MX2007008051A - Combination comprising an agent providing a signal, an implant material and a drug - Google Patents

Abstract

The present invention relates to a combination for use in implantable medical devices, comprising at least one signal generating agent, which in a physical, chemical and/or biological measurement or verification method leads to detectable signals, at least one material for manufacture of an implantable medical device and/or at least one component of an implantable medical device, and at least one therapeutically active agent, which in an animal or human organism fulfills directly or indirectly a therapeutic function. The invention further relates to implantable medical devices comprising such a combination, and to methods for the determination of the extent of active agent release from implantable medical devices comprising such a combination.

Description

COMBINATION COMPRISING AN AGENT TO PROVIDE A SIGN, AN IMPLANT MATERIAL AND A DRUG Previous applications, and all documents cited therein or during their follow-up ("cited documents of the application") and all documents cited or referred to in the cited documents of the application, and all documents cited or those referenced herein ("documents cited herein"), and all documents cited or those referencing documents cited herein, together with any manufacturer's instructions, descriptions, product specifications, and sheets of product for any products mentioned herein or in any document incorporated herein by reference, are incorporated herein by reference, and may be employed in the practice of the invention. The mention or identification of any document in this application is not an admission that such document is available as the prior art of the present invention. It is noted that in this disclosure and in particular in the claims and / or paragraphs, terms such as, for example, "comprises", "is understood", "comprising" and the like can have the meaning attributed to them in the United States patent law; for example, they may mean "includes", "includes", "including", and the like; and that terms such as, for example, "consisting essentially of" and "consists essentially of" have the meaning attributed to them in the patent law of the United States, for example, admit elements not explicitly mentioned, although they exclude elements that were found in the prior art or that affect a basic or novel feature of the invention. The embodiments of the present invention are set forth herein or are obvious from the detailed description and are encompassed by the same. The detailed description, given by way of example, which is not intended to limit the invention only to the specific embodiments described, can be better understood together with the accompanying drawings. The present invention relates to compositions or combinations of materials for non-degradable and degradable implantable medical devices with respect to the establishment of their characteristics for signal generation and the control of their therapeutic efficacy, as well as to a method for the control of degradation of degradable or partially degradable medical devices, compounds similar to these, based on their generation of the signal, and to a method for monitoring their therapeutic efficacy and / or the release of therapeutically active ingredients from these devices. Ultra-short-term implants, short-term implants such as orthopedic-surgical screws, plates, nails or catheters and needles for injection, as well as long-term implants similar to joint prostheses, artificial heart valves, prostheses vascular, endografts is also the subcutaneous or intramuscular types of implants are made of different types of materials, which are selected according to their specific biochemical and mechanical characteristics. These materials must be suitable for permanent use in the body, without releasing toxic materials and have specific mechanical and biochemical characteristics. The manufacture of these implants with new materials is increasingly allowing the functionality of the implants to be improved. In particular in this regard, systems are used that are partially degradable / soluble or totally (bio-) degradable. A significant problem with these implants is that with the use of new materials, limited physical characteristics are provided, as in the methods for medical imaging, for example during the application, monitoring or control of the correct anatomical position or for other diagnostic or therapeutic reasons, for example, radiopaque or diamagnetic properties, paramagnetic, super paramagnetic or inadequate ferromagnetic. In particular, biodegradable materials such as for example polylactonic acid and its derivatives, collagens, albumin, gelatin, hyaluronic acid, starch, cellulose and the like are typically radiolucent. This also applies for example to polyurethane-like polymers, poly (ethylene vinyl acetate), silicones, acrylic polymers similar to polyacrylic acids, polymethylacrylic acid, polyacrylcyanoacrylate; polyethylene, polypropylene, polyamide, poly (urethane ester), poly (urethane ether), poly (urea ester), polyethelene-like polyethers, polypropylene oxide, pluronics, polytetramethylene glycol; vinyl polymers similar to polyvinylpyrrolidone, polyvinyl alcohol, poly (vini lacetatof talato); Parilenos, based on the material properties are excellently suited for biomedical applications. In particular they are also suitable for non-resorbable medical implants, which consist of polymers or composite materials and mainly are only weakly radiopaque or radiolucent. In contrast to this, there are other material requirements, which are exposed to diagnosis by means of magnetic resonance tomography methods. In contrast to conventional X-ray diagnostics, which are based on the application of ionizing radiation, magnetic resonance tomography (MRI) is not based on ionizing radiation but rather on the production of a magnetic field, raph energy. iof recuence, and gradients of magnetic fields. The signals produced are based predominantly on the measured times of relaxation TI (longitudinal) and T2 (transverse) of excited protons and proton density in tissues. In this way, contrasting materials are typically applied, in order, for example, to influence the proton densities and / or relaxation times produced in tissues or tissue sections, for example, the TI, T2 or proton densities. Another problem is that implantable medical devices are typically modified to improve their properties for imaging. For example, radiopaque filling materials are added to the polymeric materials to improve their visibility. Along with this, typical fillers are BaS04 / bismuth sub carbonate or tungsten-like metals, or other bismuth salts similar to bismuth sub nitrate and bismuth oxide [see U.S. Patent 3,618,614]. Other types of modifications are, for example, the incorporation of halogenated compounds or groups in the polymer matrix. As examples of this, US Patents 4,722,344, 5,177,170 and 5,346,981 are cited herein. The disadvantages of these filling materials are, for example, that fundamental material properties are altered, such as, for example, optical properties, mechanical strength, flexibility, resistance to acid and alkali. Another disadvantage of the disclosed methods is that for example in general a minimum amount of radiopaque fillers or halogenated components must be added to produce any significant radiopaque properties, however the solubility of these fillers in the polymer precursors is limited. Definitely all along there are comparable problems, in the case for example of materials for implant with metal base, intravascular devices, which are in the body temporarily or permanently. As an example of these devices, stents, which typically are made of metals, should be cited. The application of stents is a necessarily invasive method where it is of significant clinical importance that the stent is correctly placed. For this, visualization is customary by means of a method for imaging, for example a method based on X-rays both during and after the application. Based on the alloys used and the low weights of the material, with thin walls or low material resistances, visibility is only weak when it exists in its entirety. Certain radiopaque components that absorb ionizing radiation, also those metal alloys that are biocompatible, can be used according to the prior art, however these typically have a negative impact on the mechanical and (bio) chemical properties. Other methods of the prior art are based on the application of band markers, which are placed by pressure, are stuck or are electrochemically deposited radiopaque materials or metallic coatings. The disadvantages of these solutions are, for example, that the band marker can be displaced or completely removed during application, in addition to damaging the tissue of the internal wall of the container mechanically and traumatizing the surrounding tissue, if they are sharp or are bonded to the tissue. external edges of the implant. In the worst case, band markers cause complications that can make the implant useless. In addition, these bands can lead to rough surfaces that can subsequently lead to the development of thrombosis. Other prior art methods use metal based coatings, which can be produced by C D, PVD or electrochemical methods. However, in order to obtain sufficient radiopaque coatings, the thickness of the coating to produce adhesion on metal substrates is not sufficient to satisfy the mechanical demands placed on these implants, which are insufficient to ensure the safety and efficacy of this implant. On the other hand, electrochemical methods are only adequately limited, since deposition of coatings is typically associated with rough surfaces with worsening of heme-compatibility, or even, depending on the underlying substrate, for brittleness, corrosion or lead to another weakening of the properties of the underlying material of the substrate. These limitations are typically known for alloys with a titanium base, whose mechanical properties deteriorate significantly as a result of the brittleness and therefore the functionality of the implant. Implantations of ion-assisted radiopaque materials have the disadvantage that they are extremely expensive, and have only limited applicability, especially since evaporation is carried out leaving the molten metal, in an amount that exceeds several times the actual amount when placed, the deposition and growth of the coating becomes irregular and difficult to control and for example makes it difficult to perform the implantation of alloys from fusions in a controlled manner due to the different evaporation rates of the elements. Furthermore, implantable medical devices are known which contain the active ingredients in the body for implantation or in the parts of the body for implantation or in the coatings. Through the complete or partial degradation or degradation of the implant body, the implant body parts or the coatings, the active ingredients are released. These implantable medical devices are known to those skilled in the art under the designation "combinatorial devices". It is particularly desired, for non-degradable and degradable materials containing active ingredients, to control the release of the active ingredients in vivo. A review of the prior art shows that these devices combined with the active ingredients do not allow an effective control of the release of the active ingredient from the outside of the body, because the active ingredients used by themselves do not have in their elimination any of the properties for signal generation. Also, if the materials used in which the active ingredients are degradable or soluble incorporated in the presence of physiological fluids, their rate of degradation does not correlate with the release of the active ingredients, even if the matrix materials are visible by the methods for signal detection. An example of this, especially in view of the prior art, is represented by endoprostheses for drug elution, whose release of active ingredients is determined on the basis of expensive in vitro and in vivo studies in very expensive pre-clinical studies. NeverthelessIn these clinical studies, information on the clinical usefulness of the devices can be collected only by means of indirect parameters such as, for example, rates of restenosis, thickening of the vessel wall in question, the ability to penetrate, etc. ex post, months after implantation. For the actual limitations with respect to the control of the release of the active ingredient, reference is made here to Schwart et al., Circulation. 2002; 106: 1867. Therefore, there is a need for medical implants that are detectable for diagnostic and therapeutic purposes during or after their application by methods of imaging, which are based on ionizing radiation, radiofrequency radiation, fluorescence or luminescence, or methods with base in sound and resemblance. In particular there is a need for visible implants in methods for the production of images that are totally or partially biodegradable or bioerodible, and the rate of degradation in correspondence with methods for non-invasive measurement and detection, for example, the method for production of images, is controllable with respect to residence time and allows a correlation between the effectiveness of the implant and the therapeutic result with respect to the acquisition of implantation / tissue limits and new tissue growth.

BRIEF DESCRIPTION OF THE INVENTION Therefore, the present invention in one aspect provides implants that will be visible by the methods for producing images, which can preferably be made visible at the same time as much as possible for the methods for producing images. based on different physical principles. The embodiments of the present invention allow control of the correct anatomical placement of an implantable medical device in situ during the application, conventionally by means of radiographic methods, but also for the monitoring and supervision of therapeutic efficacy, with the use of methods for base detection without causing stress or non-invasive for example based on MRI. In addition, the invention provides the assemblies of implantable medical devices, which contain therapeutically active ingredients and release them in a controllable manner, for example, since for the degradable or partially degradable components the degree of degradation can be correlated with the degree of release of the Therapeutically active ingredients, or, as for the implantable devices that release the non-degradable active ingredient, the active ingredient is coupled to a signal producing agent and the depletion of signals in the device or parts of the device indicates the degree of release of the active ingredients.

Also, in additional aspects, the present invention allows to control the release of active ingredients from an implant, to detect locally the enrichment of the active ingredients, which are released from an implantable medical device, in the specific compartments of the organism, organs, tissues or cells, especially in specific cell types. Additionally, the present invention provides methods for implantable medical devices whose therapeutic efficacy can be controlled with or without the release of the active ingredient by enriching signal-producing agents in the organism, organ, tissue or cell compartments, especially in specific cell types, where these already have the inherent properties for signal generation, or are only transformed in vivo in the agents for signal generation by biological mechanisms. This can be preferred in a special way, if for example an implantable medical device is applied as a tissue substitute in malignant tissue, and it changes after metastasis or tumor removal, and satisfies the purpose, the release of the agents for generation of signal, recurrence in the immediate or communicable surroundings of the implant by means of selective enrichment, around for example through target groups, to make them visible in this altered cell or tissue types. Also, the present invention provides methods that make it possible not to deteriorate the composition of the implant material through the mixing of detectable substances which thereby limit or even destroy the functionality. In one aspect, the present invention provides a composition or combination for implantable medical devices or components of implantable medical devices, which can be adjusted with respect to properties for signal generation thereof. In a further aspect, the invention provides a composition or combination for implantable medical devices that can be adjusted with respect to the identification period, i.e. the temporary availability of the detectable properties. In a still further aspect, the invention provides a composition or combination for implantable medical devices that is detectable by different measurement and detection methods.

Additionally, an aspect of the invention is to provide a composition or combination for implantable medical devices that allows to detect the variation of the release of therapeutically active ingredients by means of methods for signal generation., especially the release of therapeutically active ingredients from the implantable medical devices, or from the components of the implantable medical devices or the enrichment of the active ingredients that are released from the implantable medical devices or from the components of the implantable medical devices in the compartments of the organism, organs, tissues or tissue or cell types, or both. A further aspect of the invention provides a composition or combination for implantable medical devices that allows to control the effectiveness of the implant, preferably through measurement and detection methods that make visible the limits of the implant-weave, or by means of the release of agents for signal generation and / or enrichment in the compartments of the organism, organ, tissues or tissue or cell types, preferably in the immediate vicinity of the implanted medical device. A still further aspect of the invention provides a composition or combination for implantable medical devices that release agents for signal generation for diagnostic and / or therapeutic purposes after insertion into an animal or human body. In a preferred embodiment of this aspect, the signaling and therapeutic / diagnostic agents are released virtually simultaneously, and more preferably the agents are coupled or joined together. In a further aspect, the invention provides a composition or combination for implantable medical devices or components of implantable medical devices, which allows the realization of the creation of the properties for signal generation, that is, to adjust with them in whose methods for measuring and detecting the device or its components are detectable, or to be installed if the release of the agents for signal generation and / or therapeutically active ingredients results directly from the release of the implantable medical device or the components of the implantable medical devices , that is, resulting in a depletion of the agents for signal generation in the device or the components of the device, or follows indirectly, in this way through enrichment in the compartments of the organism, organs, tissues or tissue types. or cell phones or both. In a still further aspect, the present invention provides a method for controlling the degradation of degradable or partially degradable medical devices, compounds similar to these, based on their generation of signal, and a method for monitoring their therapeutic efficacy and / or the release of therapeutically active ingredients from these devices. In a further aspect, the invention provides a method, which makes it possible to determine the degree of release of the active ingredients from an implantable medical device or a component of an implantable medical device, and makes available a method that makes possible the determining the degree of enrichment of the active ingredient of the active ingredients that are released from an implantable medical device or a component of an implantable medical device. According to one embodiment, the invention provides the following combination comprising: a. at least one agent for signal generation, which leads directly or indirectly to detectable signals in a method for physical, chemical and / or biological measurement or detection, b. at least one material for the preparation of an implantable medical device and / or at least one component of an implantable medical device, c. at least one therapeutically active ingredient, which either directly or indirectly satisfies a therapeutic function in an animal or human organism and is released directly or indirectly in an animal or human organism from an implantable medical device or a component of the implantable medical device. In another modality, the invention provides an implantable medical device or a component thereof, comprising at least one agent for signal generation and at least one therapeutically active agent as will be defined hereinafter. In a preferred embodiment, the agents for signal generation and the therapeutic agents can be released practically simultaneously from the device, after their insertion into the human or animal body. In a further embodiment, the present invention includes a combination for the manufacture of implantable medical devices, comprising a first and a second agent for signal generation, which directly or indirectly lead to detectable signals in a method for physical or chemical measurement or verification. and / or biological, wherein the first agent in a method, in which the second agent that leads to detectable signals is not essentially detectable. Preferably, these combinations as mentioned above can be used in the manufacture of implantable medical devices for insertion into the human or animal body, for implants supplying drugs and the like, for example as a coating or a component of a coating of the device, or as at least a part or the construction material of the device itself. In a further embodiment, the present invention is directed to a method for determining the degree of release of an active agent from a fully or partially degradable or soluble implantable medical device, or a component thereof, the device comprises at least one agent for signal generation, which leads directly or indirectly to detectable signals in a method for physical, chemical and / or biological measurement or verification, especially in a method for imaging, and at least one therapeutically active agent that will be released in an organism human or animal, and wherein the device at least partially releases the therapeutically active agents together with the signal generating agents in the presence of physiological fluids, for example after the insertion of the device into a human or animal body, and wherein the The degree of release of the active agent can be determined by detecting the agent for generation of signal released with the use of non-invasive methods for image formation. In a still further embodiment, the present invention is directed to a method for determining the degree of release of an active agent from a non-degradable implantable medical device or a component thereof, manufactured by the use of a combination, comprising a agent for signal generation, which directly or indirectly leads to detectable signals in a method for physical, chemical and / or biological measurement or verification, especially in a method for imaging, as well as a therapeutically active agent that will be released in a human or animal organism, and wherein the degree of release of the active agent can be determined by detecting the agent for signal generation released with the use of non-invasive methods for imaging. Preferably, microspheres, optionally comprising metals and / or drugs, intended for direct injection or incorporation into the human or animal body are excluded from the embodiments of the present invention.

Material for signal generation According to the invention, the material for signal generation can be selected from inorganic, organic or inorganic-organic compounds that are degradable, partially degradable or non-degradable. Signal generation materials should be understood as those in which physical, chemical and / or biological measurement and verification methods lead to detectable signals, for example in methods for producing images. It is unimportant for the present invention if the signal processing is carried out exclusively for diagnostic or therapeutic purposes. Typical imaging methods are for example radiographic methods, which are based on ionizing radiation, for example conventional X-ray methods and methods for scattering X-ray based images such as for example computed tomography, tomography for neutron transmission , radiofrequency magnetization such as, for example, magnetic resonance tomography, in addition by means of radionuclide-based methods such as for example scintigraphy, Computed Tomography by a Single Photon Emission (SPECT), Computed Tomography by Positron Emission (PET), methods with base in ultrasound or luoroscopic methods or methods based on luminescence or fluorescence such as, for example, Intravasal Fluorescence Spectroscopy, Raman Spectroscopy, Fluorescence Emission Spectroscopy, Impedance Spectroscopy Electrical, colorimetry, optical coherence tomography, etc., as well as Electronic Spin Resonance (ESR), Radio Frequency (RF) and Microwave Laser and similar methods.

