HK1089702B - Implants comprising functionalized carbon surfaces - Google Patents

Description

The present invention relates to a method for the manufacture of medical implants with functional surfaces by providing a medical implant with at least one carbon layer on at least one part of the surface of the implant, activating the carbon layer by creating porosity, and functionalising the activated carbon layer and subsequently available functional implants.

Medical implants such as surgical or orthopaedic screws, plates, joint prostheses, artificial heart valves, vascular prostheses, stents and subcutaneous or intramuscularly implantable active substance depositories are made from a wide variety of materials selected for their specific biochemical and mechanical properties, which must be suitable for permanent use in the body, free of toxic substances and have certain mechanical and biochemical properties.

However, metals or metal alloys commonly used for stents and joint prostheses, as well as ceramic materials, often have disadvantages in terms of their biocompatibility or functionality, especially when used permanently.Implants trigger inflammatory tissue and immune responses through chemical and/or physical irritation, leading to intolerance reactions in the form of chronic inflammatory responses with defence and rejection reactions, excessive scarring or tissue degradation, which in the extreme case may require the removal and replacement of the implant, or additional therapeutic interventions of invasive or non-invasive nature.

For this reason, there are various approaches to the state of the art to coating the surfaces of medical implants in an appropriate way to increase the biocompatibility of the materials used or the functional effectiveness of the implants and to prevent rejection or repulsion reactions.

For example, US 5.891.507 describes methods for coating the surface of metallic inks with silicone, polytetrafluoroethylene and biological materials such as heparin or growth factors, which increase the bioavailability of metallic inks.

In addition to plastic layers, carbon-based layers have proved particularly advantageous.

For example, DE 199 51 477 is known to contain coronarstents with a coating of amorphous silicon carbide, which increases the biocompatibility of the stent material. US Patent 6,569,107 describes carbon-coated stents in which the carbon material was applied by chemical or physical vapor phase separation (CVD or PVD) methods. US Patent 5,163,958 also describes tubular endoprostheses or stents with a carbon-coated surface that exhibit antithrombotic properties. WO 02/09791 describes intravascular silos with coatings produced by CVD.

In addition to CVD processes for carbon separation, the state of the art describes various high vacuum sputtering processes for the production of pyrolytic carbon layers of various structures, see for example US 6.355.350.

WO 99/64085 describes a process for producing a diamond-like coating to which a layer of biomolecules is covalently bound. WO 021080996 describes a long-term stable coating to which a biodegradable coating with a medicinal product is applied.

However, the implants manufactured with modified surfaces have some disadvantages: for example, biocompatibility is not always sufficient to completely prevent rejection reactions; and the state-of-the-art surface-coated implants are usually closed-porous, which makes it difficult or impossible to grow together with the surrounding body tissue or to function. Although these state-of-the-art implants can be coated with antibiotics, for example, the effect of these substances after the implant is applied is always short-lived, as the amounts of active substance applied are limited by the nature of the implant and its surface coating or its physical or chemical activity, but not controllable or affected by their interaction.

Furthermore, it is medically useful and desirable for implants to be used not only in their supporting function, as in stents, but also to have additional functions, such as long-term pre-administration of medicinal products at the implant site to enhance the effect of the implant or to produce additional medically desirable effects.

There is therefore a need for easy to use and cost-effective methods to produce functionalised implants.

There is also a need for low-cost medical implants with improved properties.

The present invention is therefore intended to provide a method for the manufacture of implants with additional functionality.

A further objective of the present invention is to provide medical implants that can perform additional functions, such as delivering medicinal products into the body or implanting tissues, while showing increased biotransferability or biocompatibility or having a more functional implant effect.

A further purpose of the present invention is to provide medical implants which enable the permanent release of medicinal substances into the body of a patient or which have a function enhanced by surface modification.

A further function of the present invention is to provide medical implants which can release applied or incorporated pharmacologically active substances in a targeted and/or controlled manner after the implant has been inserted into the human body.

A further function of the invention is to provide implantable drug depositories with a coating that can control the release of drug substances from the deposit.

A further function of the invention is to make available medical implants containing applied or incorporated micro-organisms, viral vectors or cells or tissues, so that after insertion of the implant into the human body, a specific therapeutic effect can be produced or biotransmittance increased.

The solution of the above tasks is a procedure and the medical implants available as defined in the independent claims; preferred embodiments of the procedure or products and uses of the invention are derived from the dependent subclaims.

The present invention shows that, in particular, carbon-containing layers on implantable medical devices can be used in a simple way to provide the implant with additional physiological and therapeutic functions.

In particular, the invention makes it possible to fix therapeutically effective amounts of medicinal products on the surface of an implant or in a layer present on the implant and to release them permanently and in a controlled manner into the human body.

Accordingly, the process of manufacturing medical implants with functional surfaces according to the invention includes the following steps: (a) Provision of a medical implant with at least one carbon layer on at least part of the surface of the implant; (b) Activation of the carbon layer by creating porosity; (c) Functionalization of the activated carbon layer.

The method of the invention allows for the appropriate modification of implants with carbon-based surface coatings to allow for loading with therapeutically effective amounts of pharmacologically active substances.

The method and rate of release and the physiological and biological surface properties can be adjusted and varied in a specific way, so that tailored solutions can be made for each type of implant and active substance, each site of application and purpose of the medical implants, using simple procedures as described in the invention.

The following are the main components:

The method of the invention allows the functionalization of carbon-coated implants.

Err1:Expecting ',' delimiter: line 1 column 56 (char 55)

The implants used in the process of the invention may be made from virtually any material, preferably substantially temperature stable, and in particular from all materials from which implants are typically manufactured.

Examples are amorphous and/or (partial) crystalline carbon, all-carbon material, porous carbon, graphite, carbon composite materials, carbon fibres, ceramics such as zeolites, silicates, aluminium oxides, alumino-silicates, silicon carbide, silicon nitride; metal carbides, metal oxides, metal nitrides, metal nitrides, metal oxycarbides, metal oxynitrides and metal oxycarbides of the transition metals such as titanium, zirconium, hafnium, vanadium, niobium, tantalum, chandinite, molybdenum, copper, manganese, rhodium, iron, nickel; and glass and glass compounds, in particular those based on precious metals such as titanium, rhodium, rhodium, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nickel, nick

In preferred embodiments of the present invention, the implants used are stents, especially metal stents, preferably of stainless steel; platinum-containing radio-opac steel alloys, known as PERSS (platinum enhanced radiopaque stainless steel alloys), cobalt alloys, titanium alloys, high-melting alloys such as those based on niobium, tantalum, tungsten and molybdenum, precious metal alloys, nitin alloys, and magnesium alloys and mixtures of the foregoing.

Err1:Expecting ',' delimiter: line 1 column 179 (char 178)

The implantable medical devices used in accordance with the invention may have almost any external form; the method of the invention is not limited to certain structures.

