rinsed with distilled water and acetone and dried. This material is coated by dip coating with a commercially available packaging resin on a phenolic resin basis with an application weight of 2.0 * 10 .- " 4 g / cm .2 '. After subsequent carbonization at 800 ° C. for 48 hours under nitrogen, the coating loses weight to 0.33 * 10 "4 g / cm 2 a. The previously colorless coating becomes shiny black and is hardly transparent after carbonization.
  • Example 3 Glass, CVD coating (comparative example) Duroplan® glass is a 15 min. Subject to ultrasonic cleaning, with dist. Rinsed water and acetone and dried. This material is coated by chemical vapor deposition (CVD) with 0.05 * 10 "4 g / cm 2 carbon. For this purpose, benzene is brought into contact with the 1000 ° C hot glass surface at 30 ° C in a bubbler through a nitrogen flow for 30 minutes The previously colorless glass surface becomes gray glossy and after the deposition is muted and transparent.
  • a test of the coating hardness with a pencil, which is pulled at an angle of 45 ° with a weight of 1kg over the coated surface results in to a hardness of 6B no visually perceptible damage to the surface.
  • Example 4 Glass fiber Duroplan® glass fibers with a diameter of 200 microns are a 15 min. Subject to ultrasonic cleaning, with dist. Rinsed water and acetone and dried. This material is coated by dip coating with a commercially available packaging lacquer with an application weight of 2.0 * 10 "4 g / cm 2. After subsequent pyrolysis with carbonization at 800 ° C. for 48 hours, the coating loses weight to 0.33 * 10 " g / cm 2 a. The previously colorless coating becomes shiny black and is hardly transparent after carbonization. A test of the adhesion of the coating by bending in a radius of 180 ° shows no flaking, ie visually perceptible damage to the surface.
  • Example 5 Stainless steel 1.4301 stainless steel as 0.1mm film (Goodfellow) is a 15 min. Subject to ultrasonic cleaning, with dist. Rinsed water and acetone and dried. This material is coated by dip coating with a commercially available packaging lacquer with an application weight of 2.0 * 10 "4 g / cm 2 . After subsequent pyrolysis with carbonization at 800 ° C. for 48 hours under nitrogen, the coating loses weight to 0.49 * 10 "4 g / cm 2. The previously colorless coating becomes matt black after carbonization. A test of the coating hardness with a Pencil, which is drawn at an angle of 45 ° with a weight of 1kg over the coated surface, does not show any visible damage to the surface up to a hardness of 4B. An adhesive strip peel test, in which a Tesa® strip with at least 3 cm Glued to the surface for more than 60 seconds with the thumb and then peeled off from the surface at an angle of 90 ° results in hardly any adhesion.
  • Example 6 stainless steel, CVD coating (comparative example) Stainless steel 1.4301 as 0.1 mm foil (Goodfellow) is a 15 min. Subject to ultrasonic cleaning, with dist. Rinsed water and acetone and dried. This material is coated by chemical vapor deposition (CVD) with 0.20 * 10 "4 g / cm 2. For this purpose, benzene is brought into contact with the hot metal surface at 30 ° C in a bubbler through a nitrogen flow for 30 minutes, decomposed at high temperatures and deposited as a film on the metal surface. The previously metallic surface becomes black glossy after deposition.
  • CVD chemical vapor deposition
  • Example 7 Titanium Titanium 99.6% as 0.1 mm foil (Goodfellow) is a 15 min. Subjected to ultrasonic cleaning, with dist. Rinsed water and acetone and dried.
  • This material is coated by dip coating with a commercially available packaging lacquer with 2.2 * 10 "4 g / cm 2 ; after subsequent pyrolysis with carbonization at 800 ° C for 48 hours under nitrogen, the coating loses weight to 0.73 * 10 " 4 g / cm 2 a.
  • the previously colorless coating becomes matt, gray-black glossy.
  • a test of the coating hardness with a pencil, which is drawn at an angle of 45 ° with a weight of 1kg over the coated surface does not show any optical damage to the surface up to a hardness of 8H. Even with a paper clip, for example, the coating cannot be scratched.
  • a peel test in which a Tesa® strip with a length of at least 3 cm is stuck to the surface with the thumb for 60 seconds and then peeled off at an angle of 90 ° from the surface, does not show any adherence.
  • Example 8 Titanium, refined with CVD titanium 99.6% as a 0.1 mm foil (Goodfellow) is a 15 min. Subject to ultrasonic cleaning, with dist. Rinsed water and acetone and dried. This material is made by dip coating with a commercially available packaging varnish
  • a test of the coating hardness with a pencil that is at an angle of 45 ° with a Pulling a weight of 1kg over the coated surface does not result in any visible damage to the surface up to a hardness of 8H.
  • a peel test in which a Tesa® adhesive tape strip with a length of at least 3 cm is stuck to the surface with the thumb for 60 seconds and then peeled off from the surface at an angle of 90 °, results in gray buildup.
  • TAT thrombin-antithrombin complex
  • results show a partially significant improvement in the biocompatibility of the examples according to the invention, both with respect to the dialysis membranes and to the uncoated samples.
  • Example 10 Line growth test The coated titanium surface from example 8 and the amorphous carbon from example 1 were further examined for cell growth of mouse L929 fibroblasts. An uncoated titanium surface serves as a comparison. For this purpose, 3x10 cells per test specimen were applied to the previously steam-sterilized samples and incubated for 4 days under optimal conditions. The cells were then harvested and the number per 4 ml of medium was determined automatically. Each sample was measured twice and the mean was formed. The results are shown in Table II: Table II: Cell growth on coated titanium
  • Example 11 Coated stent A commercially available metal stent from Baun Melsungen AG, type Coroflex 2.5x19mm, is a 15 min. Subjected to ultrasonic cleaning in a surfactant-containing water bath, rinsed with distilled water and acetone and dried. This material is coated by dip coating with a commercially available packaging lacquer based on phenolic resin / melamine resin with 2.0 * 10 "4 g / cm 2. After subsequent pyrolysis with carbonization at 800 ° C. for 48 hours under nitrogen, the coating loses weight by 0.49 * 10 "4 g / cm 2 a. The previously metallic high-gloss surface turns matt black.
  • the coated stent was expanded using a balloon catheter.
  • the subsequent optical inspection with a magnifying glass showed no microscopic flaking of the homogeneous coating from the metal surface.
  • the absorption capacity of this porous layer is up to 0.005 g of ethanol.
  • Example 12 Coated Carbostent A commercially available carbon-coated metal stent from Sorin Biomedica, type Radix Carbostent 5x12mm, is a 15 min. ultrasonic cleaning subjected to rinsing with distilled water and acetone and drying. This material is coated by dip coating with a commercially available packaging varnish based on phenol resin / melamine resin with an application weight of 2.0 * 10 "4 g / cm 2. After subsequent pyrolysis with carbonization at 800 ° C. for 48 hours under nitrogen, the coating loses weight 0.49 * 10 "4 g / cm 2 a. The previously black surface becomes matt black after carbonization.
  • the coated stent was expanded to test the adhesion of the coating by expanding the stent at 6 bar to the nominal size of 5 mm.
  • the subsequent optical inspection with a magnifying glass showed no microscopic flaking of the homogeneous coating from the metal surface.
  • the absorption capacity of this porous layer of the above stent model was up to 0.005 g of ethanol.
  • Example 13 Activation The coated stent from Example 12 is activated by activation with air at 400 ° C. for 8 hours. Here, the carbon coating is converted into porous carbon. The coated stent was expanded to test the adhesion of the coating by expanding the stent at 6 bar to the nominal size of 5 mm. The subsequent optical inspection with a magnifying glass showed no microscopic flaking of the homogeneous coating from the metal surface. The absorption capacity of this now porous layer of the above Stent model amounts to up to 0.007 g of ethanol, which shows that an additional activation of the carbon-containing layer additionally increases the absorption capacity.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)