The agents for signal generation can be based on metals from the group of metals, metal oxides, metal carbides, metal nitrides, metal oxynitrides, metal carbonitrides, metal oxycarbons, metal oxynitrides, metal oxycarbonates, metal hydrides, metal alkoxides, metal halides, inorganic or organic metal salts, metal polymers, metallocenes, and other organometallic compounds, selected from powders, solutions, dispersions, suspensions, emulsions. Preferred metal-based agents are in particular nanomorphic nanoparticles from 0-valent metals, metal oxides or mixtures thereof. The metals or metal oxides used can also be magnetic; the examples are - without excluding other metals - iron, cobalt, nickel, manganese or mixtures thereof, for example mixtures of iron-platinum, or as an example for oxides of magnetic metal, iron oxide and ferrites. It may be preferred to use semiconductor nanoparticles, examples of which are semiconductors of group II-VI, group III-V, group IV. Group II-VI semiconductors are for example MgS, gSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SrTe, BaS, BaSe, BaTe, ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, HgS, HgSe, HgTe or mixtures thereof. Examples of group III-V semiconductors are for example GaAs, GaN, GaP, GaSb, InGaAs, InP, InN, InSb, InAs, AlAs, AIP, AISb, AIS, and mixtures thereof are preferred. Germanium, lead and silicon are selected as examples of group IV semiconductors. Semiconductors can also contain mixtures of semiconductors from more than one group, all the groups mentioned above are included. In addition, it may be preferred to select complex nanoparticles formed with a metal base. Included herein are the so-called Core-Shell configurations, as explicitly described by Peng et al., "Epitaxial Growth of Highly Luminescent CdSe / CdS Core / Shell Nanoparticles with Photo Stability and Electronic Accessibility", Journal of the American Chemical Society, (1997) 119: 7019-7029, and is explicitly included herein as a reference. Semiconductor nanoparticles, which form a core with a diameter of 1-30 nm, are preferred herein., especially 1-15 nm, over which other semiconductor nanoparticles are crystallized in 1-50 monolayers, especially 1-15 monolayers are preferred. In this case the core and the liner may be present in any desired combinations as described above, in special embodiments, CdSe and CdTe are preferred as the core and CdS and ZnS as the liner. In a special embodiment, the nanoparticles to produce signal have absorption properties for radiation in regions with wavelength of gamma rays up to microwave radiation, or have the property of emitting radiation, especially in the variation of 60 nm or less, where through the corresponding selection of particle size and the diameter of the core and the forum it may be preferred to adjust the emission of quanta of light in variations of 20 to 1000 nm or to select mixtures of these particles that emit quanta of different wavelengths if they are exposed to the radiation of them. In a preferred embodiment, the selected nanoparticles are fluorescent, especially without extinction. In addition, the metal-based agents for producing signals can be selected from salts or metal ions, which preferably have paramagnetic properties, for example lead (II), bismuth (II), bismuth (III), chromium (III), manganese (II), manganese (III), iron (II), iron (III), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), or ytterbium (III), holmium (III) or erbium (III) and the like. Based on particularly pronounced magnetic moments, gadolinium (III), terbium (III), dysprosium (III), holmium (III) and erbium (III) are especially preferred. In addition, radioisotopes can be selected. Examples of some applicable radioisotopes include H 3, Be 10, O 15, CA 49, Fe 60, In 111, Pb 210, Ra 220, Ra 224 and the like. Typically these ions are present as chelates or complexes, where for example they are used as chelating agents or ligands for lanthanides and paramagnetic ion compounds such as for example diethi lentriamin pentaacetic acid ("DTPA"), ethylenediamine tetra acetic acid ( "EDTA"), or tetraazacyclododecan-N, N ', N ", N'" -tetraacetic acid ("DOTA"). Other typical organic complexing agents are published for example in Alexander, Chem. Rev. 95: 273-342 (1995) and Jackels, Pharm. Med. Imag, Section III, Chap. 20, p645 (1990). Other chelating agents that can be used in the present invention are found in U.S. Patents 5,155,215, 5,087,440, 5,219,553, 5,188,816, 4,885,363, 5,358,704, 5,262,532, and Meyer et al., Invest. Radiol. 25: S53 (1990), further US Patents 5,188,816, 5,358,704, 4,885,363, and 5,219,553. The salts and chelates of the group of lanthanides with the atomic numbers 57-83 or transition metals with the atomic numbers 21-29, or 42 or 44 are especially preferred. Especially preferred are compounds containing perfluoroalkyl paramagnetics which for example they are described in the German patents disclosed to the public DE 196 03 033, DE 197 29 013 and in WO 97/26017, which according to the invention are incorporated therein, by additional reference to the substances containing perf luoroalqui the diamagnetic of the general formula: R < PF > -L < II > -G < III > , where R < PF > represents a perfluoroalkyl group with 4 to 30 carbon atoms, L < II > means a linker and G < III > means a hydrophilic group. The linker L is a direct bond, a -S02- group or a straight or branched carbon chain with up to 20 carbon atoms which can be substituted with one or more -OH groups, -C00 < - > , -S03- and / or if necessary one or more groups -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR-, -NRCO-, -S02-, -PO4-, -NH-, -NR-, an aryl ring or contains a piperazine, wherein R means an alkyl group of Ci to C20, which again may contain and / or have one or a plurality of atoms of 0 and / or be replaced with groups -C00 < - > or S03-. The hydrophilic group G < III > it can be selected from a mono or disaccharide, one or a plurality of groups -C00 < - > or -S03 < - > , a dicarboxylic acid, an isophthalic acid, a picolinic acid, a benzenesulonic acid, a tertiary hydrohydrandicarboxylic acid, a 2,6-pyrimidicarboxylic acid, a quaternary ammonium ion, an aminopolycarboxylic acid, a aminodipolyethylene glycol sulfonic acid, an amino polyethylene glycol group, a S02 - (CH2) 2 -OH group, a polyhydroxyalkyl chain with at least two hydroxyl groups or one or a plurality of polyethylene glycol chains having at least two glycol units, where the polyethylene glycol chains are terminated by a -OH or -0CH3- group, or similar bonds. In this regard, published German patent DE 199 48 651 is explicitly incorporated by reference in the invention.

It may be preferred in special modalities to select paramagnetic metals in the form of metal complexes with phthalocyanines, especially as described in Phthalocyanine Properties and Applications, Vol. 14, C. Leznoff C. and A. B. P. Lever, VCH Ed. , where as examples to be mentioned are octa (1, 4, 7, 10 - tetraoxaundecil) Gd- phtaloe ianiña, octa (1, 4, 7, 10 - tet raoxaundec il) Gd- f talocyanin, octa (1,4,7,10-tetraoxaundecyl) Mn- f talocyanin, octa (1, 4.7, 10-tetraoxaundecyl) Mn- f talocyanin, as described in the US 2004214810 and with the present explicitly as reference. In addition, it may be preferred to select from super-paramagnetic, ferromagnetic or ferrimagnetic signal generating agents. For example, among the magnetic metals, alloys are preferred, among ferrites similar to gamma iron oxide, magnetites or cobalt-, nickel- or manganese-ferrites, the corresponding agents are preferably selected, especially the particles as described in US Pat. WO83 / 03920, WO83 / 01738, WO85 / 02772 and WO89 / 03675, in U.S. Patent 4,452,773, U.S. Patent 4,675,173, in WO88 / 00060 as well as U.S. Patent 4,770,183, in US Pat. WO90 / 01295 and in WO90 / 01899, which are explicitly incorporated by reference, and others. Furthermore, magnetic, paramagnetic, diamagnetic or super-paramagnetic metal oxide crystals having diameters of less than 4000 Angstroms as the non-organic degradable agents are especially preferred. Suitable metal oxides can be selected from iron oxide, cobalt oxides, indium oxides or the like, which provide properties suitable for signal production and which have especially biocompatible or biodegradable properties. Preferred are crystalline agents of this group having diameters less than 500 Angstroms. These crystals can be covalently or non-covalently associated with macromolecular species and are modified as the metal-based signal generation agents described above. In addition, paramagnets containing zeolite and gadolinium-containing nanoparticles are selected from polyoxometalates, preferably from lanthanides, (eg, K9GdW10O36).