The implants shall have a carbon layer on at least part of their surface, which may consist of pyrolytically produced carbon, glassy amorphous carbon, evaporated carbon, CVD, PVD or sputtered carbon, diamond carbon, graphite carbon, metal carbides, metal carbonitrides, metal oxynitrides or metal oxycarbides, or any combination thereof. The carbon layer may be amorphous, crystalline or partially crystalline, with preference to layers of amorphous, pyrolytic carbon, and in some embodiments of diamond-like carbon, such as evaporated carbon.

In particular, carbon-coated implants are preferred, which are produced by applying carbon-producing materials and/or polymer films to the implant and then carbonising these materials at elevated temperatures and excluding oxygen, as described in examples in DE 10322187 and WO 2004/101483, DE 10324415 and WO 2004/101177, or DE 10333098 and WO 2004/101017 respectively.

Other suitable carbon-coated implants are commercially available carbon-coated implants, such as Radix Carbostent® (Sorin Biomedica) metallic resins and similar ones, which usually contain carbon coatings produced by physical vaporization or spraying processes, including sputtering.

The thickness of one or more carbon-containing layers may generally be between 1 nm and 1 mm, and possibly several millimetres, e.g. up to 10 mm, preferably up to 6 mm, and preferably up to 2 mm, in particular between 10 nm and 200 μm.

In preferred embodiments of the present invention, implantable medical devices may also have several carbon-containing layers of equal or different thickness and/or porosity, for example, lower porous layers may be combined with upper porous layers, which may adequately delay the release of active substances deposited in the more porous layer.

The following shall be reported:

The method of the present invention is to modify the physical and chemical properties of the carbon-based coating by appropriate activation steps and to adapt it to the intended use. Conventional carbon-coated implants usually have essentially closed surfaces, which greatly limit or reduce the effective and permanent load of e.g. active substances to very small amounts. The purpose of activation is to create a porosity in the carbon-containing layer or to form a porous carbon-containing layer on the implant, thus allowing better functionalization by means of active substances, cells, proteins, etc. to increase the absorption of carbon and the ability of the layer to contain carbon.

The activation step in the method of the invention is thus essentially to create porosity in the carbon layer on the implant.

A possible activation of the carbon layer includes, for example, reducing or oxidative treatment steps, where the layer is treated with suitable reducing and/or oxidizing agents such as hydrogen, carbon dioxide, water vapour, oxygen, air, nitric oxide, or oxidizing acids such as nitric acid and similar, and, where appropriate, one or more mixtures thereof.

The activation with air is preferred, especially at elevated temperatures.

The activation step (s) may be carried out at elevated temperatures, e.g. 40°C to 1000°C, preferably 70°C to 900°C, preferably 100°C to 850°C, preferably 200°C to 800°C and particularly around 700°C. In particularly preferred embodiments, the carbonate layer is modified reductively or oxidatively, or by a combination of these treatment steps at room temperature.

Depending on the type of oxidizing or reducing agent used, the temperature and duration of activation, pore size and pore structure may be varied. In particularly preferred embodiments, activated carbon coated medical implants of the invention may be used to control the release of active substances from the substrate to the external environment by targeting the porosity of the carbon layer.

The coatings after activation are preferably porous, in particular nanoporous, in which case, for example, medical implants of the invention can be used as drug carriers with a deposition effect, especially if the implant itself has a porous structure, whereby the activated carbon-based layer of the implant can be used as a release-regulating membrane.

In preferred embodiments, the porosity can be adjusted by washing out fillers present in the carbonated coating, such as polyvinyl pyrrolidone, polyethylene glycol, aluminium powder, fatty acids, microwaxes or emulsions, paraffins, carbonates, dissolved gases, or water-soluble salts with water, solvents, acids or alkalis, or by distillation or oxidative or non-oxidative thermal decomposition, as described in the appropriate methods in DE 103 22 187 and WO 2004/101433 of the same notifier.

If necessary, porosity can also be produced by texturing the surface with powdery substances such as metal powder, soot, phenolic resin powder, fibres, especially carbon or natural fibres.

Err1:Expecting ',' delimiter: line 1 column 208 (char 207)

The activated coating can also be subjected, if necessary, to a further optional process step, a so-called CVD (Chemical Vapour Deposition) or CVI (Chemical Vapour Infiltration) process, to further modify the surface or pore structure and their properties.

Almost all known saturated and unsaturated hydrocarbons with sufficient volatility under CVD conditions are suitable as carbon-splitting precursors, such as methane, ethanol, ethylene, acetylene, linear and branched alkanes, alkenes and alkynes with carbon numbers of C1 to C20, aromatic hydrocarbons such as benzene, naphthalene, etc., and single and multiple alkyl, alkenyl and acinyl substitute aromatics such as toluene, xylol, cresol, styrene, etc.

The ceramic precursor may be used as BCl3, NH3, silane such as SiH4, tetraethoxylan (TEOS), dichlorodimethyl silane (DDS), methyl trichlorosilan (MTS), trichlorosilyl dichloroboran (TDADB), hexadichloromethyl silyl oxide (HDMSO), AlCl3, TiCl3 or mixtures thereof.

These precursors are usually used in CVD processes in low concentrations of about 0.5 to 15% vol. in a mixture with an inert gas such as nitrogen, argon or the like. It is also possible to add hydrogen to appropriate separation gas mixtures. At temperatures between 500 and 2000°C, preferably 500 to 1500°C and particularly 700 to 1300°C, the compounds used break down hydrocarbon fragments or carbon or ceramic precursors which are essentially evenly distributed in the pore system of the pyrolysed coating, modifying the pore structure there, thus resulting in a substantially homogeneous pore size and pore distribution.

CVD methods can be used to reduce pores in the carbon layer on the implant to a point where they are completely closed/sealed, allowing the absorptive properties as well as the mechanical properties of the activated implant surface to be adjusted to the desired size.

CVD by silanes or siloxanes, where appropriate in combination with hydrocarbons, can modify the carbon-containing implant coatings to be oxidation resistant, for example by carbide or oxycarbide formation.

In preferred embodiments, the coated implants activated in accordance with the invention may be coated or modified by means of a sputtering process, which may involve the application of carbon, silicon or metals or metal compounds from suitable sputtering targets by known methods, such as the incorporation of silicon, titanium, zirconium or tantalum compounds or metals into the carbon-containing layer by means of CVD or PVD to form carbide phases which increase the stability and oxidation resistance of the layer.

In another preferred embodiment of the activation step, carbon-containing layers, e.g. also sputtered C-layers, can be mechanically treated subsequently to produce porous surfaces, e.g. the targeted abrasion of these layers by appropriate methods leads to porous layers. A preferred option is the abrasion of such carbon-containing layers in the ultrasonic bath, where the mixing of abrasive solids of different particle sizes and hardness by appropriate energy input and appropriate frequency of the ultrasonic bath can produce targeted layer effects depending on the reaction time and thus porosity.

The preferred method is the use of aqueous ultrasonic baths with the addition of clay soil, silicates, aluminates and the like, preferably toner dispersions, but any other solvent suitable for ultrasonic baths may be used instead of or in combination with water.

For example, treatment of carbon-coated implants in an aqueous ultrasonic bath with a mixture of clay, preferably 1% to 60% clay dispersions, can produce nano-abraded carbon layers with a mean pore size of about 5 nm to 200 nm.