Abstract

L'invention concerne des dispositifs médicaux implantables présentant des revêtements biocompatibles, ainsi que des procédés pour la production desdits dispositifs médicaux. L'invention concerne en particulier des dispositifs médicaux implantables revêtus d'une couche contenant du carbone, qui sont obtenus par application d'un film polymère sur au moins une partie du dispositif et par chauffage du film polymère dans une atmosphère, sensiblement exempte d'oxygène, à des températures situées dans une plage de 200 DEG C à 2500 DEG C.
EP04731916A 2003-05-16 2004-05-10 Implants medicaux revetus de maniere biocompatible Withdrawn EP1626752A2 (fr)

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DE10322182A DE10322182A1 (de) 2003-05-16 2003-05-16 Verfahren zur Herstellung von porösem, kohlenstoffbasiertem Material
DE2003124415 DE10324415A1 (de) 2003-05-28 2003-05-28 Verfahren zur Beschichtung von Substraten mit kohlenstoffbasiertem Material
DE2003133098 DE10333098A1 (de) 2003-07-21 2003-07-21 Biokompatibel beschichtete medizinische Implantate
PCT/EP2004/004985 WO2004101017A2 (fr) 2003-05-16 2004-05-10 Implants medicaux revetus de maniere biocompatible

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BR (1) BRPI0410377A (fr)
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CA2519742A1 (fr) 2004-11-25
BRPI0410377A (pt) 2006-06-13
EA200501562A1 (ru) 2006-04-28
WO2004101017A3 (fr) 2005-03-03
WO2004101017A2 (fr) 2004-11-25
KR20060003100A (ko) 2006-01-09
AU2004238026A1 (en) 2004-11-25
DE202004009060U1 (de) 2004-08-12
EA009598B1 (ru) 2008-02-28
EP1982772A1 (fr) 2008-10-22
JP2007504920A (ja) 2007-03-08

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