It is preferred to limit the average size of the agents to produce magnetic signals at a maximum of 5 μp? to optimize the properties for image production, and it is especially preferred that the particles for producing magnetic signals be from 2 nm to 1 μ ??, more preferably from 5 nm to 200 nm. Agents for the production of super paramagnetic signals can be selected, for example, from the group of so-called SPIOs (super paramagnetic iron oxides) with a particle size greater than 50 nm or from the group of USPIOs (ultra paramagnetic iron oxides). small) with particle sizes less than 50 nm. According to the invention, it is possible to select the agents for generating signals from the group of endohedral hrybenes, as set forth, for example, in US Pat. No. 5,688,486 or WO 9315768, which are incorporated by reference. It is further preferred to select fullerene derivatives and their metal complexes. Especially preferred are fullerene species, which comprise carbon groups having 60, 76, 78, 82, 84, 90, 96 or more carbon atoms. A general perspective of these species can be deduced from European patent 1331226A2 and is explicitly incorporated herein by reference. In addition, metal fullerenes or endocardic carbon-carbon nanoparticles with arbitrary metallic base components can also be selected. In particular, these endohedral fillers or endometal fulerenes are preferred, which, for example, contain rare earths, such as, for example, cerium, neodymium, samarium, europium, gadolinium, terbium, dysprosium or holmium. In addition, it would be especially preferred to use metal nanoparticles coated with carbon, such as, for example, carbides. The choice of nanomorphic carbon species is not limited to fullerenes, because it may be preferred to select from other nanomorph carbon species such as, for example, nanotubes, onions, etc. In another embodiment it may be preferred to select fullerene species of non-endohedral or endohedral forms, containing halogenated groups, preferably iodinated, as set forth in U.S. Patent 6,660,248 which is incorporated herein by reference. In certain embodiments, mixtures of these agents are also used for signal generation of different specifications, depending on the desired properties of the properties of the material for generation of wanted signals. The agents for producing signals used in general can have a size of 0.5 nm to 1000 nm, preferably 0.5 nm to 900 nm, especially from 0.7 to 100 nm. In this regard metal-based nanoparticles can be provided as a powder, in polar, non-polar or ampholylic solutions, dispersions, suspensions or emulsions. The nanoparticles can be easily modified based on their large surface at volume proportions. The nanoparticles that will be selected for example can be modified non-covalently by means of hydrophobic ligands, for example with trioctylphosphine, or are modified covalently. Examples of covalent ligands are thiol fatty acids, fatty amino acids, fatty acid alcohols, fatty acids, fatty acid ester groups or mixtures thereof, for example oleic acid and oleylamine. According to the invention, the agents for signal production can be encapsulated in micelles or liposomes with the use of amphiphilic components, or they can be encapsulated in polymeric linings, wherein the micelles / liposomes can have a diameter of 2 nm to 800 nm, preferably from 5 to 200 nm, especially from 10 to 25 nm are preferred. The size of the micelles / liposomes, without committing to a specific theory, depends on the number of hydrophobic and hydrophilic groups, the molecular weight of the nanoparticles and the number of aggregation. In aqueous solutions, the use of branched or unbranched amphiphilic substances is especially preferred., to achieve the encapsulation of the agents for signal generation in 1 iposomes / micelles. The hydrophobic core of the micelles thus contains in a preferred embodiment a multiplicity of hydrophobic groups, preferably between 1 and 200, especially between 1 and 100 and most preferably between 1 and 30 according to the desired adjustment of the micellar size. The hydrophobic groups preferably consist of hydrocarbon groups or residues, or residues containing silicon, for example polysiloxane chains. In addition, they can preferably be selected from hydrocarbon-based monomers, oligomers and polymers, or from lipids or phospholipids or comprise combinations thereof, in particular glyceryl esters such as, for example, phosphatidyl ethanolamine, phosphatidyl choline, or polyglycolides, polylactides. , polymethacrylate, polyvinylbutylether, polystyrene, polyphenyl lopentadieni lmeti Inorbornene, polyethylenepropylene, polyethylene, polyisobutylene, polysiloxane. In addition, hydrophilic polymers are also selected for encapsulation in micelles, especially polystyrene sulfonic acid, poly-N-alkylvinylpyridinium halides, poly (meth) acrylic acid, polyamino acids, poly-N-vinylpyrrolidone, polyhydroxyethyl methacrylate, polyvinyl. ether, polyethylene glycol, polypropylene oxide, polysaccharides similar to agarose, dextran, starches, cellulose, amylose, amylopectin, or polyethylene glycol or polyethylene imine of any desired molecular weight, depending on the desired property of the micelles. In addition, mixtures of hydrophobic or hydrophilic polymers or these lipid-polymer compositions employed can be used. In a further special embodiment, the polymers are used as conjugated block polymers, wherein the hydrophobic and also hydrophilic polymers or any desired mixture thereof may be selected as 2, 3- or multiblock copolymers. These signal generating agents encapsulated in micelles can also have functional groups, while the binder (groups) are joined at any desired position, preferably the amino, thiol, carboxyl, hydroxyl, succinimidyl, maleimidyl, biotin, aldehyde or nitrilotriacetate groups , to which any other corresponding chemically covalent or non-covalent molecules or compositions desired according to the prior art can be attached. Presently, biological molecules such as, for example, proteins, peptides, amino acids, polypeptides, 1 ipoproteins, glycosaminoglycans, DNA, RNA or similar bio molecules are especially preferred. It is further preferred to select agents for signal generation from agents for signal generation with a non-metallic base, for example from the group of X-ray contrast agents, which can be ionic or non-ionic. The ionic contrast agents include the salts of 3-acetyl amino-2,4-6-triiodobenzoic acid, 3,5-diacetamido-2,4,6-triiodobenzoic acid, 2,4,6-triiodo-3,5 -dipropionamido-benzoic acid, 3-acetyl amino 5- ((acetyl amino) met i 1) -2,4,6-triiodobenzoic acid, 3-acetyl amino-5 - (acetyl 1-methyl amino) -2,4 , 6-triiodobenzoic acid, 5-acetamido-2,4,6-triiodo-N- ((me tylcarbamoyl) meti 1) - isofhamic acid, 5- (2-methoxyacetamido) -2,4,6-triiodo-N acid - [2-Hydroxy-1- (methylcarbamoyl) -ethoxy 1] -isof-thalamic acid, 5-acetamido-2,4,6-triiodo-N-methylisophthalamic acid, 5-acetamido-2,4,6-triiode acid -N- (2-hydroxyethyl) -isof-thalamic acid, 2 - [[2,4-, 6-triiodo-3 [(1-oxobutyl) -amino] phenyl] methyl] -butanoic acid, beta- (3-amino- 2, 4, 6-triiodophenyl) to the fate i 1 -propanoic acid, 3-ethyl-3-hydroxy-2,4,6-triiodopheni-1-propanoic acid, 3- [[(dimethylamino) -methyl] amino]] - 2,4,6-triiodophenylpropanoic acid (see Chem. Ber. 93: 2347 (1960)), especially alpha-ethyl-2-acid is preferred., 4, 6 - triiodo-3 - (2-oxo-1-pyrrolidinyl) -phenyl) -propanoic acid, 2- [2- [3- (acetylamino) -2,4,6-triiodophenoxy] -ethoxymethyl] butanoic acid , N- (3-amino-2,4,6-triodobenzoyl) -N-phenyl-beta-aminopropanoic acid, 3-acetyl - [(3-amino-2, 4,6-triiodophenyl) amino] -2 -methylpropanoic acid, 5 - [(3-amino-2,4,6-thiodophenyl) methyl amino] -5-oxypentanoic acid, 4- [et i 1 - [2, 4, 6-triiodo-3 - (me ti 1 amino) -phenyl] amino] -4-oxo-butanoic acid, 3,3 '-oxy-bis [2, 1-ethenyloxy- (1-oxo-2, 1-ethanedi) imino] bis-2, 4 , 6-triiodobenzoic acid, 4,7,10,13-tetraoxahexadecan-1, 16-dioyl-bis (3-carboxy-2,4,6-triiodoan-1-ido), 5,5'- (azelaoyldimino) -bis [ 2, 4, 6-triiodo-3 - (acetyl-amino) -methyl-benzoic acid], 5,5'- (a-ido-imino) bis (2,4,6-t-ri -do-N-met il-isoftal acid) mico), 5,5'- (sebacoi 1 -diimino) -bis (2,4,6-triiodo-N-methylisophthalmic acid), 5,5- [?,? -diacetyl- (4 , 9-dioxy-2,11-dihydroxy-1,12-dodecanediyl) diimino] bis (acid 2,4,6-triiodo-N-methyl-isophthalamic), 5, 5 '5"- (nitrilo-triace t il t ri imino) tris (2,4,6-triiodo-N-met i 1 -isophthalamic acid) ), 4-hydroxy-3, 5-diiodo-alpha-phenylbenzenepropanoic acid, 3,5-diiodo-4-oxo-1- (4H) -pyridine acetic acid, 1,4-dihydro-3,5-diiodo acid 1 -met i 1 - 4 - oxo - 2, 6 - pyridinedicarboxylic acid, 5 - iodo - 2 - oxo - 1 (2H) - pyridine acetic acid, and N - (2 - hydroxyethyl) -2,4,6 -triyodo- [2,4,6-triiodo-3- (N-methylacetamido) -5- (methylcarbomoyl) benzamino] acetamido] -isophthalamic acid, and the like, as well as other ionic contrast agents suggested by X-rays in the literature, for example in J. Am. Pharm. Assoc, Sci. Ed. 42: 721 (1953), Swiss patent 480071, JACS 78: 3210 (1956), German patent 2229360, United States patent 3,476,802, Arch. Pharm. (Weinheim, Germany) 306: 11 834 (1973), J. Med. Chem. 6:24 (1963), FR-M-6777, Pharmazie 16: 389 (1961), United States Patents 2,705.72 6, U.S. Patent 2,895,988, Chem. Ber. 93: 2347 (1960), SA-A-68/01614, Acta Radiol. 12: 882 (1972), British Patent 870321, Rec. Trav. Chim. 87: 308 (1968), East German patent 67209, German patent 2050217, German patent 2405652, Farm Ed. Sci. 28: 912 (1973), Farm Ed. Sci. 28: 996 (1973), J. Med. Chem. 9: 964 (1966), Arzheim. - Forsch 14: 451 (1964), SE-A-344166, British Patent 1346796, U.S. Patent 2,551,696, U.S. Patent 1,993,039, Ann 494: 284 (1932), J. Pharm. Soc. (Japan) 50: 727 (1930), and United States Patent 4,005,188. The exposures listed in the present are explicitly incorporated by reference in the invention. Examples of nonionic X-ray contrast agents applicable according to the invention are metrizamide as set forth in DE-A-2031724, iopamidol as set forth in BE-A-836355, iohexol as set forth in GB- A-1548594, iotrolan as set forth in EP-A-33426, iodecimol as set forth in EP-A-49745, iodixanol as set forth in EP-A-108638, ioglucol as set forth in the US Pat. Joined 4,314,055, ioglucomide as disclosed in BE-A-846657, ioglunioe as disclosed in DE-A-2456685, iogulamide as disclosed in BE-A-882309, iomeprol as disclosed in EP-A-26281 , iopentol as set forth in EP-A-105752, iopromide as set forth in DE-A-2909439, iosarcol as set forth in DE-A-3407473, iosimida as disclosed in DE-A-3001292, iotasul as set forth in EP-A-22056, iovarsul as set forth in EP-A-83964 or ioxylan as disclosed in WO87 / 00757, and the like. The references provided are incorporated herein according to the invention. In some embodiments, it is especially preferred to select the agents based on nanoparticle signal generating agents, which after being released into tissues and cells are incorporated or enriched in intermediate cell compartments and / or have a particularly long residence time. in the organism. These particles are selected in a special form of water-insoluble agents, in another embodiment they contain a heavy element similar to iodine or barium, in a third PH-50 as a monomer, oligomer or polymer (ioyloxy-iodinated ester having the formula Empirical Cl 9H23 I 3N206, and the chemical names 6-ethoxy-6-oxohexy-3,5-bis (acetyl amino) -2,4,6-triiodobenzoate), in a fourth mode an ester of diatrizoic acid, in a fifth an aroyloxy ester iodinated modality or in a sixth modality any combinations thereof. In these embodiments, particle sizes are preferred, which can be incorporated by macrophages. A corresponding method for this is set forth in WO03039601 and the preferred agents to be selected are set forth in U.S. Patent Publications 5,322,679, 5,466,440, 5,518,187, 5,580,579, and 5,718,388, which are explicitly incorporated by reference in accordance with the invention. . Especially advantageous are, in particular, the nanoparticles which are labeled with agents for generating signals or agents for generating signals similar to PH-50., which accumulate in intercellular spaces and can make visible the interstitial compartments as well as the extrastitial ones. Agents for signal generation can be selected in addition to the group of anionic or cationic lipids, as already discussed in US Pat. No. 6,808,720 and is explicitly incorporated therein. Especially preferred are anionic lipids similar to phosphatidyl acid, phosphatidyl glycerol and their fatty acid esters, or phosphatidyl ethanolamine amides, similar to anandamide and methanandamide, phosphatidyl serine, phosphatidyl inositol and their fatty acid esters, cardiol ipin, phosphatidyl ethylene glycol, acid lysolipids, palmitic acid, stearic acid, arachidonic acid, oleic acid, linoleic acid, linolenic acid, myristic acid, sulpholipids and sulfatides, free fatty acids, both saturated and unsaturated and their negatively charged derivatives, and the like. In addition, fluorinated, halogenated, anionic lipids are especially preferred. Anionic lipids preferably contain cations from alkaline earth metals such as beryllium (Be <; +2 > ), magnesium (Mg < +2 >), calcium (Ca <+2>), strontium (Sr <+2>) and barium (Ba <+2>), or amphoteric ions, aluminum-like (Al <+3>), gallium (Ga <+3>), germanium (Ge <+3>), tin (Sn + <4>) or lead (Pb < +2 > Pb < + 4 >), or transition metals similar to titanium (Ti <+ 3> and Ti <+4>), vanadium (V < +2 > and V < +3 >), chromium (Cr < +2 > Cr < +3 >), manganese (Mn < +2 > and Mn < +3 >), iron (Fe <; +2> and Fe <+3>), cobalt (Co <+2> and Co <+3>), nickel (Ni <+2> and Ni <+3 >;), copper (Cu < +2 >), zinc (Zn < +2 >), zirconium (Zr < + 4 >), niobium (Nb < +3 >), molybdenum (Mo <+2> and Mo <+3>), cadmium (Cd <+2>), indium (In <+3>), tungsten (W <+2> and W <; +4 >), osmium (0s < +2 >, 0s < +3 &gs; and 0s < +4 >), irid io (Go < +2 > , Go < +3 > and Go < +4 > ), mercury (Hg <+2>) or bismuth (Bi <+3>), and / or lanthanides similar to rare earths, for example lanthanum (La < +3 >) and gadolinium (Gd <; +3 >). Especially preferred cations are calcium (Ca <+2>), magnesium (Mg <+2>) and zinc (Zn <+2>) and paramagnetic cations similar to manganese (Mn <+2). >) or gadolinium (Gd < +3 >). Cationic lipids should be selected from phosphatidyl ethanolamine, phosphatidylcholine, glycero-3-ethylphosphatidylcholine and their fatty acid esters, di and tri-methylammoniumpropane, di and tri-ethanolammoniopropane and their fatty acid esters. Especially preferred derivatives are N- [1 - (2,3-dioleoxyloxy) propyl] -N, N, -trimethanoammonium chloride ("DOTMA"); in addition synthetic cationic lipids with bases in for example lipids occurring in the nature similar to dimethyldioctadecylammonium bromide, sphingolipids, sphingomyelin, lysolipids, glycolipids such as, for example, G 1 gangliosides, sulfatides, glycoside ingolipids, cholesterol and esters or salts of cholesterol, N-succinyldioleoylphosphatidyl ethanolamine, 1,2-dioleoyl-sn-glycerol, 1,3-dipalmi-1-2-succinylglycerol, 1,2-dipalmitoyl-sn-3-succ ini lgl icerol, 1-hexadec y 1 - 2 -palmitoylglycerophosphatidyl ethanolamine and palmitoyl-homocysteine, fluorinated, cationic derivatized lipids are preferred. These compounds have been especially exposed in the U.S. 08 / 391,938 and is incorporated herein by reference. These lipids are also suitable as components of the liposomes for signal generation, which may especially have pH-sensitive properties as set forth in the U.S. 2004197392 and is incorporated herein explicitly. According to the invention, the agents for signal generation can also be selected from the group of so-called microbubbles or microballoons, which contain stable dispersions or suspensions in a liquid carrier substance. The gases that will be selected preferably are air, nitrogen, carbon dioxide, hydrogen or noble gases similar to helium, argon, xenon or krypton, or fluorinated gases containing sulfur-like sulfhexaf luuride, disulfurdecaf luoride or trifluoromethylsulfurpentaf luoride, or for example selenium hexafluoride, or halogenated silanes similar to methylsilane or dimethylsilane, in addition to short chain hydrocarbons similar to allynes, specifically methane, ethane, propane, butane or pentane, or cycloalkanes similar to cyclopropane, cyclobutane or cyclopentane, also alkenes similar to ethylene, propene, propadiene or butene, or also alkynes similar to acetylene or propyne. Additional ethers such as for example dimethyl ether, or ketones, or short chain halogenated esters or hydrocarbons or any desired mixture of the foregoing may be considered or selected. Especially preferred are halogenated or fluorinated hydrocarbon gases such as, for example, bromocorodium, luorornetane, chlorodoroune fluorine, dichlorodifluoromethane, bromotriforomethane., c lorotri f luoromethane, chloropentaf luoroetane, dichlorotetrafluoroethane, chlorotrif luoroethylene, f luoroethylene, ethyl fluoride, 1, 1-difluoroethane or perfluorohydrocarbons similar to for example perfluoroalkanes, perfluorocycloalkanes, perfluoroalkenes or perfluorinated alkynes. Especially preferred are the liquid emulsions of dodecaf luoropentane or decaf luorobutane and sorbitol, or the like, as set forth in WO-A-93/05819 and is explicitly incorporated herein by reference. Preferably these microbubbles are selected, which are encapsulated in compounds having the structure Rx-X-Z; R2-X-Z; OR R3-X-Z wherein R1, R2 and R3 comprise hydrophobic groups selected from alkyl, alkyl ethers, alkyl tiol ethers, alkyl disulfides, polif luoroalkylenes and straight chain polyfluoroalkyl ethers, Z comprises a polar group of C02-M < + > , S03 < - > M < + > , S04 < - > < + > , P03 < - > M < + > , P0 < - > M < + > 2 , N (R) 4 < + > or a substituted pyridine or pyridine, and a zwitterionic group, and finally X represents a binder that binds the polar group with the residues. The microspheres filled with gas or for in situ degassing have a size of < 1000 μp? they can be further selected from biocompatible synthetic polymers or copolymers comprising monomers, dimers or oligomers or other pre-polymer at the pre-stages of the following polymerizable substances: acrylic acid, methacrylic acid, ethylene imine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate (HEMA), lactonic acid, glycolic acid, [epsilon-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorohydrin, hydroxyalkyl acrylate, siloxane, dimethylsiloxane ethylene oxide, ethylene glycol, hydroxyalkyl methacrylate, acrylic amide N - substituted, methacrylamide N-substituted, N-vini 1 - 2-pyrrolidone, 2,4-pentadien-1-ol, vinyl acetate, acrylonitrile, styrene, p-aminostin, p-aminobenzylstyrene, is thiosulphonate sodium, sodium-2-sulfoxyethylmethacrylate, vinyl pyridine, aminoethylmethacrylate, 2-methacryloyloxytrimethylammonium chloride, and polyvinylidenes, such as for example Examples include polyfunctional, degradable monomers similar to, for example, N, N'-methylene bis-acrylamide, dimethyl ethylene glycol tacrilate, 2,2'- (p-phenylenedioxy) -dietyldimethacrylate, divinyl benzene, triallylamine and methylene-bi s - (4 - phenyl isociety), including any desired combinations thereof. Preferred polymers contain polyacrylic acid, polyethylene imine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polyactonic acid, poly ([epsilon] -caprolactone), epoxy resins, poly (ethylene oxide), poly ( ethylene glycol), and polyamides (for example Nylon) and the like or any arbitrary mixtures thereof. Preferred copolymers contain among others polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile and the like or any desired mixtures thereof. Methods for manufacturing these microspheres are published for example in Garner et al., U.S. Patent 4,179,546, Garner, U.S. Patent 3,945,956, Cohres et al., U.S. Patent 4,108,806, Japan Kokai. Tokkyo Koho 62 286534, British Patent 1,044,680, Kenaga et al., U.S. Patent 3,293,114, Morehouse et al., U.S. Patent 3,401,475, Walters, U.S. Patent 3,479,811, Walters et al., U.S. Pat. United States 3,488,714, Morehouse et al., U.S. Patent 3,615,972, Baker et al., U.S. Patent 4,549,892, Sands et al., U.S. Patent 4,540,629, Sands et al., U.S. Patent. 4,421,562, Sands, U.S. Patent 4,420,442, Mathiowitz et al., U.S. Patent 4,898,734, Lencki et al., U.S. Patent 4,822,534, Herbig et al., U.S. Patent 3,732,172, Himmel et al. ., patent d and the United States 3,594,326, Sommerville et al., U.S. Patent (3,015,128, Deasy, Microencapsulation and Related Drug Processes, Vol. 20, Chapters 9 and 10, p. 195-240 (Marcel Dekker, Inc., N.Y., 1984), Chang et al., Canadian J of Physiology and Pharmacology, Vol. 44, pp. 115-129 (1966), and Chang, Science, Vol. 146, pp. 524-525 (1964), and others and are incorporated herein in full accordance with the invention. The other agents for signal generation according to the invention can be selected from the group of agents, which are transformed into agents for signal generation in organisms by means of cells in vitro or in vivo, cells as a component of cell cultures, tissues in vitro, or cells as a component of multicellular organisms, such as fungi, plants or animals, in preferred embodiments from mammals such as mice or humans. These agents may be available in the form of vectors for the transfection of multicellular organisms, wherein the vectors contain recombinant nucleic acids for coding the agents for signal generation. In certain embodiments, this is related to agents for signal generation similar to metal binding proteins. It may be preferred to select these vectors from the group of viruses, for example from adenovirus, adenovirus-associated virus, herpes simplex virus, retrovirus, alpha virus, pox virus, sand-virus, vaccinia virus, influenza virus, poliovirus or hybrids of any of the above. In addition, these signal generation agents must be selected with delivery systems, to incorporate nucleic acids, which are suitable for coding for signal generation agents, in the target structure. In particular, virus particles are preferred for the transfection of mammalian cells, wherein the virus particle contains one or a plurality of coding sequences for one or a plurality of signal generating agents as described above. In these cases, the particles are generated from one or a plurality of the following viruses: adeno virus, virus associated with adeno virus, herpes simplex virus, retrovirus, alpha virus, pox virus, sand-virus, vaccinia virus , influenza virus and poliomyelitis virus. In additional embodiments, these signal generating agents are available from colloidal suspensions or emulsions, which are suitable for transfecting cells, preferably mammalian cells, wherein these suspensions and colloidal emulsions contain those nucleic acids possessing one or a plurality of sequences of coding for the agents for signal generation. These colloidal suspensions or emulsions may contain macromolecular complexes, nano capsules, microspheres, beads, micelles, oil-in-water or water-in-oil emulsions, micelles and mixed liposomes or any desired mixture of the foregoing. In additional embodiments, cells, cell cultures, organiZed cell cultures, tissues, organs of desired species, and non-human organisms may be selected to contain recombinant nucleic acids having coding sequences for the agents for signal generation. In specific modalities, the organisms are selected from the following groups: mouse, rat, dog, monkey, pig, fruit fly, nematode worms, fish or plants or fungi. In addition, the cells, cell cultures, organized cell cultures, tissues, organs or desired species and non-human organisms may contain one or a plurality of vectors as described above. Agents for signal generation preferably are produced in vivo from the group of proteins and are available as described above. These agents preferably directly or indirectly produce signals, while the cells produce (directly) a signal producing protein through transfection or produce a protein that induces (indirectly) the production of a signal producing protein. Preferably, these signal generation agents can be detected in methods such as for example MRI while the relaxation times TI, T2 or both are altered and lead to effects for signal production that can be sufficiently processed for imaging . These proteins are preferably protein complexes, especially metalloprotein complexes. The proteins for direct signal production are preferably these metalloprotein complexes that are formed in the cells. The agents for indirect signal production are these proteins or nucleic acids, for example, that regulate the homeostasis of iron metabolism, the expression of endogenous genes for the production of agents for signal generation, and / or the activity of endogenous proteins with properties for direct signal generation, for example the Iron Regulatory Protein (IRP), Transferrin receptor (for Absorption of Fe), eri troide-5-aminobevulinate synthase (for the utilization of Fe, H-Ferritin and L-Ferritin in order to accumulate Fe). In specific embodiments it may be preferred to combine both types of agents for signal generation, which is direct and indirect, with each other, for example an agent for indirect signal generation, which regulates homeostasis with iron and a direct agent, which represents a protein of union with metals. In these embodiments, where preferably the metal-binding polypeptides are selected as indirect agents, it is advantageous if the polypeptide binds to one or a plurality of metals that possess the properties for signal generation. In particular, metals with odd electrons are preferred in the Dorf orbitals, such as, for example, Fe, Co, Mn, Ni, Gd, etc., where in particular Fe is available in high physiological concentrations in organisms. It is also preferred if these agents form metal-rich aggregates, for example crystalline aggregates, whose diameters are greater than 10 picometers, preferably greater than 100 picometers, 1 nm, 10 nm or especially greater than 100 nm. These metal-binding compounds are preferred, which have sub-nanomolar affinities with dissociation constants of less than 10"15 M, 10" 2 M or less. Typical polypeptides or metal-binding proteins are lac toferrin, ferritin, or other layered dimethalocarboxy proteins or the like, or the so-called metal collector with ideroforic groups, similar to for example hemoglobin. A possible method for the preparation of these agents for signal generation, their selection the possible direct or indirect agents that can be produced in vivo and are suitable as signal generating agents are disclosed in WO 03/075747 and incorporated in the same according to the invention. Another group of agents for signal generation can be agents for producing photophysical signals consisting of peptide dye conjugates. These dye peptide conjugates are preferred which provide a broad spectrum of maximum absorption, for example polymethine dyes, in particular cyanine, merocyanine, oxonol and schiaryl dyes. From the class of polymethine dyes cyanine dyes, for example, indocarbo-indodicarbo- and indotricarbocyanines based on an indole structure are especially preferred. These dyes may be preferred in specific embodiments, which are substituted with suitable binding agents and may be functional groups with other groups as desired. Accordingly, see also DE 19917713, which is explicitly incorporated by reference. In accordance with the invention, the agents for signal generation can be functional groups as desired. It should be understood that functionalization is preferred by so-called "white" groups, as functional chemical compounds that bind to the agent for signal generation or its specifically available form (encapsulation, micelles, microspheres, vectors, etc.). ) towards a specific functional location, or towards a specific cell type, type of tissue or other target structures desired. The target groups preferably allow the accumulation of agents for signal production in specific target structures. Therefore, target groups can be selected from these substances, which are primarily suitable for providing useful enrichment of the signal generation agents in their specifically available form via physical, chemical or biological routes or combinations thereof. The useful white groups that will be selected can therefore be antibodies, cell receptor ligands, hormones, lipids, sugars, dextran, alcohols, bile acids, fatty acids, amino acids, peptides and nucleic acids, which can be chemically or physically bound to the agents for signal generation, in order to bind the agents for signal generation in / on a specifically desired structure. In a first embodiment, target groups are selected, which enrich the agents for signal generation in / on a tissue type or on cell surfaces. It is not necessary for the function, that the agent for signal generation is absorbed in the cytoplasm of the cells. As white groups, peptides are preferred, for example chemotactic peptides are used to cause inflammation reactions in visible tissues by means of signal generating agents.; in this regard also see WO 97/14443, which is explicitly incorporated by reference. Antibodies are also preferred, including antibody fragments, Fab, Fab2, single chain antibodies (eg Fv), chimeric antibodies, and the like, as is known from the prior art, in addition to the antibody-like substances, example the so-called anticalines, where it is unimportant if the antibodies are modified after the preparation, recombinants are produced or if they are human or non-human antibodies. It is preferred to select from humanized or human antibodies, examples of humanized forms of non-human antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments (similar to Fv, Fab, Fab ', F (ab ") 2 or other sub-sequences of antigen-binding antibodies, which partially contain non-human antibody sequences, humanized antibodies contain for example human immunoglobulins (receptor antibodies or containers), in which the groups of a CDR (Complementary Determinant Region) of the receptor are replaced by groups of a CDR of a non-human antibody (strenuous or donor), wherein the strenuous species eg mouse, rabbit or other has a specificity, affinity, and ability to bind the target antigens. The groups of the Fv structure of human inmunglobulins are replaced by the corresponding non-human groups. Furthermore, they can contain groups that do not appear in the CDR or the sequence of the Fv structure of the strenuous or the container. Humanized antibodies essentially comprise at least one or preferably two variable domains, in which all or the substantial components of the CDR components of the CDR regions or the sequences of the Fv structure correspond to those of the non-human immunoglobulin , and all or the substantial components of the FR regions correspond to a human consensus sequence. According to the invention, the target groups of this embodiment can also be hetero-conjugated antibodies. The preferred function of the selected antibodies or peptides is that of markers or molecules of cell surfaces, in particular of cancer cells, where many surface structures are known, such as for example HER2, VEGF, CA 15-3, CA 549, CA 27.29, CA 19, CA 50, CA242, MCA, CA 125, DE-PAN-2, etc., and the like. In addition, it is preferred to select target groups that contain the functional binding sites of ligands. These can be selected from all types, which are suitable for binding to any desired cellular receptors. Examples of possible target receptors are, without limitation of choice, the receptors of the group of insulin receptors, insulin-like growth factor receptor (and IGF-I and IGF-2), growth hormone receptor, transporter glucose (particularly the GLUT 4 receptor), transferrin receptor (transrhiprin), epidermal growth factor receptor (EGF), low density lipoprotein receptor, high density lipoprotein receptor, leptin receptor, or estrogen receptor; interleukin receptors including the IL-1 receptor, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12 , IL-13, IL-15, and IL-17, VEGF receptor (VEGF), PDGF receptor (PDGF), transforming growth factor receptor (including TGF- [alpha] and TGF- [beta]), receptor EPO (EPO), TPO receptor (TPO), ciliary neurotrophic receptor, prolactin receptor, and T cell receptors. It may be preferred to select hormone receptors, especially for hormone-like hormones or steroid proteins or peptide-based hormones , for example, however not limited to the same, epinephrines, thyroxins, oxytocin, insulin, thyroid stimulating hormone, calcitonin, chorionic gonadotropin, cort icotropin, follicle stimulating hormone, glucagons, lute ini zante hormone, lipotropin, melanocyte stimulating hormone, norepinef fights, parathyroid hormone, hormone stimulant of the thyroid (TSH), vasopressin, enkephalin, serotonin, estradiol, progesterone, testosterone, cortisone, and glucocorticoid. The receptor ligands include those that are on the cellular surface receptors of hormones, lipids, proteins, glycol proteins, signal transducers, growth factors, cytokines, and other biomolecules. In addition, white groups can be selected from carbohydrates with the general formula: Cx (H20) and, wherein monosaccharides, disaccharides and oligo- as well as polysaccharides are also included herein, as well as other polymers consisting of sugar molecules that contain glycosidic bonds. Especially preferred carbohydrates are those in which all or portions of the carbohydrate components contain glugosed proteins, including the monomers and oligomers of galactose, mannose, fructose, galac tosamine, glucosamine, glucose, sialic acid, and especially the glugosed components, which they make possible the union to specific receivers, especially receptors of cellular surfaces. Other useful carbohydrates to be selected contain monomers and polymers of glucose, ribose, lactose, raffinose, fructose and other carbohydrates that occur biologically, especially polysaccharides, for example, but not exclusively, arabinogalactan, gum arabic, morning tea and the like, which they can be used in order to introduce the agents for signal generation in the cells. Reference is made to this in U.S. Patent 5,554,386 which is incorporated herein in accordance with the invention.