Furthermore, the surface properties of the implant can be further modified by ion implantation of metals, particularly transition metals, and/or non-metals, for example by nitrogen implantation of nitrides, oxynitrides or carbon nitrides, particularly those of transition metals.

The carbon-containing layer is preferably porous after activation, with pore diameters in the range of 0.1 to 1000 μm, preferably between 1 μm and 400 μm. Macroporous layers can also be obtained by the activation steps of the invention.

The carbon-containing layer after activation is particularly preferably nanoporous, with pore diameters from 1 nm to 1000 nm, preferably from 5 nm to 900 nm.

In a particularly preferred embodiment of the invention, activation is already carried out during the manufacturing step of the carbon-containing layer, e.g. by application of one or more porous carbon-containing layers, by carbonisation of carbon-producing substances, by coating with carbon by CVD or PVD, and/or by application of suitable layers of porous biodegradable or absorbable or non-biodegradable or absorbable polymers.

In particular, it is preferable to apply one or more porous carbonic layers by coating the implant with a foamed or filler film, if applicable, and then carbonising the polymer film at temperatures between 200 and 3500 °C, preferably up to 2000 °C, in an oxygen-free atmosphere, which may subsequently be partially oxidised in the air stream.

For example, the addition of polyethylene glycol to the polymer film to be carbonised leads to defects in the polymer network which, after heat treatment or release in suitable solvents, results in porous carbon layers. By choosing the polymer system, the molecular weight of polyethylene glycol and the solid content of polyethylene glycol, porosities appropriate to the application can be adjusted, in particular the average pore size, the pore size distribution and the degree of porosity. For example, by choosing polyethylene glycols with a molecular weight of 1000-80000000 dalton, porosity sizes of 10 to 1000 nm can be produced in the form of a 50 to 1000 nm implementation.

Another example of this type of combined production and activation of the carbon layer is the addition of soot to the polymer film.

The choice of the medium particle size and the solid content in the polymer film allows the production of porous matrices, the degree of porosity and the medium pore size of which can be adjusted by the choice of suitable polymer systems, the russ-particle size and the solid content according to the application, for example, by mixing russ particles of a medium particle size of 10 nm to 1 mm, preferably 10 nm to 1000 nm, with a solid content of 20 to 80%, preferably 30% to 60%, an average porosity of 30-60% can be produced, with the produced pore sizes between 10 nm to 1000 nm, preferably 10 nm to 800 nm, being adjustable.

Furthermore, the surface properties and porosity of the carbon-containing layer can be modified by optionally parylene-lining the implants before or after the activation step, whereby the implants are first treated at a higher temperature, usually about 600 °C, with paracyclophan, which forms a polymer film of poly (p-xylenes) on the surface of the implants, which can be converted into carbon in a subsequent carbonisation step by known processes.

If necessary, in particularly preferred embodiments, the activated implant may be subjected to further chemical and/or physical surface modifications. Cleaning steps to remove any residues and impurities may also be provided for. Acids, especially oxidizing acids, or solvents may be used, preferably boiling in acids or solvents.

Before medical use or loading with active substances, the implants of the invention may be sterilised by conventional methods, such as autoclaving, ethylene oxide sterilisation or gamma radiation. According to the invention, all possible activation methods can be combined with each other as well as with any of the functionalization steps described below.

The Commission has already adopted a proposal for a directive.

The implants may be supplemented by a variety of functions by appropriate measures. Orthopaedic and surgical implants or vascular prostheses may be used as drug carriers or depositories. The biocompatibility and functionality of the implants of the invention may be specifically affected or modified by the incorporation of additives, fillers, proteins, which can reduce or eliminate the effects of rejection in the body of implants of the invention or increase the effectiveness of the implant or produce additional effects.

Functionalisation in the present invention generally refers to actions that result in the carbon layer acquiring further, additional functions. Functionalisations according to the invention consist of the incorporation of substances into the carbon layer or the fixation of substances to the carbon layer. Suitable substances are selected from pharmacological agents, linkers, microorganisms, plant or animal including human cells or cell cultures and tissues, minerals, salts, metals, synthetic or natural polymers, proteins, peptides, amino acids, solvents, etc.

According to the invention, the appropriately activated implant can be functionalized by making it more bioavailable before or after a possible loading with active substances by adding at least one additional layer of biodegradable or absorbable polymers such as collagen, albumin, gelatine, hyaluronic acid, starch, cellulose such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose phthalate; casein, dextrane, polysaccharides, fibrinogen, PolyD, L-tarragonic poly (PolyD, L-lactide), PolyGlycol, PolyGlycol, Polybutyrene, Polybutyl, Poly (L-arginic poly (Poly) nitrate), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly), Poly (Poly, Poly (Poly), Poly (Poly), Poly (Poly, Poly (Poly), Poly (Poly, Poly (Poly), Poly (Poly), Poly (Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly, Poly

In the process of the invention, active substances such as medicinal products can also be applied or introduced into the activated carbon layer in the functionalisation step, which is particularly useful where active substances cannot be applied directly to the implant or to the implant, such as in the case of metals.

For example, heavy water-soluble lipophilic agents such as paclitaxel, which tend to form a crystalline film, can be applied to metallic surfaces. Usually, the immobilizable amounts are limited and the release is not controllable. Direct coating of such metallic surfaces with paclitaxel results in maximum loads of about 3 mg/mm2, the release of which under physiological conditions in physiological buffer solutions results in uncontrolled desorption of up to 30% within 1 to 5 days.

The invention's activated carbon layers, preferably glassy amorphous, with a layer thickness in the range of 80 nm to 10 μm, preferably 100 nm to 5 μm, preferably with a porosity of 5 nm to 1 μm, preferably 5 nm to 1000 nm, can, for example, already control the release of active substances up to a hundredfold of those active substances from non-activated carbon coated or metallic implants on and depending on the porosity, pore size and surface properties, as appropriate, at porosities of 5% to 50%, preferably 10% to 50%, and at a mean pore size of 5 nm to 1 μm, preferably 5 nm to 500 nm.

At loading levels of 0,5 to 3,0 μg/mm2 paclitaxel and hydrophobic carbon surfaces with a layer thickness of 200 nm, for example, 70-100% of the administered amount of paclitaxel can be released in a controlled manner under physiological conditions over 25 to 35 days, at a constant daily rate of release, in an embodiment of the invention with a pore size of 50 nm and a 5% degree of porosity.

In particularly preferred embodiments, peptides and proteins, as well as glycoproteins and lipoproteins, can be immobilized by appropriate functionalization of any carbon layer.

A form of functionalization according to the invention is the covalent or non-covalent adsorption of substances that allow the binding of affinity tags or labeled peptides, proteins, glycoproteins or lipoproteins.

Such substances include, for example, ions, cations, especially metal cations such as cobalt, nickel, copper, zinc cations, antibodies, calinodulin, chitin, cellulose, sugars, amino acids, glutathione, streptavidin, strep-tactin or other mutants for binding to substances labelled with strep or SBP tags, or S-protein for binding to substances labelled with S-tags, and the like.

These affinity attachments are appropriately attached to the peptide, protein, glycoprotein or lipoprotein domains to be immobilized either at the C-terminal or N-terminal end of the primary sequence, usually by recombinant genetic engineering or biotinylation, preference being given to affinity attachments, in particular polyarginine (Arg-tag) which are preferably composed of five to six arginins, polyhistidine (Histag), any longest polyhistidine sequence, typically 2 to 10 R positions, FLAG (FREQ) with sequence DDDQ, lipoproteins (Strep-Q), the S-terminal binding protein, such as the S-terminal binding protein, or the S-terminal binding protein, such as the S-terminal binding protein, but also the other cell-bound proteins, such as the S-terminal binding protein, G-PEG-Q, the S-terminal binding protein, the S-terminal binding protein, the S-terminal binding protein, the S-terminal binding protein, the S-transferase (G-PEG-Q), the S-terminal binding protein, the S-transferase (G-PEG-Q), the S-transferase (G-Q), the S-transferase (G-G-G-G), the B-G-G, the B-G, the B-G, the B-G, the B-G, the B, the B, the B, the B, and the other proteins (G-G, and the other proteins), but also the B-binding protein, in particular the B-transfermental binding protein, the B-transferase (G-G, the B, the B-G-G, the B, and the B-G-G, and the other proteins, the B-G, the B, the B, the B, and the B-G, and the other proteins, the B, the B, the B, the B, the B, the B, and the B, and the B, and the B, and the other proteins, the B, the B, the B

The modification of the substances to be applied to the functionalised carbon surfaces is in accordance with the usual systems which are possible in the purification and in particular chromatographic marking.

The functionalization of the carbon surface is achieved by adsorption of corresponding substances in and/or on the carbon layer, which can bind to the affinity attachments.

The adsorption of the M1 antibody on the carbon surfaces allows the binding of FLAG attachments, streptavidin or strep tactin or other mutants to bind to strep-tag or SBP-tag-labelled substances, or the adsorption of the S-protein on the surface to bind to S-tag-labelled substances.

In another embodiment, the functionalization consists in the use of calmodulin, which is to be adsorbed on the carbon surface, allowing substances labeled with calmodulin binding peptides to bind to the carbon-containing layer.

In other embodiments, functionalization is achieved by adsorption of cellulose to bind modified substances with cellulose binding domains or by adsorption of chitin to bind substances with chitin binding domains.

Analogue functionalization can be performed with glutathione to bind substances labelled with glutathione S-transferase tags, with maltose or amylose to bind substances labelled with maltose-binding proteins.

The expert will select an appropriate affinity system according to the genetically possible conditions, functional and structural characteristics of the peptide, protein, glycoprotein or lipoprotein.

For example, on porous carbon surfaces with a pore size of 100-900 nm, a porosity of 30-60% and a layer thickness of 1-5 μm, a strep-tactin solution can be sprayed or dipped to produce functionalised carbon layers with 0,1-8 μg/mm2 of adsorbed strep-tactin.

In another embodiment, the carbon layer is co-bonded, with the porous carbon matrix containing a co-bonding content of 0.1 to 50% of the solid content, preferably up to 60% in glassy porous carbon layers. At 50% porosity, layer thicknesses of 500 nm to 1000 nm, recombinant IL-2 labeled with polyarginine tag can be adsorbed by metal ion endotion in the matrix of 0.1 to 100 μg.

Another embodiment involves, for example, the functionalization of carbon surfaces by adsorption of linker substances, preferably carboxymethylated dextrans, e.g. as hydrogels, which allow the physical binding of substances, preferably biomolecules or active substances, and/or have chemical reactivity, so that such substances can be covalently bound by covalent bonds, preferably by the formation of amino, thiol or aldehyde bonds.

The specialist will select the appropriate type of linker depending on the type of ligand.

For the production of an amine bond, the carbon layer can be functionalized in preferred embodiments by adsorption of carboxymethylated dextran, followed by modification by incubation in NHS/EDC to convert the carboxymethyl groups into N-hydroxysuccinimidesters.

In this way, ligands can be adsorbed, which form covalent amino bonds with the esters. Unreacted esters can be inactivated again in a further step, for example by incubation in 1M ethanolamine hydrochloride solution. For example, the adsorption of 1 μg of carboxymethylated dextran per mm2 of a porous, carbon-containing composite layer of glassy carbon and russ particles gives a functionalization that can covalently bind 0.01 to 5000 μg/mm2 of peptides with a molecular weight of 60-90 μg.

In addition, the porous layers activated in accordance with the invention may be loaded with medicinal products, microorganisms, cells and/or tissues during the process of functionalisation, or may be equipped with diagnostic aids such as markers or contrast agents to locate coated implants in the body, for example, therapeutic or diagnostic amounts of radioactive radiation.

The product is then applied to the skin.

In preferred embodiments, the implant activated in accordance with the invention is loaded with active substances at the functionalization step. The loading of active substances may be carried out in or on the carbon layer by appropriate sorptive methods such as adsorption, absorption, physorption, chemisorption, in the simplest case by impregnating the carbon coating with active solutions, active dispersions or active suspensions in suitable solvents. Covalent or non-covalent binding of active substances in or on the carbon coating may also be a preferred option depending on the active substance used and its chemical properties.

In preferred embodiments, the active substance is applied in the form of a solution, dispersion or suspension in an appropriate solvent or solvent mixture, with drying, if necessary, followed by drying. Suitable solvents include, for example, methanol, ethanol, N-propanol, isopropanol, butoxydiglycol, butoxyethanol, butoxyisopropanol, butoxypranol, n-butyl alcohol, t-butyl alcohol, butyleneglycol, butyloctanol, diethyl glycol, methyl dimethoxy, phenyl benzoyl, diethyl tetrahydroxycol, ethoxydiglycol, ethoxygen, ethoxygen, ethoxygen, ethoxygen, ethoxygen, ethoxygen-3, ethoxygen-1, ethoxygen-3, ethoxygen-3, ethoxygen-3, ethoxygen-3, ethoxygen-3, ethoxygen-3, ethoxygen-3, ethoxygen-3, ethoxygen-3, ethoxygen-3, ethoxygen-2, ethoxygen-2, ethoxygen-2, ethoxygen-2, ethoxygen-2, ethoxygen-4, ethoxygen-4, ethoxygen-2, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxygen-4, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, etho

The preferred solvents include one or more organic solvents from the group of ethanol, isopropanol, n-propanol, dipropylene glycol methyl ether and butoxyisopropanol (1,2-propylene glycol-n-butyl ether), tetrahydrofuran, phenol, benzene, toluene, xylol, preferably ethanol, isopropanol, n-propanol and/or dipropylene glycol methyl ether, in particular isopropanol and/or n-propanol.

In the activated porous carbon layers, appropriately sized active substances can also be occluded in pores.

The charge may be temporary, i.e. the active substance may be released after implantation of the medical device, or the active substance may be permanently immobilized in or on the carbon layer. In this way, active medical implants can be produced with static, dynamic or combined static and dynamic charges, resulting in multifunctional coatings based on the carbon layers of the invention.