Additional white groups of the lipid group can be selected, which also include fats, fatty oils, waxes, phospholipids, glycolids, terpenes, fatty acids and glycerides, especially triglycerides. Also included are eicosanoids, steroids, esterols, suitable compounds thereof can also be hormones similar to pros taglandins, opiates and cholesterol and the like. According to the invention, all functional groups can be selected as the target group, which possesses inhibitory properties, such as, for example, enzymatic inhibitors, preferably those which bind the agents for generating senna in / on enzymes. In a second embodiment, the target groups may be selected from a group of functional compounds that make possible the internalization or incorporation of the agents for signal generation in cells, especially in the cytoplasm or in specific cellular compartments or organelles, such as for example a cell nucleus. For example, it is preferred that the target group contains all or portions of HIV-I tat proteins, analogs and similar proteins derived or functionally similar, and thus allow a particularly rapid absorption of substances into cells. As an example, reference is made to Fawell et al., PNAS USA 91: 664 (1994); Frankel et al., Cell 55: 1189, (1988); Savion et al., J. Biol. Chem. 256: 1149 (1981); Derossi et al., J. Biol. Chem. 269: 10444 (1994); and Baldin et al., EMBO J. 9: 1511 (1990), which are incorporated herein explicitly in accordance with the invention. The target groups can also be selected from the so-called Nuclear Localization Signal (NLS), where it is understood that under the short positively charged (basic) domains they bind to the specifically targeted structures of the cell nuclei. Many NLS and their amino acid sequences are known including a single basic NLS similar to the SV40 long T antigen (monkey virus) (pro Lys Lys Arg Lys Val), Kalderon (1984), et al., Cell, 39: 499-509), the nuclear localization signal of the teinoic acid [beta] -receptor (ARRRRP); NFKB p50 (EEVQRKRQKL; Ghosh et al., Cell 62: 1019 (1990); NFKB p65 (EEKRKRTYE; Nolan et al., Cell 64: 961 (1991), as well as others (see for example Boulikas, J. Cell. Biochem 55 (l): 32-58 (1994), and the basic double NLS similar to for example xenopus proteins (African toothed toad), nuc leoplasmin (Ala Val Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Leu Asp), Dingwall, et al., Cell, 30: 449-458, 1982 and Dingwall, et al., J. Cell Biol., 107: 641-849, 1988. All of these are incorporated herein. As reference in accordance with the invention, many localization studies have shown that NLS, which are synthetic peptides that normally do not target the cell nucleus and do not bind to the reporter proteins, lead to an enrichment of these proteins and peptides in cell nuclei In this regard the example references are Dingwall, and Laskey, Ann, Rev. Cell Biol., 2: 367-390, 1986, Bonnerot, et al., Proc. Nati, Acad. Sci. USA, 84: 6795-6799, 1987; Galileo, et al., Proc. Nati Acad. Sci. USA, 87: 458-462, 1990. It may be particularly preferred to select target groups for the hepatobiliary system, where corresponding groups are suggested in US Patents 5,573,752 and 5,582,814. Both publications are included herein as a reference.

THERAPEUTICALLY ACTIVE AGENTS According to the invention, at least one therapeutic agent is also selected in addition to an agent for signal generation. The therapeutic agents include all substances that develop local and / or systemic physiological and / or pharmacological effects in animals, especially mammals, for example, including all mammals similar, but not exclusively, according to the invention., animals similar to dogs and cats, beasts of burden and for agriculture such as pigs, cattle, sheep, or goats, laboratory animals such as mice, rats, primates such as monkeys, chimpanzees, etc., and humans. In the composition or combination according to the invention therapeutic agents may be present in crystalline, polymorphous or amorphous forms or any mixture thereof. Therapeutically active ingredients useful can be selected from many therapeutically effective substances, for example, but not exclusively, from the group of enzyme inhibitors, hormones, cytokines, growth factors, receptor ligands, antibodies, antigens, ionic binding materials, among which Also listed are crown ethers and other chelating agents, substantially complementary nucleic acids, nucleic acid binding proteins including transcription factors, toxins, etc. In addition, useful materials include cytokines similar to erythropoietin (EPO), thrombopoietin (TPO), interleukin (including IL-1 to IL-17), insulin, insulin-like growth factors (including IGF-1 and IGF-2). , epidermal growth factor (EGF), transforming growth factors (including TGF- [alpha] and TGF- [beta]), human growth hormone, transferrin, epidermal growth factor (EGF), low density lipoprotein, lipoprotein high density, leptin, VEGF, PDGF, ciliary neurotrophic factor, prolactin, icotropic adrenocortone hormone (ACTH), calcitonin, gonadot human chorionic gonadot, cortisol, estradiol, hormone for follicular stimulation (FSH), hormone for thyroid stimulation (TSH) , leutinizing hormone (LH), proges terone, testosterone, toxin including ricin, and all other materials listed in the publications Physician's Desk Reference, 58ava. Edition, Medical Economics Data Production Company, Montvale, N.J., 2004 and the Merck Index, 13th. Edition (especially the pages Ther-1 to Ther-29), where both are explicitly incorporated herein by reference. In a preferred embodiment, the therapeutically active substance is selected from the group of active substances for the therapy of oncological diseases and cell or tissue changes. Useful therapeutic agents are for example, but not exclusively ant ineneptically active substances, including alkylating agents such as alkyl sulfonates (e.g., busulfan, improsulphan, piposulfane), aziridines (e.g., benzodepa, carboquone, meturedepa, uredepa); ethylene imines and methylmelamine (for example, altretamine, triet i lenme sheet, triethylene phosphoramide, triethylene glyphosate, trimethoxymelamine); the so-called nitrogen mustards (for example, chlorambucil, chlorofuran, cyclophosphamide, is tramadin, ifosfamide, mee loretamine, mechlore hydrochloride, taminoxide, melphalan, novembichin, phenesterine, prednimust, trofosfamide, uracil mustard); nitrosourea compounds (carmustine, c lorozotocin, fotenmust ina, lomustine, nimustine, ranimustine); dacarbazine, manomustine, mitobrani tol, mitolactol; pipobroman; doxorubicin, and cis-platina (including derivatives), or the like and its derivatives. In another preferred embodiment, the therapeutically active substance is selected from the group of antiviral and antibacterial active substances including aclacinomycin, actomycin, anthramycin, azaserin, bleomycin, cuct inomic ina, carubicin, carzinof ilin, chromomycin, duct inomycin, daunorubicin, 6-diazo. -5-oxn-1-norieucine, duxorubicin, epirubicin, mitomycin, mycophenolic acid, nogalumin, olivomycin, peplomycin, plicamycin, poromicron, puromycin, streptonigrin, is treptozocin, tuborcidin, ubenimex, zinostatin, zorubicin, aminoglycosides or polyenes or macrolide antibiotics, and the like or its derivatives. In a preferred embodiment, the therapeutically active substance is selected from the group of radio sensitizing drugs. In a further preferred embodiment, the therapeutically active substance is selected from the group of steroid active substances, as well as the nonsteroidal anti-inflammatory active substances. In a further preferred embodiment, the therapeutically active substance is selected from active substances that are related to angiogenesis (eg, but not exclusively, endostatin, angios tat ina, interferons, platelet factor 4 (PF4), thrombospondin, beta factor. of transforming growth, tissue inhibitors of metalloproteinase -1, -2 and -3 (TIMP-1, -2 and -3), TNP-470, marimastat, neovastate, BMS-275291, COL-3, AG3340, thalidomide, squalamine, com sta sta tat ina, SU5416, SU6668, IFN- [alpha], EMD121974, CAI, IL-12 and IM862, and the like or its derivatives In a further preferred embodiment, the therapeutically active substance is selected from the group of acids nucleic acids, including also oligonucleotides in addition to nucleic acids and wherein at least two nucleotides are covalently linked together, for example, but not exclusively, to produce therapeutic or antisense gene effects. Preference contains phosphodiester linkages, wherein also those are included which are present as analogs with various structures. Analogs may also contain as structures for example, but not exclusively, phosphoramides (Beaucage et al., Tetrahedron 49 (10): 1925 (1993) and the references provided, Letsinger, J. Org. Chem. 35: 3800 (1970)). Sprinzl et al., Eur. J.

Biochem. 81: 579 (1977); Letsinger et al. , Nucl. Acids Res. 14: 3487 (1986); Sawai et al, Chem. Lett. 805 (1984), Letsinger et al. , J. Am. Chetn. Soc. 110: 4470 (1988); and Pauwels et al. , Chemica Scripta 26: 141 91986)), phosphorothioates (Mag et al., Nucleic Acids Res. 19: 1437 (1991), and U.S. Patent 5,644,048), phosphodiesodiolates (Briu et al., J. Am. Chem. Soc. 111: 2321 (1989), 0-methylphosphoramidite compounds (see Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press), and Nucleic Acid Structures with Peptides and their compounds (see, Egholm, J. Am. Chem. Soc. 114: 1895 (1992), Meier et al., Chem. Int. Ed. Engl: 31: 1008 (1992), Nielsen, Nature, 365: 566 (1993), Carlsson et al. , Nature 380: 207 (1996), where the references provided therewith are explicitly incorporated in accordance with the invention Other analogs contain those ionic structures, see (Denpcy et al., Proc. Nati. Acad. Sci. USA 92 : 6097 (1995), or non-ionic structures, see U.S. Patents 5,386,023, 5,637,684, 5,602,240, 5,216,141 and 4,469,863; Kiedrowshi et al., Angew. Chem. In. Ed. English 30: 423 (1991); Letsinger et al., J. Am. Chem. Soc. 110: 4470 (1988); Letsinger et al., Nucleosides & Nucleotides 13: 1597 (1994); Chapters 2 and 3, ASC Symposium Series 580, "Carbohydrate Modification in Antisense Research", Ed. Y. S. Sanghui and P. Dan Cook; Mesmaeker et al., Bioorganic & Medicinal Chem. Lett. 4: 395 (1994); Jeffs et al., J. Biomolecular NMR 34:17 (1994); Tetrahedron Lett. 37: 743 (1996), and Estructuras Sin Ribosa, incorporated the only ones described in United States patents 5,235,033 and 5,034,506, and chapters 6 and 7, ASC Symposium Series 580, "Carbohydrate Modif ications in Antisense Research", Ed. YS Sanghui and P. Dan Cook. The references cited are incorporated explicitly in accordance with the invention. Nucleic acids having one or a plurality of carbocyclic sugars can also be used as nucleic acids according to the invention, see Jenkins et al., Chem. Soc. Rev. (1995) pp 169-176, as well as others described in Rawls, C & E News June 2, 1997, page 35, and are explicitly incorporated with it. In addition to the selection of nucleic acids that can be used and nucleic acid analogs known from the prior art, any desired mixtures of naturally occurring nucleic acids and nucleic acid analogues or mixtures of analogs of nucleic acid can also be used. nucleic acid. In one embodiment, the therapeutically active substance is selected from the group of metal ionic complexes, as generally described in PCT US95 / 16377, PCT US95 / 16377, PCT US96 / 19900, PCT US96 / 15527 and is fully incorporated herein as a reference, wherein these agents reduce or inactivate the bioactivity of their target molecules, preferably proteins, for example, but not exclusively, enzymes. Preferred therapeutically active substances are anti-migratory, antiproliferative or immunosuppressive, antiinflammatory and additional re-endothelial active substances such as, for example, but not exclusively, everolimus, tacrolimus, sirolimus, mycophenolate mofetil, rapamycin, paclitaxel, actinomycin D, angiopeptide, Batimastat, Oestradiol, VEGF, Statins and their derivatives and analogues. Especially preferred are active substances or combinations of active substances, which are selected from heparin, analogs of synthetic heparin (for example, fondaparinux), hirudin, antithrombin III, drotrecogin alfa; fibrinolytics similar to alteplase, plasmin, lysosinases, factor Xlla, prouroc inasa, urokinase, anistreplasa, streptoc inasa; inhibitors of thrombocyte aggregations similar to acetylsalicylic acid, ticlopidine, clopidogrel, abciximab, dextran; corticosteroids similar to alclometasone, amcinonide, increased betamethasone, beclomethasone, betamethasone, budesonide, cortisone, clobetasol, clocortolone, desonido, desoximetasone, dexame tasone, flucinolone, indolef luoc, furandrenolide, flunisolide, fluticasone, halcinonide, halobetasol, hydrocortisone, methylprednisolone, mometasone, prednicarbate, prednisone, prednisolone, triamc inolone; the so-called non-steroidal anti-inflammatory drugs similar to diclofenac, diflunisal, etodolaco, fenoprofen, furburbfen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, celecoxib, rofecoxib; ci to-estatiks similar to podophyllum alkaloids and toxins similar to vinblastine, vincris t ina; alkylating agents similar to nitrous urea, analogs lacking nitrogen; cytotoxic antibiotics similar to daunorubicin, doxorubicin and other anthracyclines and related substances, bleomycin, mitomycin, folic acid-like antimetabolites, purine analogs or pyrimidine; paclitaxel, docetaxel, sirolimus; platinum compounds similar to carboplat ino, cisplatin or oxali-platinum; amsacrine, irinotecan, imatinib, topotecan, interferon alfa 2a, interferon alfa 2b, hydroxycarbamide, miltefosine, pentoes tat ina, porfimer, alces leucine, bexarotene, tretinoin; antiandrogens, and antigens; antiarrhythmics, especially Class I antiarrhythmics similar to quinidine antiarrhythmics, for example, quinidine, disopyramide, ajmaline, praj mal iobitartrate, detajmiobitartrate; antiarrhythmics of the lidocaine type, for example, lidocaine, mexiletine, phenytoin, tocainide; class I C antiarrhythmics, for example, propafenone, flecainide (acetate); class II antiarrhythmics, beta-receptor blockers similar to metoprolol, esmolol, propranolol, metoprolol, atenolol, oxprenolol; class III antiarrhythmics similar to amiodarone, sotalol; class IV antiarrhythmics similar to diltiazem, verapamil, gallopamil; other antiarrhythmics similar to adenosine, orciprenaline, ipratropium bromide; agents for the stimulation of angiogenesis in myocardiums similar to the Vascular Endothelial Growth Factor (VEGF), Basic Fibroblast Growth Factor (bFGF), non-viral DNA, viral DNA, endothelial growth factors: FGF-I, FGF-2, VEGF , TGF; antibodies, monoclonal antibodies, anticalin; hemocytoblasts, Endothelial Progenitor Cells (EPC); digitalisglucosides similar to acetyldigoxin / methyldigoxin, digitoxin, digoxin; cardiac glycosides similar to quabain, proscilaridin; antihypertensive drugs similar to centrally acting antiretran energetic substances, for example, centrally active anti-adrenergic substances, for example, methyldopa, imidazoline receptor agonists; calcium channel blockers of the dihydropyridine type similar to nifedipine, nor trendipin; ACE inhibitors: quinapri lato, cilazaprilo, moexiprilo, trandolapri lo, espiraprilo, imidaprilo, trandolapri lo; angiotensin II antagonists: candesartan cilexetil, valsartan, telmisartan, olmesartan medoxomil, eprosartan; Alpha Receptor blockers that operate peripherally similar to prazosin, urapidil, doxazosin, bunazosin, terazosin, indoraraine; vasodilators similar to dihydralazine, diisopropy lamindic loracetate, minoxidil, sodium or troprusidic; other antihypertensive drugs similar to indapamide, co-dergocrine mesylate, dihydroergotoxinmetansulfonate, cyclintanin, bosentan, f ludrocort isone; phosphodiesterase inhibitors similar to milrinone, enoximone and antichyotonic, especially similar to adrenal and dopaminergic, in particular adrenergic and dopaminergic substances similar to dobutamine, epinephrine, etilefrine, norphenephrine, ñor epinephrine, oxylofrine, dopamine, midodrine, foledrine, ameziniomet ilo; and partial adrenoceptor agonists similar to dihydroergotamine; f ibronect ina, polylysine, ethylene vinyl acetate, similar inflammatory cytokines: TGF, PDGF, VEGF, bFGF, TNFa, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6, Growth hormone; as well as, adhesive substances similar to cyanoacrylates, beryllium, silica; and growth factors similar to eri tropoyet ina, hormones similar to cort icotropin, gonadotropin, somatropin, thyrotrophin, desmopressin, terlipressin, oxytocin, cetrorelix, corticorelin, leuprorelin, triptorelin, gonadore 1 ina, ganirelix, buserelin, nafarelin, goserelin, as well as also regulatory peptides similar to somatos tat ina, octreotide; bone and cartilage stimulating peptides, Bone Morphogenetic Proteins (BMPs), especially recombinant BMPs similar to, for example, recombinant human BMP-2 (rhBMP-2)), bisphosphonates (e.g., risedronate, pamidronate, ibandronate, zoledronic acid , lodroninic acid, etidronic acid, alendronic acid, tiludronic acid), fluorides similar to disodium luorophosphate, sodium fluoride; calcitonin, dihydrotaquies t irene; Growth factors and cytokines similar to Epidermal Growth Factor (EGF), Platelet Derived Growth Factor (PDGF), Fibroblast Growth Factors (FGFs), Transforming Growth Factor-b (TGFs-b), Factor-A of Transformant growth (TGF-a), Eri tropoyet ina (Epo), Insulin-like Growth Factor I (IGF-I), Insulin-like Growth Factor II (IGF-II), Interleukin-1 (IL-I), Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-a (TNF-a), Tumor Necrosis Factor-b (TNF-b) , Interferon-g (INF-g), Colony Stimulating Factors (CSFs); monocyte chemotactic ica protein, fibroblast stimulating factor 1, histamine, fibrin or fibrinogen, endothelin-1, angiotensin II, collagens, bromocrine, methylserbed, methotrexate, carbon tetrachloride, thioacetamide, and ethanol; in addition silver (ions), titanium dioxide, antibiotics and anti- infectious agents, especially similar to β-lactam antibiotics, for example penicillins sensitive to β-lactamase similar to benzyl penicillins (penicillin G), phenoxymethyl penicillin (penicillin V); β-lactamase-resistant penicillins similar to aminopenicillins similar to amoxicillin, ampicillin, bacampicillin; acylamino penicillins similar to mezlocillin, piperacillin; carboxypenicillins, cephalosporins similar to cefazolin, cefuroxime, cefoxitin, cefotiam, cefaclor, cefadroxil, cephalexin, loracarbef, cefixime, cefuroximexetil, ceftibuten, cefpodoximproxetyl; aztreonam, ertapenem, meropenem; ß-lactamase inhibitors similar to sulbactam, sultamicilintostosate; tetracyclines similar to doxycycline, minocycline, te trac ic 1 ina, chlortetracycline, oxytetracycline; aminoglycosides similar to gentamicin, neomycin, streptomycin, tobramycin, amikacin, netilmicin, paromomycin, framycetin, inomycin; macrolide antibiotics similar to azithromycin, clarithromycin, er i thromycin, roxithromycin, spiramycin, j osamic ina; 1 clindamycin-like incosamides, lincomycin, luceroquinolone-like gyrase inhibitors similar to ciprofloxacin, ofloxacin, moxif loxacin, norf loxacin, gatif loxacin, enoxacin, fleroxacin, levof loxacin; quinolones similar to pipemidic acid; sulfonamides, trimethoprim, sulfadiazine, sulfalene; idico glycopeptibic antibiotics similar to vancomycin, teicoplanin; polypeptide antibiotics similar to polymyxin similar to colistin, polymyxin-B, nitroimidazole derivatives similar to me tronidazole, tinidazole; aminoquinolones similar to chloroquine, mefloquine, hydroxychloroquine; Proguanyl-like biguanides; quinine and diaminopyrimidine alkaloids similar to pyrimethamine; amphenicols similar to chloramphenicol; rifabutin, dapsone, fusidinic acid, fosfomycin, nifuratel, teromatin 1, fusafungin, fosfomycin, pentamidindi isethionate, rifampin, taurolidine, atovaquone, linezolid; virumatics similar to acyclovir, ganciclovir, famciclovir, foscarnet, inosine- (dimepranol-4-acetamidobenzoate), valganciclovir, valaciclovir, cidofovir, brivudine; antiretroviral active substances (reverse transcriptase inhibitors for nucleoside analogs and derivatives) similar to lamivudine, zalcitabine, didanosine, zidovudine, tenofovir, stavudine, abacavir; nucleoside analog reverse transcriptase inhibitors: amprenavir, indinavir, saquinavir, lopinavir, ritonavir, nelfinavir; amantadine, ribavirin, zanamivir, oseltamivir and lamivudine, and the like as well as arbitrary combinations and mixtures thereof. In addition, the therapeutically active substances can be selected from cells of microorganisms, plants or animals including human cells or cell cultures and tissues, especially recombinant cells or organized cells or tissues, preferably from mammals, especially heterologous cells or tissues are preferred or autologous, or transfected cells, that express and release physiologically or pharmacologically active substances. Also preferred are hemocytes coughs, primary cells as well as differentiated primary cell progenitor cells or arbitrary mixtures thereof. Furthermore, it may be preferred to use cells or cells or tissues organized as therapeutic agents, which are not transferred and / or altered by means of gene technology.