When activated by static loading, active substances are essentially permanently immobilized on or in the coating, the active substances used being inorganic substances such as hydroxylapatite (HAP), fluorapatite, 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 antibodies such as polylactonic acid, chitosan, pharmacological agents or combinations thereof.

In dynamic loading, the release of the applied active substances is provided after implantation of the medical device in the body. In this way, the coated implants can be used for therapeutic purposes, whereby the active substances applied to the implant are successively released locally at the implant site. Active substances used in dynamic loading for the release of active substances are, for example, hydroxypatite (HAP), fluorapatite, tritium phosphate (TCP), zinc; and/or organic substances such as peptides, proteins, carbohydrates, mono-, oligo- and polysacids, lipid, antibodies, lipoproteins, lipoproteins, glycoproteins, glycoproteins, or proteins, such as DNA, polymers, proteins, proteins, or other substances, as well as antibodies, such as antibodies, lipoproteins, lipoproteins, glycoproteins, or proteins, or proteins, such as proteins, proteins, proteins, or proteins, or proteins, such as proteins, proteins, proteins, proteins, or proteins, or proteins, or proteins.

Pharmacologically active substances or mixtures of substances suitable for the static and/or dynamic loading of coated implantable medical devices as defined in the invention include active substances or combinations of active substances selected from heparin, synthetic heparin analogues (e.g. fondaparinux), hirudin, antithrombin III, drotrecogin alpha; fibrinolytics such as alteplase, plasmin, lysokinases, factor XIIa, prourokinase, urine ketone, anistreptase, streptokinase; thrombocyte-regulating inhibitors such as acylsalicylic acid, ticodamide, dropidamine, abrogenocyl, dextromethyl; corticosteroid, aloproxycinnamide, diclofenac, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydroxycinnamide, dihydrocinnamide, dihydrocinnamide, dihydrocinnamide, dihydrocinnamide, dihydrocinnamide, dihydrocinnamide, dihydrocinnamide, dihydrocinnamide, dihydrocinnamide, dihydrocinnamide, dihydramid, dihydrocinnam, dihydramid, dihydramid, dihydramid, dihydramid, dihydramid, dihydramid, dihydramid, dihydramid, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, dihydram, diNaproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, celecoxib, rofecoxib; cytotoxic agents such as alkaloids and podophyllum toxin such as vinblastin, vincristine; alkylating agents such as nitrosoharrin, nitrogen-loss analogue; cytotoxic antibiotics such as daunorubicin, doxorubicin and other anthracyclines and related substances, bleomycin, mitomycin; antimetabolites such as folic acid, purine or pyrimidine analogue; paclitaxel, trombetaxel, sirolimus; conjugates such as carboplatin, cisplatin or docetaxel; amine, oxytocin, imatinib, imatinib, timodipine, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interferon, interBeta-blockers such as metoprolol, esmolol, propranolol, metoprolol, atenolol, oxprenolol; class III antiarrhythmic agents such as amiodarone, sotalol; class IV antiarrhythmic agents such as diltiazem, verapamil, gallopamil; other antiarrhythmic agents such as adenosine, orciprenalin, ipratropium bromide; agents to stimulate angiogenesis in the myocardium such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), non-viral DNA, viral DNA, endothelial growth factors such as FGF-1, FGF, VEGF, TGF; monoclonal anti-apopril, spiral antipyridine; moepamicin, and other anti-inflammatory agents such as Cytomel, nitripropion, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, Cytomel, CytomelOther antihypertensive agents such as indapamide, co-dergocrinmesilate, dihydroergotoxin methansulfate, cieletanin, bosentan, fludrocortisone; peripherally active alpha receptor blockers such as prazosin, urapidil, doxazosin, bunazosin, terazosin, indoramin; vasodilators such as dihydralazin, diisopropylamine dihydrochloride, minoxidil, nitroprussidium sodium; other antihypertensive agents such as indapamide, co-dergocrinmesilate, dihydroergotoxin methansulfate, cieletanin, bosentan, fludrocortisone; phosphodiesterase inhibitors such as enoxytron, gonadotropin, and antihypertensive agents such as especially adrenergic and dopaminergic substances such as dobutamine, epinephrine, euphrin, norepinephrine, oxytocin, wachin-1, oxycodonephrine, phenylephrine, phenylephrine, phenylephrine, phenylephrine, phenylephrine, phenylephrine, phenylephrine, phenylephrine, phenytophrine, phenylephrine, phenylephrine, phenytophrine, phenylephrine, phenylephrine, phenyl, phenylephthalate, phenyl, phenyl, phenylephthalate, phenyl, phenyl, pheny, phenylephthalate, pheny, pheny, phenylephthalate, pheny, pheny, pheny, pheny, phenylephthalate, pheny, pheny, pheny, pheny, phenylephthalate, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny, pheny,Leuprorelin, triptorelin, gonadorelin, ganirelix, buserelin, nafarelin, goserelin, as well as regulatory peptides such as somatostatin, octreotid; bone and cartilage stimulating peptides, bone morphogenetic proteins (BMPs), especially recombinant BMPs such as recombinant human BMP-2 (rhBMP-2), bisphosphonates (such as risedronate, pamidronate, ibandronate, zoledronic acid, clodronic acid, ethydronic acid, aldendronate, tiludronic acid), fluorides such as dinatrium fluorophosphat, natriuride; calcium fluoride, dihydrochloride; insulin, growth factors and epitoxins such as platelet-derived factor TGF (FIGF-1), platelet-derived factor TGF-2, growth factor interleukin (TIGF-2, TIGF-2, TIGF-II), growth factor interleukin (TIGF-II), growth factor interleukin (TIGF-II), growth factor TIGF-III, growth factor interleukin (TIGF-III), growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF, growth factor TIGF-III, growth factor TIGF-III, growth factor TIGF, growth factor TIGF-III, growth factor TIGF, growth factor TIGF-III, growth factor TIGF, growth factor TIGF-II, growth factor TIGF, growth factor TIGF-II, growth factor TIGF, growth factor TIGF-II, growth factor TIG-TIG-T, growth factor TIG-T, growth factor TIG-TIG-TIG-T, growth factor TIG-T, growth factor TIG-TIG-TIG-T, growth factor TIG-T, growth factor TIG-TThe following are the active substances that may be used in the active substance: monocyte chemotactic protein, fibroblast stimulating factor 1, histamine, fibrin or fibrinogen, endothelin-1, angiotensin II, collagen, bromocriptine, methylsergid, methotrexate, carbon tetrachloride, thioacetamide, and ethanol; also silver (ions), titanium dioxide, antibiotics and anti-infective agents, including beta-lactam antibiotics, such as beta-lactamase sensitive penicillins such as benzylpenicillin (Penicillin G), phenoxymethylpenicillin (Penicillin V); beta-lactamase-resistant tetracycline, such as penicillin, bactericillin, bactericillin, amoxicillin, amoxicillin, amoxicillin, cephalomyephritis, amoxicillin, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephalomyephritis, cephritis, cephalomyephritis, cephalomyephritis, cephritis, cephalomyephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephritis, cephClarithromycin, erythromycin, roxithromycin, spiramycin, josamycin; lincosamides such as clindamycin, lincomycin, gyrase inhibitors such as fluoroquinolones such as ciprofloxacin, ofloxacin, moxifloxacin, norfloxacin, gatifloxacin, enoxacin, fleroxacin, levofloxacin; quinolones such as pipemide acid; sulfonamides such as trimethoxine, sulfadiazine, sulphalenes; glycopeptide antibiotics such as clindamycin, teicoprin; non-peptide antibiotics such as polymyxins such as polycysteine, polymethyl cycloxyxin-B, nitrociclocyte derivatives such as fosforic acid, pentanocyl, tetanocyl; tincyl; fosforic acid, nitrocicloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocycloquin, nitrocyclo, nitrocyclo, nitrocyclo, nitrocyclo, nitrocyclo, nitrocyclo, nitrocyclo, nitrocyclo, nitrocyclo, nitrocyclo, nitrocyclo, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc, nitrocyc,Saquinavir, lopinavir, ritonavir, nelfinavir; amantadine, ribavirin, zanamivir, oseltamivir and lamivudine, and any combination or mixture of these.

The following

Particularly preferred embodiments of the present invention are coated vascular endoprostheses (intraluminary endoprostheses) such as stents, coronarstents, intravascular stents, peripheral stents and the like.

These can be made biocompatible in a simple way by the method of the invention, which can prevent, for example, the residual stenosis commonly seen in percutaneous transluminal angioplasty with conventional stents.

Thus, by immobilizing suitable active substances on porous carbon-containing coatings, in particular paclitaxel, rapamycin or dexamethasone, the local inflammatory response in the vascular wall tissue can be inhibited or suppressed by temporary local release of these active substances. The use and efficacy of such active substances are sufficiently known according to the state of the art. However, their applicability is limited by state of the art coating systems, in particular due to insufficient load capacity leading to insufficient bioavailability, insufficient or incomplete release of these active substances or incompatibilities between coating system and active substance due to undesirable physical or chemical interactions.

In preferred embodiments of the present invention, glassy carbon or composite layers with additive russ particles are produced and activated with layer thicknesses between 80 nm and 10 μm, pore sizes from 5 nm to 1 μm and porosities from 1 to 70% preferably by introduction of fillers and their subsequent removal from the carbon layer or by the addition of russ particles with spherical or ellipsoidal or rod-shaped morphology and particle sizes from 10 nm to 200 nm to form a porous matrix, allowing sufficient absorption of active substances. The surface area of the stent implant is increased to 2000 m2/m3.

In preferred embodiments of the invention, activation of the carbon-containing layer, e.g. with air at elevated temperature, can increase the hydrophilicity of the coating, which further increases the bioavailability and makes the coating more receptive to active substances, particularly hydrophilic active substances.

In particularly preferred embodiments, stents, in particular coronary stents and peripheral stents, are loaded with pharmacologically active substances or mixtures of substances, or with cells or cell cultures, according to the method of the invention.

Heparin, synthetic heparin analogues (such as fondaparinux), hirudine, antithrombin III, drotrecogin alpha, fibrinolytics (alteplase, plasmin, lysokinases, factor XIIa, prourokinase, urokinase, anistreplase, streptokinase), thrombocyte aggregation inhibitors (acetylsalicylic acid, clopidogrel, abciximab, dextrane), corticosteroids (including altimidase, amcinolone, augmented betamethasone, beclomomomidase, ketamine, ketamine, budesonide, cortisone, clomiphene, cloramphenic acid, cloramphenic acid, desoxyran, duloxetine, fluoxetine, fluoxetine, fluoxetine, fluoxetine, fluricone, fluricone, fluricone, fluricone, and other drugs such as hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinones, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucinogens, hallucin, hallucinogens, hallucinogens, hallucin, hallucin, hallucinogens, hallucin, hallucin, hallucin, hallucin, hallucin, hallucin, hallu

For systemic cardiological effects, the activated stents of the invention may be loaded with:

Other antiarrhythmic agents include: Lidocaine, mexiletin, phenytoin, tocainide; Class I C antiarrhythmic agents: propafenone, flecainide acetate) and Class II antiarrhythmic agents (antiarrhythmic agents such as methotrexate, methotrexate, methotrexate, methotrexate, oxprenolol), class III antiarrhythmic agents such as minoxidil, methotrexate, and lidocaine; class I C antiarrhythmic agents such as propafenone, flecainide acetate; class II antiarrhythmic agents such as antiarrhythmic agents such as methotrexate (Methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate); class IV antiarrhythmic agents such as lidocaine, mexiletin, methotrexate, phenytoin, tocainide; class IV antiarrhythmic agents such as propafenone, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methythrin, methythrin, methythrin, methylen, methyroxate, methyroxate, methyroxate, methyphen, methyroxate, methyroxate, methyroxate, methyroxate, methyroxate, methyroxate, methyphen, methyroxate, methyroxate, methyroxate, methyroxate, methyroxate, methyroxate, methy

To increase tissue adhesion, especially in peripheral stents, components of the extracellular matrix, fibronectin, polylysine, ethylene vinyl acetate, inflammatory cytokines such as TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6, growth hormones, and adhesive substances such as cyanoacrylates, beryllium, or silica may be used.

Other suitable substances, systemic and/ or local, are growth factors, erythropoietin.

Hormones may also be provided in the stent coatings, such as corticotropins, gonadotropins, somatropin, thyrotropin, desmopressin, terlipressin, oxytocin, cetorelix, corticorelin, leuprorelin, triptorelin, gonadorelin, ganirelix, buserelin, nafarelin, goserelin, as well as regulatory peptides such as somatostatin and/ or octreotide.

Other embodiments include functionalization by loading the carbon surfaces with cells, such as pluripotent stem cells, endothelial cells or connective tissue cells, which may be obtained from organisms, cultured in the laboratory from cell cultures or genetically modified.

For example, vascular implants with activated carbon layers in a special embodiment can be loaded with endothelial cell cultures by using them as a substrate or as a culture and carrier system for cell cultures in a bioreactor, as described in DE 103 35 131 and WO 2005/02 1462.

For example, nanoporous activated carbon layers of the invention with a surface area of 200 to 3000 m2/m3 can be cultured with endothelial cells, with possible cell densities ranging from 101 to 1016 cells/ml layer volume, preferably from 103 to 1012 cells/ml.

The following are the main components of the system:

In the case of surgical and orthopaedic implants, it may be advantageous to activate the implants with one or more carbon-containing layers so that the layers are macroporous.

In addition, for orthopaedic and non-orthopaedic implants and cardiac valves or artificial heart parts functionalised in accordance with the invention, the same active substances as those used in the stent applications described above may be used for local suppression of cell adhesion, platelet aggregation, complement activation, inflammatory tissue response or cell proliferation, if these are to be loaded with active substances.