MULTI-FUNCTIONAL AGENTS According to the invention, various agents for signal generation can be coupled together with bifunctional, trifunctional or multifunctional signal generating agents, while they are constituted of various functional units that are linked together. By this it is possible to link any desired different signal generating agents to each other, such that agents for complex signal generation combine different properties for signal generation in a conjugate. Also these additionally conjugated signal generating agents may contain target groups or active therapeutic substances, which bind as therapeutic groups to the conjugate complex. Therefore, according to the invention, the agents for bifunctional signal generation consist of an agent for generating signal and an additional agent having different properties for signal generation, for example, but not exclusively, of a paramagnetic agent. for the generation of signal by means of MRI and a coupled fluorescence marker as set forth for example, in WO 04/026344, or of a paramagnetic and diamagnetic group coupled in the MRI signal generation agent as set forth in EP 1105162 or WO 00/09170; in addition to the agents for dimeric signal generation of a super paramagnetic or ferromagnetic and the X-ray contrast components as set forth in U.S. Patent 5,346,690, or an agent composed of paramagnetic and iodinated components for MRI and X-rays, as set forth in U.S. Patent 5,242,683; the references are incorporated herein according to the invention. According to the invention, the agents for bifunctional signal generation also consist of a signal generating agent and a therapeutically active substance or of a signal generating agent and a target group. Examples of agents for signal production combined with therapeutically active substances are set forth in U.S. Patent 6,207,133, U.S. Patent 6,479,033, German Patent 10151791, Canadian Patent 1336164, WO 02/051301, WO 97/05904, European patent 0458079, German patent 4035187, WO 04 / 071-536, United States patent 6,811,766, WO 04/080483 and others and are explicitly incorporated herein by reference. Examples of agents for signal generation combined with target groups are set forth in U.S. Patent 6,232,295, CN 1224622, WO 99/20312, WO 04/071536, U.S. Patent 6,207,133, WO 97. / 36619, U.S. Patent 6,652,835, WO 03/011115, WO 04/080483 and others and are explicitly incorporated herein by reference. The agents for generating a trifunctional signal comprise according to the invention at least one component for generating a signal and a component for generating additional signal or a therapeutically active component or a target group and its component for generating additional signal or a therapeutically active agent. active or a white group. The agents for generating multifunctional signal can be selected correspondingly of a multifunctional signal generation agent having at least one other component that can be selected arbitrarily. In particular, it is exhibited in the U.S. No. of Ser. 08 / 690,612, the way in which the agents for generating multifunctional or multimeric signal are manufactured in principle, where this is incorporated explicitly.

The agents for generating bi, tri and multifunctional signal can be presented correspondingly with the prior art totally or partially as covalent or non-covalent unit macromolecules, as micelles or microspheres, encapsulated in liposomes or encapsulated in polymers or covalently bound in polymers. For covalent bonds, substituents in the form of functional groups according to the prior art are coupled to the individual components, they will be selected, for example, from amino, carboxyl, oxo or thiol groups. These groups can be linked together directly or through a linker. The binders of the prior art have been described many times, for example, the homo or heterofune binders as described in Pierce Chemical Company catalog, technical section on cross-linkers, pages 155-200, (1994), and incorporated herein by reference. the present as a reference. Preferred binders include, but are not limited to, alkyl groups including substituted alkyl groups and alkyl groups with heteroatom groups, esters of short chain alkyl groups, amides, amines, epoxy groups, nucleic acid, peptide, ethylene glycol, hydroxyl, succinimidyl, maleicidyl, biotin, aldehyde or nitrilotriacetate groups and their derivatives. According to the invention, the agents for generating mono, bi, tri or multifunctional signal can be linked non-covalently or partially or totally covalently, they can be encapsulated in micelles where the micelles can have a diameter of 2 nm to 800 nm, preferably from 5 to 200 nm, especially from 10 to 25 nm are preferred. The size of the micelles, without being linked to any established theory, will depend on the number of hydrophobic and hydrophobic groups, the molecular weight of the signal generation agents used and the number of aggregation. In aqueous solutions, it is especially preferred to use branched or non-branched amphiphilic substances present as a monomer or oligomer or polymer to achieve the encapsulation of the agents for signal generation. The hydrophobic core of the micelles contains a multiplicity of hydrophobic groups, preferably between 1 and 200 according to the desired size adjustment of the micelle. Agents for signal generation, the target groups of the therapeutic agents, according to the invention, may also be present in the micelles that will be provided partially covalently linked to each other. The hydrophobic groups preferably comprise hydrocarbon groups or residues or silicone, for example, polysiloxane chains. In addition, they can preferably be selected from hydrocarbon-based monomers, oligomers and polymers, or from lipids or phospholipids or from any desired combinations, especially glyceryl esters such as, for example, phosphatidyl ethanolamine, phosphatidyl cholines, or polysulfides. , polylactides, polymethacrylate, polyvinyl butyl ether, polystyrene, pol icic lopentadienylmeti Inorbornene, polyethylene propylene, polyethylene, polyisobutylene, polysiloxane. In addition, for the encapsulation in micelles, hydrophilic polymers can also be selected, especially polystyrene sulfonic acid, poly-N-alkylvinylpyridinium halides, poly (meth) acrylic acid, polyamino acids, poly-N-vinylpyrrolidone, pol ihidroxie ti 1metacri lato, polyvinyl ether, polyethylene glycol, polypropylene oxide, polysaccharides similar to agarose, dextran, starch, cellulose, amylose, amylopectin, or polyethylene glycol or polyethylene imines of arbitrary molecular weight, according to the desired micellar property. In addition, mixtures of hydrophobic or hydrophilic polymers or these lipid-polymer compounds used can also be used. In a further special embodiment, the polymer is conjugated as a block copolymer, wherein hydrophilic, as well as hydrophobic polymers or any desired mixtures thereof can be selected as 2, 3 or multiple block copolymers. These signal generation agents encapsulated in micelles and other functional components can be further functionalized, while the linkers bind in any desired positions of the micelle, preferably amino, thiol, carboxyl, hydroxyl, succinimidyl, maleimidyl, biotin, aldehyde or nitrilotriacetate, to which, according to the prior art, the additional molecules or compounds can be chemically bound, covalently or non-covalently. Particularly preferred in the present are biological molecules such as, for example, proteins, peptides, amino acids, polypeptides, lipoproteins, glycosaminoglycans, AD, RNA or organic bio molecules.

According to the invention, the agents for generating mono, bi-, tri, or multifunctional signal are provided, linked non-covalently or partially or totally covalently, also in microspheres and liposomes. The preferred microspheres in a size of < 1000 μp? they may preferably be selected from biocompatible synthetic polymers or copolymers, which consist of monomers, dimers or oligomers or other preferred pre-polymeric precursors of the following polymerizable substances: acrylic acid, methacrylic acid, ethylene imine, crotonic acid, acrylamide, ethylacrylate , methylmethacrylate, 2-hydroxyethylmethacrylate (HEMA), lactonic acid, glycolic acid, [eps i Ion] - caprolactone, acrolein, cyanoacrylate, bisphenol-A, epiclohydrin, hydroxyalkylacrilate, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkylmetacri lato, N-substituted acrylamide, N-substituted methacrylamide, N-vinyl-2-pyrrolidone, 2-4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, - aminostine, p-aminobenzylstyrene, styrene sulfonate sodium, methacryloyl chloride, trimethylammonium chloride, 2-sulfoxyethyl-methacrylate sodium, vinyl pyridine, aminoethylmethacrylate, chloride of 2-methacryloyloxytrimethylammonium, also polyvinylidene, or degraded functional polymers such as, for example, N ('-methylene-bis-acrylamide, ethylene glycol dimethacrylate, 2, 2' - (p-phenylenedioxy) - diet i 1-dimethacrylate, divinyl benzene, triallylamine or met i len-bi s - (4-phenylisocyanate), and the like or its derivatives or copolymers including any combinations thereof. Preferred polymers include polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactonic acid, poly ([epsilon] -caprolactone), epoxy resins, poly (ethylene oxide), poly (ethylene glycol), and polyamide (nylon) and the like or its derivatives or copolymers or any desired mixtures thereof. Preferred copolymers include, inter alia, polyvinylidene polyacrylonitrile, polyvinylidene polyacrylonide polyacrylonitrile, or polystyrene polyacrylonitrile and the like or their derivatives or any mixtures thereof. Methods for making these microspheres are discussed, for example, in Garner et al., U.S. Patent 4,179,546, Garner, U.S. Patent 3,945,956, Cohrs et al. , U.S. Patent 4,108,806, Japan Kokai Tokkyo Koho 62 286534, British Patent 1,044,680, Kenaga et al., U.S. Patent 3,293,114, Morehouse et al., U.S. Patent 3,401,475, alters, U.S. Patent 3,479,811, Walters et al., U.S. Patent 3,488,714, Morehouse et al., U.S. Patent 3,615,972, Baker et al., U.S. Patent 4,549,892, Sands et al., U.S. Patent 4,540,629, Sands et al. , U.S. Patent 4,421,562, Sands, U.S. Patent 4,420,442, Mathiowitz et al., U.S. Patent No. 4,898,734, Lencki et al., U.S. Patent 4,822,534, Herbig et al., U.S. Pat. United States 3,732,172, Himmel et al., U.S. Patent 3,594,326, Sommerville et al., U.S. Patent 3,015,128, Deasy, Microencapsulation and Related Drug Processes, Vol. 20, Chapters. 9 and 10, pp. 195-240 (Marcel Dekker, Inc., N.Y., 1984), Chang et al., Canadian J of Physiology and Pharmacology, Vol. 44, pp. 115-129 (1966), and Chang, Science, Vol. 146, pp. 524-525 (1964), and others and are fully incorporated by reference herein according to the invention. According to the invention, the agents for generating mono, bi, tri or multifunctional signal, linked non-covalently or completely covalently are available in liposomes partially or it is preferred to select them from the group of anionic or cationic lipids as already explained in the section adequate The agents for signal generation, present as mono, bi, tri or multi-functional agents, can also be linked with polymers. A general review of the related methods will be found in PCT US95 / 14621 and the U.S. Ser. No. 08 / 690,612, both are explicitly incorporated herein by reference. In general, agents for signal generation for example can be linked to polymers, while the chemical groups that are available, allow a bonding of the signal generating agents to be made with the selected polymer or mixture of polymers. Polymers should be understood as compounds containing at least two or three subunits that are covalently linked together. At least a portion of a monomeric subunit contains one or a plurality of functional groups that allow covalent attachment to the agent for signal generation. In a few modalities, coupling groups are used to link the monomer subgroups with the signal generating agents. According to the prior art, a multiplicity of polymers is suitable for this. Preferred polymers include, but are not limited to, styrene with functional groups, similar to amino styrene, dextran and polyamino acids with functional groups. Preferred polymers are polyamino acids, (poly i -D-amino acids as well as poly-L-amino acids), for example, polylysine, and polymers containing lysine or other suitable amino acids. Other useful polyamino acids are polyglutamic acids, polyaspartic acids, lysine and glutamine copolymers or aspartic acid, lysine copolymers with alanine, tyrosine, f-enylalanine, serine, tryptophan and / or proline. The polymers used may be selected primarily from polymers with functional or non-functional groups similar to, for example, but not exclusively, thermoplastic, thermoplastic, synthetic rubbers, extrudable polymers, injection molding polymers, moldable polymers, and the like. or mixtures, additionally as components of any compounds. In addition, additives that improve the compatibility of the components used for the production of materials can be selected, for example, silane-like coupling agents, surfactants or fillers, similar to organic or inorganic fillers. In one embodiment, the polymer is selected from polyacrylates similar to polymethacrylate, or from unsaturated polyesters, saturated polyesters, a polyolefin (e.g., polyethylene, polypropylene, polybutylene, and the like), and alkyd resin, an epoxy-polymer, a polyamide, a polyimide, a polyetherimide, a polyamideimide, a polyesteramide, a polyesteramideimide, polyurethanes, polycarbonates, polystyrenes, polyphenols, polyesters, polysilicone, polyacetal, cellulose acetates, polyvinyl chlorides, polyvinyl acetates, alcohols polyvinyls, polysulfones, polyphenylsulphones, polyestersulphones, polyketones, polyetherketones, polyether ether ketones, polyestertetonaketones, polbenz imidazoles, polybenzoxazoles, polbenzathiazoles, polyfluorocarbons, polyphenylene, polyarylates, cyanatoesterpolymers, copolymers of two or more those mentioned, and the like. The polymers that can be used in particular are acrylics, monacrilates, diacrylates, triacrites, tetraacrylates, pentacrites, and the like are most preferred. Examples of polyacrylates are polyisobornyl acrylate, polyisobutyl methacrylate, polyethoxyethoxyethacrylate, poly-2-carboxyethylacrylate, polyethylhexylacrylate, poly-2-hydroxyethacrylate, poly-2-phenoxylethacrylate, poly-2-phenoxy lmetacri lato, poly-2-et i lbut l methacrylate, poly-9-anthraceni lmet i methacrylate, poly-4-chlorophenylacrylate, polycyclohexylacrylate, polydicyclopentenyloxyethyl acrylate, poly-2- (N, N-diethylamino) ethyl methacrylate, poly-dimethylaminoopentyl acrylate, 2 - (methacryloxy) ethyl ester of polycaprolactone, or polyfurfuryl methacrylate, poly (ethylene glycol) methacrylate, polyacrylic acid and poly (propylene glycol) methacrylate. Preferred examples of diacrylates which can be used, from which polyacrylates can be produced, are 2,2-bis- (4-me tacri loxi-pheni 1) -panoxy, 1,2-butanedioldiacrilate, 1,4- butanediol diarylate, 1,4-butanediol dimethacrylate, 1,4-cyclohexandioldimetacrilate, 1,10-decanediol di-methacrylate, diethylene glycol diacrylate, dipropylen glycolide, dimethylpropanediol dimethacrylate, triethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, 1-6 hexandioldiacri lato, neopentylglycoldiacrylate, polyethylene glycol dimethylmethacrylate, tripropylene glycol diacrylate, 2,2-bis- [4- (2-acryloxyethoxy) phenyl] propane, 2,2-bis - [4- (2-hydroxy-3-methacryloxypropoxy) phenyl ] -propane, bis (2-methacrylate loxieti 1), - 1, 9 -noni lenbis-carbamate 1,4-cyclohexanedimetanoldimetacrylate, and diacrylic urethane oligomers. Examples of triacrylates which can be used for the preparation of polyacrylates are preferably tris (2-hydroxyethyl) isocyanurate tri-methacrylate, tris (2-hydroxyethyl) isocyanuratetri-acrylate, trimethylolpropanetrimethacrylate, trimethylolpropanetriacrylate or pentaerythritol triacrylate. Examples of preferred tetraacrylates are pentaerythritoltetraacrylate, ditrimeti lopropane ethoxylated Examples of pentaacrylates are dipentaeri tri tolpentaacrylate and pentaacri lato-ester.