In addition, the following agents may be used to stimulate tissue growth, particularly in orthopaedic implants, for improved implant integration: bone and cartilage stimulating peptides, bone morphogenetic proteins (BMPs), especially recombinant BMPs (e. g. recombinant human BMP-2 (rhBMP-2)), bisphosphonates (e. g. risedronate, pamidronate, ibandronate, zoledronic acid, clodronic acid, ethidronic acid, almonic acid, tiludronic acid), fluoride (drinate metfluorophosphate, sodium sulphate), collagen, dihydroxybutyrate. all of these are growth factors and insulin-like substances, in addition to risedronate, pamidronate, ibandronate, zoledronic acid, clodronic acid, ethidronic acid, almonic acid, caludronic acid, fluoride (DNF), methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, met

The Commission shall adopt implementing acts laying down the rules for the application of this Regulation.

In addition, the implants, stents and the like activated in accordance with the invention may be provided with antibacterial anti-infective coatings or impregnations instead of or in addition to pharmaceuticals, using the following substances or mixtures of substances: silver ions, titanium dioxide, antibiotics and anti-inflammatory agents; in particular, beta-lactam antibiotics (beta-lactam antibiotics: β-lactamase sensitive penicillins such as benzylpenicillin (Penicillin G), phenoxymethylpenicillin (Penicillin V); β-lactamase resistant tetracyclin tetracyclin such as bactericillin, penicillin, cepicin; aminoacetylpenicillin such as cepicin; amoxicillin such as methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine, methylamine,Other quinolones include pipemidine, erythromycin, erythromycin, roxithromycin, spiramycin, josamycin, lincosamide (clindamycin, lincomycin), gyrase inhibitors (including fluoroquinolone such as ciprofloxacin, ofloxacin, moxifloxacin, norfloxacin, glitoamines such as enoxacin, fluoroxacin, levoxacin, other quinolones such as pipemidic acid), sulphonamides and trimethoprim (such as sulphonylureazin, virgin sulphate, trimethic), glycoprotein anti-inflammatory drugs (such as vancomycin, telicoprin), family of phenylalanediamine (such as polyimide, ofloxacin, ofloxacin, ofloxacin, ofloxacin, amyl sulphate, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin, ofloxacin,It is also used in the treatment of other viral agents (including zolcitabine, didanosine, zidovudine, tenofovir, stavudine, abacavir; non-nucleoside analogues of reverse transcriptase inhibitors: amprenavir, indinavir, saquinavir, lopinavir, ritonavir, nelfinavir) and other virulence drugs such as amantadine, ribavirin, zanamivir, oseltamivir, lamivudine.

In particularly preferred embodiments of the present invention, the implants of the invention with carbon-containing layers before or after charging can be modified by other agents to suit their chemical or physical properties, such as to modify hydrophilicity, hydrophobicity, electrical conductivity, adhesion or other surface properties. Substances used are biodegradable or non-degradable polymers, such as in the case of biodegradable: collagen, albumin, gelatin, hyaluronic acid, starch, polycarbonate (Methyl polyethylene, Polypropyl polyethylene, Polypropyl polyethylene, Polypropyl methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L-methyl, L

The non-biodegradable materials include: poly (ethylene vinyl acetate), silicone, acrylic polymers such as polyacrylic acid, polymethyl acrylic acid, polyacrylic cyanoacrylate; polyethylene, polypropylene, polyamide, polyurethane, poly (ester urethane), poly (ether urethane), poly (ester urea), poly (ether), poly (ether) such as poly (ethylene oxide, poly (propylene oxide), pluronics, poly (tetramethylene glycol); vinyl polymers such as poly (vinyl) pyrrolidone, poly (vinyl alcohol), poly (vinyl) acetate; poly (phenol).

It is generally accepted that polymers can be produced with anionic (e.g. alginate, carrageenan, carboxymethyl cellulose) or cationic (e.g. chitosan, poly-L-lysine, etc.) or both properties (phosphocyclol).

These polymers can be applied to the surface of the implants and cover them completely or partially.

For example, to modify the release properties of active substances in the implants of the invention, specific pH or temperature-dependent release properties can be obtained by application of other polymers. PH-sensitive polymers are for example Poly (acrylic acid) and derivatives, for example: homopolymers such as Poly (arninocarboxylic acid), Poly (acrylic acid), Poly (methyl acrylic acid) and their co-polymers. The same applies to polysaccharides such as Cellulose acetate phthalate, Hydroxypropyl methyl methyl acetate, Hydroxypropyl Poly (poly) polypropyl acetate, Poly (poly) polypropyl acetate, Poly (poly) polypropyl acetate and Chloramphenic acid, such as N-methyl acetate, N-methyl methyl acetate, L-methyl methyl acetate, L-methyl methyl acetate, L-methyl methyl acetate, L-methyl methyl acetate, L-methyl methyl acetate, L-methyl methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, L-methyl acetate, and N-methyl acetate.

Additional modifications of the porous carbon layer by chemical modification (anionic, cationic) allow for modification of the release, e.g. pH-dependent. Another application is the release of active carrier substances, namely microcapsules, liposomes, nanocapsules, nanoparticles, microcells, synthetic phospholipids, gas dispersions, emulsions, micro-mulsions, nanospheric oxides, etc., which are already adsorbed in the carbon layer and then released by the above mentioned lipid or polycarbonate therapeutically, which does not include the above mentioned polycarbonate, etc.

In the case of additional coating of the porous carbon-containing layers of the invention with additional layers, a distinction can therefore be made between physical barriers such as inert biodegradable substances (poly-1-lysine, fibronectin, chitosan, heparin, etc.) and biologically active barriers. The latter may be sterically inhibiting molecules that are physiologically bioactivated and allow the release of active substances or their carriers. For example, enzymes that mediate the release, activate biologically active substances or bind non-active coatings and lead to exposure to active substances. All mechanisms and properties specifically listed here are applicable to both the primary carbon and layers applied to it in addition.

The release of active substances from the implant can be controlled over a wide range by application of the above-mentioned release modifying polymer layers and/or adaptation of the pore structure of the carbonated layer.

The implants of the invention may also be loaded and functionalized in particular applications with living cells or microorganisms, which may settle in suitable porous carbon-containing layers, and the implant thus settled may 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, so that the cells or microorganisms can be supplied by the organism through the membrane coating.

In this way, for example, the technology of the invention can be used to produce implants containing insulin-producing cells which, after implantation in the body, produce and release insulin depending on the glucose level in the environment.

Claims (34)

1. A method for producing medical implants having functionalized surfaces comprising the following steps:

   a) providing a medical implant with at least one carbon-based layer on at least a part of the surface of the implant;

   b) activating the carbon-based layer by creating porosity;

   c) functionalizing the activated carbon-based layer.
2. The method according to Claim 1, characterized in that the carbon-based layer is selected from pyrolytically produced carbon, vapour-deposited carbon, carbon applied by CVD, PVD or sputtering, diamond-like carbon, metal carbides, metal carbonitrides, metal oxynitrides or metal oxycarbides, as well as any combinations thereof.
3. The method according to Claim 1 or 2, characterized in that the implant consists of a material which is selected from carbon, carbon composite material, carbon fibres, ceramics, glass, plastics, metals, alloys, bone, stone or minerals.
4. The method according to any one of the preceding claims, characterized in that the implant is selected from medical or therapeutic implants such as vascular endoprostheses, stents, coronary stents, peripheral stents, surgical or orthopaedic implants, bone prostheses or joint prostheses, artificial hearts, artificial heart valves, subcutaneous and/or intramuscular implants.
5. The method according to any one of the preceding claims, characterized in that activating the carbon-based layer is performed with suitable oxidizing agents and/or reducing agents.
6. The method according to any one of the preceding claims, characterized in that the carbon-based layer is activated by oxidation with air, oxygen, nitrous oxide, and/or oxidizing acids, optionally at an elevated temperature.
7. The method according to any one of the preceding claims, characterized in that the activation is performed by abrasion.
8. The method according to any one of the preceding claims, characterized in that activating causes the carbon-based layer to become porous, preferably macro porous, with pore diameters in the range of 0.1 to 1000 µm, optionally also by pre-structuring the substrate.
9. The method according to any one of the preceding claims, characterized in that the activation causes the carbon-based layer to become nano porous, preferably with a pore diameter of 1 nm to 1,000 nm.
10. The method according to any one of the preceding claims, characterized in that the activated porous carbon-based layer is subsequently densified and/or sealed by CVD and/or CVI of volatile organic substances.
11. The method according to any one of the preceding claims, characterized in that the functionalization of the activated carbon-based layer comprises loading the layer with at least one substance selected from pharmacologically active agents, linkers, microorganisms, plant or animal cells including human cells or cell cultures and tissue, minerals, salts, metals, synthetic or natural polymers, proteins, peptides, amino acids, solvents, ions, cations, in particular metal cations such as cobalt, nickel, copper, zinc cations, antibodies, calmodulin, chitin, cellulose, sugars, amino acids, glutathione, streptavidin, Strep-Tactin or other mutants or S protein, dextrans, as well as their derivatives, mixtures and combinations.
12. The method according to any one of the preceding claims, characterized in that the functionalization is performed by adsorption of substances corresponding to affinity tags in and/or on the carbon-based layer, whereby the corresponding substances are selected so that they can enter into a bond with the affinity tags.
13. The method according to Claim 11 or 12, characterized in that the substance(s) is/are applied to and/or immobilized on the carbon-based layer by adsorption, absorption, physisorption, chemisorption, electrostatic covalent bonding or non-covalent bonding.
14. The method according to Claim 11, characterized in that the at least one substance is essentially permanently immobilized on the carbon-based layer(s).
15. The method according to Claim 11, characterized in that the at least one substance applied to the carbon-based layer, in particular a pharmacological active ingredient, can be released from the layer in a controlled manner.
16. The method according to Claim 15, characterized in that the pharmacologically active agents are incorporated into microcapsules, liposomes, nano capsules, nano particles, micelles, synthetic phospholipids, gas dispersions, emulsions, micro emulsions or nano spheres which are adsorbed in the pores or on the surface of the carbon-based layer and can then be released therapeutically.
17. The method according to any one of Claims 14 through 16, characterized in that a coating which influences the release of the active ingredient is also applied, the coating being selected from pH-sensitive and/or temperature-sensitive polymers and/or biologically active barriers such as enzymes.
18. The method according to any one of the preceding claims, characterized in that the functionalization includes applying biodegradable and/or absorbable polymers such as collagen, albumin, gelatin, hyaluronic acid, starch, celluloses such as methyl cellulose hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose phthalate; casein, dextrans, polysaccharides, fibrinogen, poly(D,L-lactide), poly(D,L-lactide-co-glycolide), poly(glycolide), poly(hydroxybutylate), poly(alkyl carbonate), poly(orthoester), polyester, poly(hydroxyvaleric acid), polydioxanone, poly(ethylene terephtalate), poly(malic acid), poly(tartronic acid), polyanhydrides, polyphosphazenes, poly(amino acids) and their copolymers, optionally before or after loading with active agents.
19. The method according to any one of the preceding claims, characterized in that the functionalization includes applying non-biodegradable and/or non-absorbable polymers such as poly(ethylene vinyl acetate), silicones, acrylic polymers such as polyacrylic acid, polymethyl acrylic acid, polyacryl cyanoacrylate; polyethylenes, polypropylenes, polyamides, polyurethanes, poly(ester urethanes), poly(ether urethanes), poly(ester ureas), polyethers, polyethylene oxide, polypropylene oxide, pluronics, polytetramethylene glycol; vinyl polymers such as polyvinylpyrrolidones, poly(vinyl alcohols), poly(vinyl acetate phthalate), as well as their copolymers.
20. An implant having a functionalized surface, producible according to any one of the preceding claims.
21. The implant according to Claim 20, characterized in that it is made of metals such as stainless steel, titanium, tantalum, platinum, gold, palladium, alloys, in particular shape memory alloys such as nitinol or nickel titanium alloys, or carbon fibres, solid carbon material or carbon composites.
22. The implant according to any one of Claims 20 or 21, comprising multiple carbon-based layers optionally loaded with active ingredient.
23. The implant according to any one of Claims 20 through 22, further comprising anionic or cationic or amphoteric coatings selected from alginate, carrageenan, carboxymethyl cellulose, poly(meth)acrylates, chitosan, poly-L-lysines and/or phosphorylcholine.
24. The implant according to any one of Claims 20 through 22, wherein the implant is loaded with at least one pharmacologically active agent.
25. The implant according to Claim 24, wherein the implant is an active agent coated stent.
26. The implant according to Claim 24 or 25, wherein the implant comprises a stent having a carbon-based layer of pyrolytically produced carbon, vaper deposited carbon, carbon deposited with the use of CVD, PVD or sputtering, diamond-like carbon, metal carbides, metal carbonitrides, metal oxynitrides or metal oxycarbides, and combinations thereof.
27. The implant according to any one of claims 24 through 26, wherein the at least one active agent selected from heparin, synthetic heparin-analogues, hirudin, antithrombin III, drotrecogin-alpha, fibrinolytics, thrombocyte aggregation inhibitors, corticosteroids, so called non-steroidal anti-inflammatory drugs, or cytostatics.
28. The implant according to any one of Claims 24 through 27, wherein the active agent comprises paclitaxel.
29. The implant according to any one of Claims 24 through 28, wherein the at least one pharmacologically active agent applied to the carbon-based layer can be controllably released from the layer.
30. The implant according to any one of Claims 24 through 29, comprising markers or contrast agents for localizing the coated implant in the body.
31. The implant according to any one of Claims 24 through 30, comprising therapeutic or diagnostic amounts of radioactive emitters.
32. The implant according to any one of Claims 20 through 23, being the form of an orthopaedic bone prosthesis or joint prosthesis, a bone substitute or a vertebral substitute in the thoracic or lumbar region of the spinal column.
33. The implant according to Claim 24, wherein the implant is an active agent depot which can be inserted subcutaneously and/or intramuscularly, providing for a controlled release.
34. The implant according to any one of Claims 20 through 33, comprising applied and/or incorporated microorganisms, viral vectors, cells or tissue.