Polyacrylates also comprise other aliphatic unsaturated organic compounds such as, for example, polyacrylamides and unsaturated polyesters from the condensation reactions of unsaturated dicarboxylic acids and diols, and vinyl compounds, but also compounds with terminal double bonds. Examples for vinyl compounds are N-vinylpyrrolidone, styrene, vini 1-naphillie or vinylfimide. For particularly preferred methacrylamide derivatives belonging to substituted or unsubstituted (meth) acrylamide of N-alkyl or N-alkylene, similar to, for example, acrylamide, methacrylamide, N-methacrylamide, N-methylmethacrylamide, N-ethylacrylamide, N, N-dimethylacrylamide, dimethylmethacrylamide, N, N-diethyl, lacrylamide, N- and lmetacri-lamide, N-methyl-N-y-acrylamide, N-isopropylacrylamide, Nn-polyacrylamide, N-isopropylmethacrylamide N-propymetacri lamide, N-acryloyl pyrrolidine, N-methacri loi Ipirrol idine, N-acryloylpiperidine, N-methacryloylpiperidine, N-acryloylhexahydroazepine, N-acri loi lmorfol ina or N-methacryloylmorpholine. Other polymers useful in accordance with the invention are unsaturated and saturated polyesters, in particular also including alkyd resins. The polyesters may contain polymer chains, various saturated or aromatic dibasic acids and anhydrides. In addition, the epoxy resins, which can be used as tnonomers, oligomers or polymers, especially those containing one or a plurality of oxirane rings, have one of the aliphatic, aromatic or aliphatic-aromatic molecular structures mixed, or exclusively without benzoids , in this way the aliphatic or cycloaliphatic structures with or without their halogen-like constituents, ester groups, ether groups, sulfonate groups, siloxane groups, nitro groups or phosphate groups or any combinations thereof. In particular, epoxy resins of the glycidyl-epoxy type are preferred, for example, with diglycidyl ether groups of bisphenol-A. Further preferred are, in particular, epoxy-derived amino resins, tetragl icidi -diadianediphenium methane, triglycidyl-p-aminophenol, triglycid 1 -amino-enol or triglycidylaminocresol and their isomers, epoxy-phenol resins -derivatives similar to, for example, bisphenol resins- A-epoxy, bisphenol-F-epoxy resins, bisphenol-S-epoxy resins, phenol-novolak epoxy resins, cresol -novolak epoxy resins or resorcinol epoxy resins, or alicyclic epoxy resins. In addition to halogenated epoxy resins, glycidyl ethers of polyhydric phenols, diglycidyl ethers of bisphenol A, glycidyl ethers of Novolak phenol-formaldehyde resins and resorcinol digilcidyl ethers, as well as other epoxy resins, as described in United States Patent 3,018,262 and incorporated with the same as reference explicitly. According to the invention, the choice is not restricted to the examples mentioned only; It is also possible in particular to select mixtures of two or a plurality of epoxy resins as well as mono epoxy components. The selected epoxy resins also include UV and cycloaliphatic crosslinkable resins. Preferred polymers are also polyamides (nylons) similar to, for example, aliphatic or aromatic polyamides among others also in specific embodiments nylon-6- (polycaprolactam), nylon 6/6 (polyhexamet and lenadipamide), nylon 6/10, nylon 6/12, nylon 6 / T (teref talamide polyhexamethylene), nylon 7 (polyenantamide), nylon 8 (polycaprylactam), nylon 9 (polypelargonamide), nylon 10, nylon 11, nylon 12, nylon 55, nylon XD6 (poly meta-xylylene adipamide), nylon 6/1, polyalanine. In addition to the polymers, but not restricted to them, which are preferably used are polyimides, polyesterimides, polyamideimides, polyesterimides., polyesters teramideimides. In a specific embodiment, conductive polymers are selected, preferably from saturated or unsaturated poliparafeni lenvini leno, poly iparafeni leno, polyaniline, polythiophene, polyazines, polyfurans, polypyrroles, polyselenophene, pol i -p-pheni lensul furo, polyacetylene either as monomers, oligomers or polymers, in any combination and mixtures with other monomers, oligomers or polymers or copolymers of the monomers mentioned above. It is especially preferred that they contain ono or a plurality of organic radicals, for example, alkyl or aryl radicals or the like, or inorganic radicals, such as for example, silicon or germanium or the like, or any mixtures thereof. Conductive or semiconducting polymers with resistances between 1012 and 105 Ohm »cm are preferred. It may be especially preferred to select those polymers in which complexed metal salts are contained which is the reason why polymers containing nitrogen, oxygen, sulfur or halides or double bonds or triple unsaturated bonds are preferred, and others that are suitable for the formation of complexes For example, without restricting the selection of polymers suitable therefor, elastomers are similar to polyurethanes and rubbers, adhesive polymers and plastics. Preferred metal salts include transition metal halides such as, for example, CuCl 2, CuBr 2, CoCl 2, ZnCl 2, NiCl 2, FeCl 2, FeBr 2, FeBr 3, Cul 2, FeCl 3, Fel 3, or Fel 2, in addition to the Cu-like salts (N 3) 2, metal lactates, metal glutamates, metal succinates, metal tartrates, metal phosphates, metal oxalates, LiBF4, and H4Fe (CN) 6 and the like. In addition, biocompatible polymers, in this case biodegradable, are for example, but not exclusively, collagens, albumin, gelatin, hyaluronic acid, starch, cellulose (methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, phthalate); also casein, dextran, polysaccharides, fibrinogen, poly (D, L-lactide), poly (D, L-lactide-co-glycolide), poly (glycolide), poly (hydroxybutylate), pol i (alkyl carbonate), poly (ortho) teres), polyesters, poly (hydroxyvaleric acid), polydioxanone, poly (ethyleneetrephthalate), poly (malic acid), poly (tartronic acid), polyanhydride, polyphosphohazene, poly (amino acids), and all their copolymers or any mixtures. In specific embodiments, it may be particularly preferred to select from pH sensitive polymers, similar to, for example, but not exclusively: poly (acrylic acid) and derivatives, for example: homopolymers similar to poly (carboxylic acid), poly (acrylic acid), poly (methyl acrylic acid) and its copolymers. This also applies to polysaccharides similar to cellulose acetate-phthalate, hydroxypropylmethylcellulose-talate, hydroxypropyl-1-methylcellulose-succinate, cellulose-acetate-trimellitate and chitosan. In certain embodiments, it may be especially preferred to select from temperature-sensitive polymers, similar to, for example, but not exclusively: poly (N-isopropylacrylamide-co-sodium-acrylate-co-n-alkyl acrylamide), poly (N-) methyl-N-propylacrylamide), poly (N-methyl-N-isopropylacrylamide), poly (NN-propylmethacrylamide), poly (N-isopropylacrylamide), poly (N, N-diethylacrylamide), poly (N-isopropylmethacrylamide), poly (N-cyclopropylacrylamide), poly (N-ethylacrylamide), poly (N-ethylmethylacrylamide), poly (N-methyl-N-ethylacrylamide), poly (N-cyclopropylacrylamide). Other polymers with thermogel characteristics are hydroxypropyl cellulose, methylsilicate, hydroxypropylmethylcellulose, ethylhydroxyethylcellulose and pluronics similar to F-127, L-122, L-92, L-81, L-61. In certain embodiments, it may be especially preferred to use the polymers for the encapsulation of agents for signal generation, wherein predominantly there is no covalent bond between the agents for mono, bi-tri- or multi-function signal generation, or the agents for Generation of bound signal in the polymers as described above are provided in the form of polymer spheres or particles in suspension or emulsion. It is well known in the art to manufacture these capsules in the form of a mini- or micro-emulsion. UA 9169501, EP 1205492, U.S. Patent 6,380,281, CN 1262692T, U.S. 2004192838, EP 1401878, EP 1352915, CA 1336218, EP 1240215, BE 949722, DE 10037656 provide a general perspective, in addition S. Kirsch, K. Landfester, O. Shaffer, MS El-Aasser: "Particle morphology of carboxylated poly- ( n-butyl acrylate) / (poly (me thyl methacrylate) composite latex particles investigated by TEM and NMR "Acta Polymerica 1999, 50, 347-362; K. Landfester, N. Bechthold, S. Fórster, M. Antonietti:" Evidence for the preservation of the particle identity in miniemulsion polymerization "Macromo 1. Rapid Commun., 1999, 20, 81-84; K. Landfester, N. Bechthold, F. Tiarks, M. Antonietti:" Miniemulsion polymerization with cationic and nonionic surfactants: A Very efficient use of surfactants for heterophase polymerization "Macromolecules 1999, 32, 2679-2683; K. Landfester, N. Bechthold, F. Tiarks, M. Antonietti:" Formulation and stability mechanisms of polymerisable miniemulsions "Macromolecules 1999, 32, 5222 -5228; G. Baskar, K. Landfester, M. Antonietti: "Comb-like p olymers with octadecyl side chain and carboxyl functional sites: Scope for efficient use in polymerization miniemulsion "Macromolecules 2000, 33, 9228-9232; N. Bechthold, F. Tiarks, M. Willert, K. Landfester, M. Antonietti: "Miniemulsion polymerizat ion: Applications and new materials" Macromol. Syrap. 2000, 151, 549-555; N. Bechthold, K. Landfester: "Kinetics of miniemulsion polymerization as revealed by calorimetry" Macromolecules 2000, 33, 4682-4689; BM Budhlall, K. Landfester, D. Nagy, ED Sudol, VL Dimonie, D. Sagl, A. Klein, MS El-Aasser: "Characterization of partially hydrolyzed poly (vinyl alcohol) I. Sequence distribution via HI and C- 13-NMR and a reversed-phased gradient elution HPLC technique "Macromol. Symp. 2000, 155, 63-84; D. Columbie, K. Landfester, E.D. Sudol, M.S.A.Asser: "Competitive adsorption of the anionic surfactant Triton X-405 on latex latex PS" Langmuir 2000, 16, 7905-7913; S. Kirsch, A. Pfau, K. Landfester, O. Shaffer, M. S. El-Aasser: "Partiole morphology of carboxylated poly- (n-butyl acrylate) / poly (methyl methacrylate) latex latex composite" Macromol. Symp. 2000, 151, 413-418, K. Landfester, F. Tiarks, H.-P. Hentze, M. Antonietti: "Polyaddition in miniemulsions: A new route to polymer dispersions" Macromol. Chem. Phys. 2000, 201, 1-5; K. Landfester: "Recent developments in miniemulsions -Formation and stability mechanisms" Macromol. Symp. 2000, 150, 171-178; K. Landfester, M. Willert, M. Antonietti: "Preparation of polymer particles in non-aqueous direct and inverse rainiemulsions" Macromolecules 2000, 33, 2370-2376; K. Landfester, M. Antonietti: "The polymerization of acrylonitrile in miniemulsions:" Crumpled Latex Particles "or polymer nanocrystals" Macromol. Rapid Comm. 2000, 21, 820-824; B. z. Putlitz, K. Landfester, S. Fórster, M. Antonietti: "Vesicle forming, single tail hydrocarbon surfactants with sulfonium- headgroup" Langmuir 2000, 16, 3003-3005; B. Z. Putlitz, H.-P. Hentze, K. Landfester, M. Antonietti: "New cationic surfactants with sulfonium-headgroup" Langmuir 2000, 16, 3214-3220; J. Rottstegge, K. Landfester, M. Wilhelm, C. Heldmann, H. Spiess: "Different types of water in film formation process of latex dispersions as detected by solid-state nuclear magnetic resonance spectroscopy" Colloid Polym. Sic. 2000, 278, 236-244; M. Antonietti, K. Landfester: "Single molecule chemistry with polymers and colloids: A way to handle complex reactions and physical processes?" ChemPhysChem 2001, 2, 207-210; K. Landfester, H.-P. Hentze: "Heterophase polymerization in inverse systems" In Reactions and Synthesis in Surfactant Systems; J. Texter, Ed .; Marcel Dekker, Inc.: New York, 2001; pp 471-499; K. Landfester: "Polyreact ions in miniemulsions" Macromol. Rapid Comm. 2001, 896-936; K. Landfester: "The generation of nanoparticles in miniemulsion" Adv. ater 2001, 10, 765-768; K. Landfester: "Chemie Rezept ionsgeschichte" in "Der Neue Pauly Enzyklop die der Antike"; J.B. Metzler: Stuttgart, 2001; Vol. 15; B. z. Putlitz, K. Landfester, H. Fischer, M. Antonietti: "The generation of" armored latexes "and hollow inorganic shells made of clay sheets by templating cationic miniemulsions and latexes" Adv. Mater. 2001, 13, 500-503; F. Tiarks, K. Landfester, M. Antonietti: "Preparation of polymeric nanocapsules by miniemulsion polymerization" Langmuir 2001, 17, 908-917; F. Tiarks, K. Landfester, M. Antonietti: "Encapsulat ion of carbon black by miniemulsion polymerization" Macromol. Chem. Phys. 2001, 202, 51-60; F. Tiarks, K. Landfester, M. Antonietti: "One-step preparation of polyurethane dispersions by miniemulsion polyaddi t ion" J. Polym. ScL, Polym. Chem. Ed. 2001, 39, 2520-2524; F. Tiarks, K. Landfester, M. Antonietti: "Silica nanoparticles as surfactants and fillers for latexes made by miniemulsion polymerization" Langmuir 2001, 17, 5775-5780. The references provided will be expressly incorporated herein according to the invention.

MATERIALS / COMPONENTS Implantable medical devices or materials for implantable medical devices or their components are a part of the combination according to the invention. This has to be fundamentally decided whether a bulk material is provided with the properties for signal generation in which the signal generation agents are bound in the matrix of the material of the implantable medical device, or if the medical device prepared is will provide, at least in part, with a coating for signal generation. In accordance with the invention, there is also the possibility of combining both variants. In a generally applicable embodiment, the medical device itself is part of the inventive combination, and the device is combined with at least one agent for signal generation and at least one therapeutically active agent. This may be the incorporation of agents for signal generation and therapeutically active agents in the material of the implantable device itself, which is especially preferred if the device is made of resorbable or degradable materials.

In another generally applicable embodiment, the implantable device itself is not part of the inventive combination, and can be equipped, for example, with a coating comprising the inventive combination, that is, the at least one device for generation of signal, the at least one therapeutically active agent and the at least one material for the manufacture of an implantable medical device, which in this case may for example be a suitable coating material similar to for example pyrolytic carbon, a polymer, a film coating or the like. The term "at least one material for the preparation of an implantable medical device and / or at least one component of an implantable medical device" includes all the modalities described above. According to the invention, the implantable medical device or component of the provided implantable medical device may consist of a flat or spherical body, or any desired three-dimensional shape in different dimensions, also in particular tubular or other hollow body shapes. The form of the implantable medical device or component of the implantable medical device is not relevant for the application of the present invention. With implantable medical devices, any devices that are incorporated within an organism are designed as ultra-short-term, short-term or long-term devices for diagnostic or therapeutic or prophylactic or combined diagnostic-therapeutic / prophylactic purposes. In the following the terms "implantable medical device" and "implant" are used synonymously. According to the invention, the selected mammals are related to organisms. Mammals according to the invention include all mammals, for example, but not exclusively, domestic animals similar to dogs and cats, agricultural livestock such as, for example, cattle, sheep, or goats, laboratory animals similar to mice, rats , primates similar to apes, chimpanzees etc., and humans. In preferred embodiments, implants and implanted active substances, which are designed for use in humans, will be selected. The implantable medical devices that will be selected are not limited to any particular implant such that, for example, but not exclusively, stent grafts, intraluminal stent grafts, stent grafts, coronary stent grafts, peripheral stent grafts, pacemakers or parts of the same, surgical and orthopedic implants for temporary purposes similar to alveolar inserts in joints, surgical screws, plates, nails, implantable auxiliaries for orthopedic support, surgical and orthopedic implants such as for example, bone or joint prostheses, for example, vertebral bone and bodily means for artificial hip or knee joints, artificial hearts or parts thereof, artificial heart valves, accommodation for cardiac pacemakers, electrodes, subcutaneous and / or intramuscular implants, deposits of active substances or microplates or the like. The materials for implantable medical devices can be selected from non-degradable or fully degradable materials or any combinations thereof. The implant materials may also consist of materials based entirely on metal or alloys or composites, also laminated materials, carbon or carbon composites, also composite materials thereof, or any desired combinations of the mentioned materials. In certain embodiments, materials with a ceramic and / or metal base, such as, for example, amorphous and / or (partially) crystalline carbon, excess carbon material ("Vol lkarbon"), porous carbon, graphite, materials, are especially preferred. carbon compounds, carbon fibers, ceramics similar to for example, zeolites, silicates, aluminum oxides, aluminum silicates, silicon carbide, silicon nitride; metal carbides, metal oxides, metal nitrides, metal carbides, metal oxycarbons, metal oxynitrides and metal oxycarbonitrides of transition metals similar to titanium, zirconium, hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, manganese, rhenium, iron , cobalt, nickel; metals and metal alloys, especially of noble metals such as gold, silver, ruthenium, rhodium, palladium, osmium, iridium, platinum; metals and metal alloys of titanium, zirconium, hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, manganese, rhenium, iron, cobalt, nickel, copper, magnesium; steel, especially stainless steel, especially 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- 2 lCr - ??? - 1N (stainless steel without nickel) or radiopaque steel alloys containing platinum, called PERSS (radiopaque stainless steel alloys improved with platinum), as well as shape memory alloys similar to nitinol, nickel-titanium alloy, glass, stone, glass fibers, minerals, natural or synthetic bone substance, carbonates based on imitation bone or alkaline earths similar to calcium carbonate, magnesium carbonate, strontium carbonate, hydroxyapatite as well as any combinations of materials 1 iares In further embodiments, polymers are preferred, for example, selected on the basis of polyacrylates similar to polymethyl methacrylates or unsaturated polyesters, from saturated polyesters, a polyolefin (for example, polyethylene, polypropylene, polybutylene, and the like). ), an alkyd resin, an epoxy-polymer, a polyamide, a polyimide, a polyetherimide, a polyamideimide, a polyesterimide, a polyurethane imide, polyurethane, polycarbonate, polystyrene, polyphenol, polyvinyl ester, polysilicone, polyacetal, cellulose acetate, chloride polyvinyl acetate, polyvinyl acetate, polyvinyl alcohols, polysulfones, polyphenylsulphones, polyethersulphones, polyketones, polyetherketones, polyetheretherketones, polyetherketone ketones, polybenzimidazoles, polbenzoxazoles, polbenzosol, polyfluorocarbons, polyphenylene ethers, polyarylates, cyanatoesterpolymers , copolymers of two or more of those mentioned and the like. The polymers that can be used are especially acrylics, so monoacri lates, diacrylates, triacrylates, tetraacrylates, pentacrites, and the like are preferred. Examples of polyacrylates are polyisobornyl acrylate, polyisobromylmethacrylates, polyethoxyethoxyethyl acrylates, poly-2-carboxy tarylacrylates, polyethylethexyl acrylates, poly-2-hydroxyethyl acrylates, poly-2-phenoxy lactylalates, poly-2-phenoxyethyl methacrylates, poly-2-ethylbutylmethacrylates, poly-Santracenylmethyl methacrylates, poly-4-chlorophenylacrylates, polycyclohexylacrylates, polydicyclopentenyloxy-ethacrylates, poly-2 - (, - diethylamino) and -l-methacrylates, poly-dimethylamino-pentylacrylates, - (methacryloxy) ethylesters of pol i-caprolactone, or polyfurfurylmethacrylates, poly (ethylene glycol) -methacrylates, polyacrylic acid and poly (propylene glycol) methacrylates. Preferred examples of diacrylates which can be used, from which polyacrylates can be prepared are 2, 2-bis (4-methacryloxy-3-methylpropane, 1,2-butanediol diacrylate, 1, 4 -butanediol diarylate, 1,4-butanediol dimethacrylate, 1,4-cyclohexandioldimetacrilate, 1,10-decanediolmethacrylate, diethylene glycol diacrylate, dipropyl glycol diacrylate, dimethylpropandioldi-methacrylate, triethylglycoleldimethacrylate, tetraethylene glycol dimethacrylate, , 6-hexandioldiacri lato, neopentyl glycol diacrylate, polyethylene glycol dimethacrylate, tripropylene glycol diacrylate, 2,2-bis [4- (2-acryloxyethoxy) phenyl] propane, 2,2-bis [4- (2-hydroxy-3-methacryl ipropoxy) phenyl] -propane, bis- (2-methacryloxyethyl) N, Nl, 9-nonylene-biscarbamate, 1,4-cyclohexanedimethanol-dimethacrylate, and diacrylic urethane oligomers. Examples for triacrylates, which can be used for the preparation of polyacrylates, are preferably tris (2-hydroxyethyl) isocyanurate trimethacrylate, tris (2-hydroxyethyl i) isocyanurate triacrylate, trimethylolpropanetrimethacrylate, trimethylolpropanetriacrylate or pentaeri tri toltriacrilate . Preferred examples for tetraacrylate are pentaerythritoltetraacrylate, ditrimethylpropane tetraacrylate, or ethoxylated pentaerythritoltetrahydrate. Examples for pentaacri lates are dipentaerythritol pentaacrylate and pentaacrylate esters. The polyacrylates also include other unsaturated aliphatic organic compounds such as, for example, polyacrylamides and unsaturated polyesters from the condensation reactions of unsaturated dicarboxylic acids and diols, and vinyl compounds, but also compounds with terminal double bonds. Examples for vinyl compounds are N-vinylpyrrolidone, styrene, vinyl naphthalene or vinylfimide. For methacrylamide, derivatives which belong to substituted or unsubstituted (meth) acrylamide of N-alkyl or N-alkylene, similar to, for example, acrylamide, methacrylamide, N-methacrylamide, N-met i lme tac ri lamide, are especially preferred. - et lacrylamide, N, N-dimethylacrylamide, N, N-dimet i lmetacri lamide, N, N-diethylacrylamide, N- et i lme tacri lamide, N-methyl-N-ethylacrylamide, N-isopropylacrylamide, Nn-propi lacrylamide,? - isopropylmethacrylamide,? -? - propylmethacrylamide, N-acryloyloylpyrrolidine, limetacri loi Ipyrrol idine, N-acryloylpiperidine, N-methacryloylpiperidine, N-acryloylhexahydroazepine, N-acryloylmofoline or N-methacryloylmofoline. Other useful polymers, according to the invention, are unsaturated and saturated polyesters, also including especially alkyd resins. The polyesters may contain polymer chains, various numbers of saturated or aromatic dibasic acids and anhydrides. In addition to the epoxy resins, which can be used as monomers, the oligomers or polymers containing one or plural oxirane rings, have an aliphatic, aromatic or aliphatic-aromatic molecular structure mixed, or exclusively without benzenoids, therefore aliphatic structures or cycloaliphatic, with or without halogen-like substituents, ester groups, ether groups, sulfonate groups, siloxane groups, nitro groups or phosphate groups or any combinations thereof. Especially preferred are epoxy resins of the glycidyl-epoxy type, for example, having diglycidyl ether groups of bisphenol-A. Especially preferred are further derived amino epoxy resins, for example, tetraglycidyldiamine-diphenylmethane, triglycidyl-p-aminophenol, triglycidyl-m-aminophenol or triglycidylaminocresol and their isomers, epoxy resins derived from phenol similar to, for example, bisphenol-A epoxy resin , bisphenol-F epoxy resin, bisphenol-S epoxy resins, phenol -novolak epoxy resins, cresol -novolak epoxy resins or resorcinol epoxy resins, or alicyclic epoxy resins. In addition halogenated epoxy resins, glycidyl ether of polyhydric phenols, diglycidyl ether of bisphenol A, glycidyl ethers of novolak phenol-formaldehyde resins and resorcinol-diglycidyl ether, as well as other epoxy resins as described in the United States Patent 3, 018,262 and is incorporated herein by reference explicitly. According to the invention, the selection is not restricted to the aforementioned single epoxy resins, mixtures of two or three epoxy resins as well as the mono epoxy components can also be especially selected. The epoxy resins to be selected also include UV and cycloaliphatic crosslinked resins. Preferred polymers are also polyamides, similar to, for example, aliphatic or aromatic polyamides (the examples are included), inter alia also in specific embodiments Nylon-6 - (polycaprolactam), nylon 6/6 (polyhexamethylene adipamide), nylon 6/10, nylon 6/12, nylon 6 / T. { teref talamide of polihexamet ileno), nylon 7 (polyenantamide), nylon 8 (polycaprylactam), nylon 9 (polypelargonamide), nylon 10, nylon 11, nylon 12, nylon 55, nylon XD6 (polymethylamine adipamide), nylon 6 / 1, poly-alanine. Furthermore, although not restricted thereto, the polymers that are preferably used are polyimides, polyesterimides, polyamideimides, polyesterimides, polyesteramideimides. In a specific embodiment, conductive polymers are selected, preferably from poliparafeni lenvini leno, polyparaphenylene, polyaniline, polythiophene, polyazines, polyfurans, polypyrrole, polyselenophene, pol i -p-pheni lensulfide, saturated or unsaturated polyacetylene either as monomers, oligomers or polymers, in any combination and mixtures with other monomers, oligomers or polymers or copolymers of the monomers mentioned above. It is especially preferred that they contain one or a plurality of organic radicals, for example, of alkyl or aryl or the like, or inorganic radicals, such as for example, silicon or germanium or the like, or any mixtures thereof. Conductivities or semiconductor polymers with resistivities between 1012 and 105 ohm cm are preferred. It may be especially preferred to select these polymers in which complexed metal salts are contained which is why it is preferred that the polymers contain nitrogen, oxygen, sulfur or halides or double bonds or triple unsaturated bonds, and others that are suitable for the formation of complexes For example, without restricting the choice of polymers suitable thereto, mention must be made of elastomers similar to polyurethanes and rubbers, adhesive polymers and plastics. Preferred metal salts include transition metal halides such as, for example, CuCl 2, CuBr 2, CoCl 2, ZnCl 2, NiCl 2, FeCl 2, FeBr 2, FeBr 3, Cul 2, FeCl 3, Fel 3, or Fel 2, in addition to the Cu-like salts (N 3) 2, metal lactates, metal glutamates, metal succinates, metal tartrates, metal phosphates, metal oxalates, LiBF4, and H4Fe (CN) 6 and the like. In a specific embodiment, conductive polymers are selected, preferably from polyparaphenylenevinylene, polyparaphenylenes, polyanamines, polythiophenes, polyazines, polyfurans, polypyrroles, polyselenophenes, poly-p-phenols, sulphide, saturated or unsaturated polyacetylenes either as monomers , oligomers or polymers, in combination and arbitrary mixtures with other monomers, oligomers or polymers or copolymers of the monomers mentioned above. It is especially preferred that they contain one or a plurality of organic radicals, for example, of alkyl or aryl or the like, or inorganic radicals, such as for example, silicon or germanium or the like, or arbitrary mixtures thereof. Conductivities or semiconductor polymers with resistivities between 1012 and 105 ohm cm are preferred. It may be especially preferred to select these polymers in which complex metal salts are contained which is why they will be preferred to contain nitrogen, oxygen, sulfur or halides or double bonds or triple unsaturated bonds, and others which are suitable for the formation of complex. Here, for example, mention may be made without restriction of the choice of suitable polymers, polyurethane-like elastomers and rubber, adhesive polymers and plastics. Preferred metal salts include transition metal halides such as, for example, CuCl2, CuBr2, CoCl2, ZnCl2, NiCl2, FeCl2, FeBr2, FeBr3, Cul2, FeCl3 / Fel3, or Fel2, in addition to the Cu-like salts (N03). 2, metal lactates, metal glutamates, metal succinates, metal tartrates, metal phosphates, metal oxalates, LiBF4, and H4Fe (CN) 6 and the like. In addition, biocompatible polymers, in the present biodegradable, are especially preferred.for example, but not exclusively, collagens, albumin, gelatin, hyaluronic acid, starch, cellulose (methylocellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose-phthalate, - besides casein, dextran, polysaccharides, fibrinogen, poly ( D, L-lactivity), poly (D, L-ido-co-glycolide), poly (glycol), poly (hydroxybutyl), poly (alkyl carbonate), poly ( orthoester), polyesters, poly (hydroxyvaleric acid), poly idioxanone, poly (ethylene terephthalate), poly (malic acid), poly (tartronic acid), polyanhydrides, polyphosphohazenes, poly (amino acids), and all their co-polymers or any mixtures thereof Metal-based materials, such as, for example, biodegradable or biocorrodible metal alloys, similar to, for example, but not exclusively alloy, can be selected especially preferably from the degradable materials. is magnesium, or glass-ceramic degradable materials similar to bioglass, silicates, or ceramics or ceramic-type materials such as, for example, hydroxyapatite and the like. Especially preferred implantable medical devices are for example, but not exclusively, non-degradable, or partially degradable or fully biodegradable devices selected from the types of implants for complete or partial bone replacement, for complete or partial replacement of joints, for replacement complete or partial vascular, coronary or peripheral endoprostheses, or other endoluminal vascular implants, for complete or partial vascular replacement, deposits of active agents or seed implants.

CHOICE OF MATERIALS According to the invention, the choice of the individual elements of the present invention has a special importance. In the preparation or use of materials for signal generation and the selection of implants or implant materials provided, the provision of agents for signal generation of the type of implant and the purpose of the implant must be considered, in accordance with the medical indication primary and the modalities for desired signal generation. According to the invention, the fundamental teaching is provided as follows: The determination of the end of the agents for signal generation, under which the following will be established: a) if the agents for signal generation will be selected exclusively to elaborate the device implantable doctor; b) whether the agents for signal generation will be selected exclusively to produce a surrounding tissue or compartments in the immediate or communicable limit area of the implantable medical device; c) whether the signal generating agents will be selected exclusively for the production of any desired tissues, cell types, organs or organic regions independent of the boundary zone for implantable medical devices, where these implantable medical devices can have the exclusive purpose of bring agents for signal generation within the body; d) if the signal generation agents in addition to the preparation of the implant are also selected for the production of surrounding tissue or compartments in the immediate or communicable limit area of the implant; e) if the agents for signal generation, besides the elaboration of the implantable medical device, will also be selected to produce any desired independent tissues, cell types, organs or organic regions of the limit area of the implantable medical device, where these devices can have the exclusive purpose of bringing agents for signal generation into the body; f) if the agents for signal generation are not selected primarily for the manufacture of implantable medical devices, but mainly for the production of surrounding tissue, or compartments in the immediate or communicable limit area of the implantable medical device; g) whether the agents for signal generation will not be selected mainly or not in their entirety for the development of implantable medical devices, although mainly for the production of any tissues, cell types, organs or organic regions regardless of their boundary area with the device, wherein these devices can have the exclusive purpose of bringing the agents for signal generation to the interior of the organism; h) whether the agents for signal generation will not be selected or not primarily for the manufacture of implantable medical devices, but also for the production of surrounding tissues, or compartments in the immediate limit area or communicable with the device also for the production of any cell types, organs or organic regions independent of the limit area of the device, wherein these devices can have the exclusive purpose of bringing the agents for signal generation to the interior of the organism; i) whether the agents for signal generation will also be selected in combination with therapeutic agents and performed up to h); j) whether the agents for signal generation will also be selected as signal generation agents combined with different signal modalities, wherein according to the modalities the physical and chemical properties and the detection methods are denoted; k) whether the signal generation agents selected up to now from a) to j) will be selected from agents for direct or indirect or mixed signal generation; In addition, the determination of the duration of the detection of the agents for signal generation, under which it is necessary to determine especially: a) whether the signal generation agents must be verifiable during ultra-short periods, according to the definition during the detection periods of a few seconds up to a maximum of 3 days; b) if the signal generation agents must be verifiable for short periods, according to the definition of 3 days up to 3 months. c) if the signal generation agents must be verifiable in the long term according to the definition for 3 months and more; d) whether the signal generation agents must be permanently verifiable for at least 12 months or more, preferably during the total life time of a non-degradable implant; In addition, the determination of the preferred embodiments, under which it is especially necessary to determine: a) it is preferred that the modality corresponds to the detection method, for example radiographic methods for X-rays, methods based on MRI and phosphorescence; b) it must prefer that the modalities are combined and available, for example, the combination of agents for generating radiopaque and paramagnetic signals; c) modalities will be selected in combination with agents for therapeutic signal generation; And finally, the functionality of the agents for signal generation in combination with the underlying implantable medical device, under which will be determined especially: a) if the signal generation agents should be selected exclusively for the verification of the correct anatomical location; b) whether the signal generating agents will be selected for the control of the operation of the implantable medical device, for example, but not exclusively, for biodegradable implants to detect the course of degradation; c) if the interaction of the implantable medical devices with the limiting tissues, for example, but not exclusively, the graft and / or the inflammatory reactions in the immediate surrounding or communicable areas of a implant; d) if for the agents for signal generation only, the release of additives should be controlled, especially for the so-called implantable medical device combined with function for drug delivery, such as for example, but not exclusively, drug eluting stents, in the present preferably through the use of agents for combined signal generation, combined with therapeutic agents; e) if the signal generating agents must comply with at least one of the aforementioned functions in accordance with a) to d) together with at least one or a plurality of the functions mentioned in accordance with a) to d); According to the invention, the underlying material or the composition or combination of implantable medical devices or components of the implantable medical devices, or the combination according to the invention, will be selected from non-degradable or partially degradable or fully degradable materials. The choice of the composition or combination may follow the expected end of the signal generation and the function of the agents for signal generation, or inversely the signal generation agents and their shape provided as a function of the material selected from a implantable medical device. It is clear to one skilled in the art that the choice of preferred materials should be made in accordance with the purpose of use and the end of indication of the implantable medical device and the underlying primary disease. However, there are the following criteria of choice for an improved implantable medical device according to the invention: The provision of implant materials for the complete or partial introduction of agents for signal generation in the integrated material system, where it will be established: a) if the material is processed by means of thermal agglomeration processes, in which the integration of the material for signal generation in the implant matrix is carried out before or during processing; b) if the material is processed by means of thermal agglomeration processes, where the integration of the material for signal generation in the implant matrix is carried out after processing, where at least one layer of material must be present open pore; c) if the material is processed by chemical processes without thermal stress, which leads to partial degradation or degradation of the materials for signal generation in the corresponding provided form; wherein the integration of the material for signal generation in the implant matrix is carried out before or during processing; d) if the material is processed by chemical processes without thermal stress, which leads to partial degradation or degradation of the materials for signal generation in the implant matrix where the integration of the materials for signal generation in the The implant matrix is carried out after processing, wherein at least one layer of open pore material must be present; e) if dealing with a completely, partially or non-degradable material where combinations of a to d) are possible or as desired thereof; The provision of implants for the complete or partial incorporation of agents for signal generation as a coating, where it has to be established: f) if the coating is made by means of thermal agglomeration processes, plasma spray methods, ion bombardment , etc., wherein the integration of the materials for signal generation in the coating is carried out before or during processing; g) if the coating is made by means of thermal agglomeration processes, plasma spray methods, sputtering, etc., where the integration of materials for signal generation in the coating is carried out after processing, where the coating may be enclosed or porous; h) if the coating is processed by chemical or thermal processes, which leads to a partial degradation or degradation of the signal generation agents in the corresponding proportioned form, where the integration of the material for signal generation in the coating is Carry out before or during processing; i) if the coating is processed by chemical processes without heat treatment which leads to partial degradation or degradation of the signal generation agents in the corresponding proportioned form, where the integration of the material for signal generation in the coating it is carried out after the elaboration; j) if it is dealing with a completely, or partially or non-degradable material, where f) to i) or any desired combinations thereof are possible. For the choice of essentially non-porous and non-degradable implants, the coating of the implant according to the invention is preferred. The coating can be selected from degradable or non-degradable materials, wherein the incorporation of the agents for signal generation and / or the therapeutically active agents can be carried out during or after processing. One of skill in the art can make the selection of any desired coating method corresponding to the prior art. The thermal coating methods require the choice of thermally stable signal generating agents. Non-thermal methods similar to spray coating, dip coating, etc., allow the selection from a multiplicity of possible types of preparation and their combinations as desired. If degradable coatings are selected, then types of biodegradable coatings are especially preferred, for example, formulated with polymers, either as mixtures, wherein the agents for signal generation are provided from solutions, suspensions, emulsions, dispersions, powders and similar, or as polymer formulations covalently linked to the agents for signal generation. Especially preferred are the degradable coatings having agents for generating bi-functional, tri-functional or multi- functional signal, most preferably combined with at least one therapeutic agent. In a further preferred embodiment, the implantable device or part thereof, for example, a coating on the device, comprises a porous material, within which, whether degradable or not, agents for signal generation are incorporated, for example, as a crosslinked network of particles. In this embodiment it is preferred to select at least one therapeutically active agent that can be soaked in the matrix by techniques known in the art, for example, by using suitable drug solvents, the device can be immersed or sprayed with a therapeutically active agent containing the solution with the subsequent incorporation of the drug in the matrix. In a specific embodiment, agents for signal generation are provided in inorganic, organic or inorganic-porous organic coatings, especially composite materials are preferred. Here, for example, porous coatings, although not exclusively, may comprise ceramic or metal-based materials, where these may also be biodegradable, for example, but not exclusively, from hydroxylapatites or the like or derivatives or similar, or bio-degradable species degradable. It is preferred to integrate these materials inherently for signal generation with other signal generation agents, either of the same modality for the intensification of the image forming signal, or one or a plurality of other especially preferred embodiments; in particular, signal generation agents are selected from nanoparticles. For degradable coatings it is preferred to select agents for biocompatible signal generation. It is mainly preferred to provide porous coatings from the signal generating agents, for example, but not exclusively, from inorganic or organic or inorganic-organic compounds mixed non-degradable or degradable, with polymeric forms provided, the nano or micro forms -amorfa provided or nanoparticles with metal base. The degradable implants are preferably provided with degradable signal generation coatings, preferably from degradable materials, having equal or similar or shorter degradation times. According to the invention, the coating of non-porous, degradable implants is particularly preferred, if the signal generation is to be fulfilled mainly in order to verify the correct anatomical location or is semi-quantitatively implied together with the course and therapeutic control of the degradation, of the graft and the interaction with the surrounding tissues, although not exclusively. In addition, the coating of non-porous and degradable implants is especially preferred when their material leads to a detriment of the function of the implant relative to the properties of the material if signal-generating agents are incorporated into the composite material. Thus, for example, with biodegradable implants similar to endografts, comprising biodegradable polymers such as, for example, PLA, no mechanical stability is provided for a function of the functional implant, if foreign substances similar to pharmacologically active substances are used. Coatings for signal generation of degradable implants are preferred to be provided especially in the form of coatings, in which the signal generating agents are in the desired forms, preferably as biocompatible nanoparticles, liposomes, micelles, micro- spheres, etc. they are incorporated in degradable polymers. Especially preferred are coatings, which have radiopaque signaling properties, or which contain bi-tri, or multi-functional signal generation agents, especially preferred with therapeutic agents. In a specific embodiment, the implants are prepared from biocompatible metal alloys, essentially non-toxic, which are degraded by corrosion, for example, but not exclusively, alloys with a magnesium or zinc base. If therapeutically active substances are released from the materials during the decomposition of these implants in the body, it is optionally possible, according to the invention, to be carried out without the addition of a separate active ingredient. Thus, in preferred embodiments, an implant or part of an implant based on a magnesium or zinc alloy is used, for example, a stent, which itself comprises the therapeutically active agent, because in the human organism or animal, magnesium ions are released by and during degradation in body fluids, resulting in the physiologically induced formation of H2, hydroxyl apatite and magnesium ions. In these embodiments, the release and availability of magnesium ions and the formation of hydroxyl apatite have biological effects well known in the art. Preferably, the implant or part thereof comprises the magnesium and / or zinc in the material itself for the construction of the implant, or in a coating, for example, by partial or total coating of the implant with magnesium and / or zinc particles. incorporated in a polymeric matrix or other coating material. In these embodiments, the combination of the therapeutically active agent and for signaling together with the implant material is constituted by the use of the signaling agent, Mg or Zn as a component of the alloy itself or as part of the implant, or as part of a coating. It is additionally preferred to provide these implants with biodegradable signal generation coatings, it is especially, but not exclusively preferred, with the signal generation agents, which are provided directly or incorporated into degradable polymers as nanoparticles, in the form of liposomes, microspheres, macrospheres, encapsulated in micelles or polymers, or covalently linked to polymers, are mainly preferred as bi, tri, or multifunctional agents for signal generation, especially, but not exclusively, together with less a therapeutic agent. In addition, it is preferred to provide these implants with porous biodegradable coatings, for example, hydroxylapatients and derivatives or the like, or bioglass, where any biocompatible, preferably biodegradable, signaling agents of nanomaterial particles are incorporated. in the porous coating, or any desired form of biocompatible or biodegradable signal generating agents, or both combined, in the hollow spaces of the porous matrix. Also, more preferably, degradable porous coatings of nanomorphic particles can be provided, which are selected from the signal generating agents, wherein the hollow spaces of these porous coatings for signal generation can be further loaded with the agents for generating sign in any way. In addition, non-porous, degradable coatings of the signal generating agents, preferably made of degradable nanomorphic particles, are possible. For the choice of essentially non-porous and essentially non-degradable implants, according to the invention, signal generating agents can be added as a part of the precursor components for the implant material. If thermal methods are selected for the preparation of the implant corresponding to the prior art, thermally stable forms of the agents for signal generation are preferred. For metal-based implant materials, it is preferred that the signal generating agents impart the inherent signal generating properties of the starting material used in at least one other additional property for signal generation from the modalities of the starting material . In addition, for essentially non-porous and non-degradable implants from polymeric materials or polymer composites it is preferred to select from these agents for signal generation, which can be added to the reactive components formed from solutions, emulsions, suspensions , dispersions, powders etc. or as covalent components from monomers, dimers, trimers or oligomers or else from prepolymer precursors that can be synthesized to polymers, and produce the material thereof. For essentially non-porous and non-degradable implants from polymeric materials or polymeric composite materials, it is preferred to provide at least one embodiment that represents a property for signal generation, preferably agents for bifunctional, tri-functional signal generation or multifunctional, wherein the non-porous and non-degradable materials or implants according to the invention do not contain any of the therapeutic agents or target groups within the composite of materials. It may be especially preferred for non-porous and non-degradable implants to provide the reactive components of the implant material with signal generation agents in a suitably terminated form and to provide the finished implant with an additional coating for signal generation. For the choice of essentially non-porous and essentially degradable implants, according to the invention, the signal generation agents can be added as a part of the precursor components to the implant material. Preferred implant materials are polymers or polymeric compounds, as well as metal-degradable materials or their degradable compounds or materials based on naturally occurring apatites, hydroxy lapatites, their analogues and derivatives, or materials comparable to bone substitutes or based on bio-vitreous species. Furthermore, for essentially non-porous and essentially degradable implants from polymeric materials or polymer composites, it is preferred to select these signal generation agents which can be added to the reactive components from solutions, emulsions, suspensions, dispersions, powders etc. or as covalent components of monomers, dimers, trimers or oligomers or other pre-polymeric precursors, which can be synthesized to polymers and produce the active substance thereof. In contrast to WO04 / 064611, the signal generating agents are added to degradable biopolymers similar to those or polylactides, polyglycolides, their derivatives and mixtures thereof or their copolymers, which preferably have radiopaque properties and and combine with at least another embodiment, or at least bifunctional radiopaque properties in combination with a therapeutic agent or at least one non-radiopaque modality. Especially preferred are those agents for signal generation that are coupled with one or a plurality of target groups and / or a plurality of therapeutic agents. This is additionally preferred for materials that are based on apatites that occur in nature, hydroxyl apatites, their analogues and derivatives, comparable bone substitutes or bioglass and the like. It may be especially preferred for non-porous and degradable implants to add the signal generating agents to the reactive components of the implant in a suitable form and to provide the shaped implant with an additional coating for signal generation. In a specific embodiment, the implants are prepared from biocompatible metal alloys, essentially non-toxic, which are degraded by corrosion, for example, but not exclusively, alloys with a magnesium or zinc base. It is preferred to add the thermally stable finished forms of the signal generating agents to the residual components of these implant materials if they are made by the thermal methods corresponding to the prior art. Especially it is preferred that the signal generating agents have radiopaque, bi and trifunctional properties, as well as the agents for generating multifunctional signal in the appropriate proportioned forms, it is preferred that the signaling agents are coupled with the therapeutic agents. and / or white groups. It may be especially preferred for non-porous and degradable materials that the signal generating agents be added to the reactive components of the implant materials in a suitable manner, to provide the implant formed with an additional coating for signal generation. Porous, essentially non-degradable or degradable implants can already contain the agents for signal generation in their composite structure of materials, for example, as described above according to the invention. It is especially preferred to provide porous implants with the agent for signal generation after processing. According to the invention, it must be distinguished whether the implants according to the manufacturing process already have a porous composite material, or whether the implants are provided with porous coatings. It is preferred, but not exclusively, that the implants have a structure of porous material. The preferred pore sizes, according to the invention, are pores having an average size of 1 nm to 10 mm, especially from 1 nm to μp ?, especially from 2 nm to 1 μp are preferred. The provision of at least one sufficiently porous surface is important, which can be loaded with the agents for signal generation. In fact, with regard to this, whether this surface is created later, or not, if the porosity is produced by a specific process for the manufacture of implants or if a composite of open-pore materials is involved. The signal generation agents are introduced into the porous compartment preferably from solutions, suspensions, dispersions or emulsions or with the additives selected by someone skilled in the art, such as, for example, surfactants, stabilizers, flow improvers, etc. by means of suitable methods, for example, immersion, spray, injection and other suitable methods of the prior art. The porous implants may be selected from any materials similar to, for example, but not exclusively, polymers, glass, metals, alloys, bones, stone, ceramics, minerals or compounds. It is not important if they are degradable, non-degradable or partially degradable. It is preferred to provide agents for monofunctional signal generation, it is mainly preferred to select agents for bi-functional or tri-functional signal generation, especially those coupled with therapeutic agents are preferred. In another specific embodiment, the porous materials are produced by the introduction of suitable forms of the agents for signal generation. In this way, non-degradable polymers, polymeric compounds or ceramics or ceramic composites or metal-based materials or metal-based composites or similar materials can already contain materials for signal generation in the form of materials of filling during the manufacturing process, in such a way that they serve as the components of the matrix of basic materials of the total composition. It is then especially preferred to select agents for signal generation encapsulated in polymers, for example, in the form of polymer capsules, drops or beads, produced in the form of mini or micro-emulsion, or especially for the polymer-based materials select a starting from the signal generation agents encapsulated in polymers, micelles, liposomes or microspheres, or, however, from nanoparticles. These implantable medical devices have an in-vivo porous matrix structure, when by dehydration or degradation they release the filling materials and the agents for signal generation and / or the therapeutic agents contained in the filling materials, the matrix of basic materials remains . According to the invention, adjuvants or fillers are added to the composition or combination of materials. The adjuvants or fillers can be selected to allow a binding between the signal generating agents or the therapeutic agents with the implant material and / or between the agents. A further objective of the adjuvants and fillers may comprise enabling the material to be bound to the composition or combination by physical or chemical forms, or modulating the elasto-mechanical, chemical or biological properties. In particular, the adjuvants and fillers are selected as described above to form micelles, microspheres, macrospheres, or liposomes, nano, micro- and macro-capsules, micro-bubbles etc. or functional units, for example, by linking functional groups and suitable compounds. In addition, adjuvants and fillers are selected to join the composition as a component of an implantable medical device to another component or a part of the implantable device., for example, in the form of a coating. In this way, the adjuvants can consist of polymeric, non-polymeric, organic or inorganic materials or compounds. The adjustment of the elasto-mechanical properties can be carried out by adding carbon, polymer, glass, or other fibers of any size in woven or non-woven form. It is especially preferred to select adjuvants, which modulate, for example, retard the release of the signal and / or therapeutic agents. One skilled in the art, with reference to this, will select adjuvants which are in accordance with the purpose and location of insertion of the implantable medical device, a degradable or non-degradable material is selected as the component of the composition or combination, or a hydrophobic or hydrophilic material or any desired mixtures thereof, or the crystalline, semi-crystalline or amorphous forms of these adjuvants. For release from partially degradable or degradable or non-degradable devices, the rate of degradation in the physiological medium can be adjusted, for example, by the mixture of hydrophobic and hydrophobic adjuvants. Furthermore, by choosing substances by their melting point, the predominant presence of crystalline, semi-crystalline or amorphous phases can be adjusted, also of the mixtures of hydrophobic and hydrophobic substances, for example, by selecting polymers having melting points, near, above or below the body temperature of the target organism, and thus the solubility of the adjuvants, which for example, exist as a matrix, micelles, microspheres, liposomes or capsules or similar structures, and which adjusts the elution or erosion or degradation of the agents or medical devices. Another possibility according to the invention is to adjust the solids content of the adjuvants, and to influence the rates of leaching, liberation or degradation desired for example, via the adjustment of the coating thickness or the matrix volumes. In exemplary embodiments of the devices and methods of the present invention, an implantable medical device, eg, a metal stent or a pacemaker electrode or an artificial heart valve, is coated with a porous coating, for example, with a coating of pyrolytic carbon as described in DE 202004009060U. The coating is subsequently loaded with at least one agent for signal generation as described above, and simultaneously or subsequently with at least one therapeutic agent as described above, selected according to the intended use of the device, wherein the order of the load with the different agents can be selected as deemed appropriate. The loading can be done by spraying, impregnation with solutions or in any other suitable way. If necessary, adjuvants or overdrafts can also be applied to control the release rates of the agents. The average release rates of the agent for signal generation and the therapeutic agent from the thus produced implantable device can be determined by the common use of in-vitro tests in balanced salt solution or any other suitable means. From the concentration measurements, optionally combined with methods for non-invasive physical detection for the signal generation agents, a correlation coefficient can be determined for the amount of the therapeutic agent released by the amount of signal strength obtained from the agent for signal generation, which allows an indirect determination of the amount of the therapeutic agent released in relation to the signal intensity obtained from the detection of the agent for signal generation. With this method, the supervision of the quantity and regional distribution of the liberated therapeutic agent is possible precisely through simple non-invasive physical detection methods.

DESCRIPTION OF THE FIGURES Figure 1 shows the correlation between the release of paclitaxel from a coronary stent in the form of the active substance adsorbed to encapsulated nanoparticles and the in-vivo activity of the fluorescence color of the signal generating agent Calcein. -AM according to a preferred embodiment of the invention. The invention will now be further explained in the following, based on the examples, to represent the principle of the composition or combination and the exemplary preferred embodiments, which do not indicate any of the limitations necessary to the invention as described in the paragraphs. : EXAMPLES Example 1 A commercially available X-ray non-fluorescent coronary stent from Fortimedix Company (KAON Stent), the Netherlands, 18.5 mm long, and made of 316L stainless steel was coated with a composite coating of Carbon-Si according to the DE 202004009060U. A phenoxy resin, Beckopox EP 401, from UCB Company was used as the precursor polymer, and a dispersion of Aerosil R972 commercially available from Degussa in R-ethyl-ethyl ketone was prepared. The solids content of the polymer amounted to 0.75% by weight, the solids content of Aerosil 0.25% by weight, the solids content of the solvent to 99% by weight. The precursor solution was sprayed on the substrate as a polymeric film, tempered by the application of hot air at 350 ° C in ambient air and subsequently the crude weight of the polymeric film was determined, where the coating had a weight in the area surface of approximately 2.53 g / m2. The sample was subsequently examined in a Nikon fluorescence microscope for its inherent fluorescence. The crude coating had no fluorescence. Subsequently, the sample was thermally treated according to DE 202004009060U in a commercial tube reactor. The thermal treatment was carried out in accordance with nitrogen atmosphere with a heating and cooling ramp of 1.3 K / min with a holding temperature of 300 ° C and a maintenance time period of 30 minutes.

The sample was then treated in an ultrasonic bath in 10 ml of a 50% ethanol solution at 30 ° C for 20 minutes, washed and dried in a commercial convection oven set at 90 ° C. The gravimetric analysis indicated a shrinkage after the heat treatment of about 29% and a weight in the surface area of the amorphous carbon / Si composite layer of 1.81 g / m2. The scanning electron microscope investigation shows a porous layer with average pore diameters of approximately lOOnm. Further investigation in a fluorescence microscope showed intensive fluorescence of the coated stent in the green and blue region as well as a weak fluorescence in the red region.

Example 2 As in Example 1, an X-ray opaque, non-fluorescent coronary stent, commercially available from Fortimedix Company (KAON Stent), The Netherlands, 18.5 mm long and made of 316L stainless steel was coated with a coating of material Composed of Carbon-Si according to the DE 202004009060U. For modifying the emission spectrum by fluorescence in the red region, the composition of the precursor was modified. As the precursor polymer, a phenoxy resin, Beckopox EP 401 from UCB Company, was used and combined with a dispersion of Aerosil R972 commercially available from Degussa in methyl ethyl ketone. Additionally, a degradation agent, isophorone diisocyanate, was introduced from Sigma Aldrich Company. The solids content of the polymer amounted to 0.55% by weight, the solids content of Aerosil to 0.25% by weight, the solids content of the agent for degradation to 0.2% by weight, the solid portion of solvent to 99% by weight. The precursor solution was sprayed on the substrate as a polymer film, tempered by the application of hot air at 350 ° C in ambient air and subsequently the raw weight of the polymer film was determined, where the coating had a weight in the surface area of approximately 2.20 g / m2. The sample was subsequently examined in a Nikon fluorescence microscope for its inherent fluorescence. The crude coating had no fluorescence. Subsequently, the sample was thermally treated according to DE 202004009060U in a commercial tube reactor. The heat treatment was carried out under a nitrogen atmosphere with a heating and cooling ramp of 1.3 K / min with a holding temperature of 300 ° C and a maintenance period of 30 minutes. Subsequently, the sample was treated in an ultrasonic bath in 10 ml of a 50% ethanol solution at 30 ° C for 20 minutes, washed and dried in a commercial convection oven set at 90 ° C. The gravimetric analysis indicated a contraction after the heat treatment of approximately 23% and a weight in the surface area of the composite layer of carbon / Si amorphous similar to glass of 1.69 g / m2. The scanning electron microscope investigation showed a porous layer with average pore diameters of approximately 100 nm. Further investigation in a fluorescence microscope showed intensive fluorescence of the coated stent in the green and blue region as well as strong fluorescence in the red region.

Example 3 The coronary stent produced in Example 1 and Example 2 were subsequently exchanged with an active agent. Paclitaxel obtained from Sigma Aldrich was used as a model substance. A solution of Paclitaxel having a concentration of 43 g / 1 was prepared in ethanol. Before and after being changed by immersion in 5 ml of ethanolic solution with paclitaxel, the samples were subjected to a gravimetric analysis .. The loading was carried out by immersion for 10 minutes in the solution of the active agent. The total load was determined from the mass increase. The sample of Example 1 had a load of 0.766 g / m2, the sample of the Example had a load of 0.727 g / m2. After drying in air for 60 minutes, another investigation was carried out by fluorescence microscopy, which showed the same fluorescence characteristics of the non-charged porous coatings (strong fluorescence of blue and green, the sample of Example 1 weak red fluorescence, the sample of Example 2 strong red fluorescence).

EXAMPLE 4 Three non-fluorescent, non-fluorescent coronary stents, commercially available from Fortimedix Company (KAON Stent), the Netherlands, 18.5 mm long, made of 316L stainless steel were coated with a carbon-carbon composite material coating in accordance with the DE 202004009060U. As the precursor polymer, a phenoxy resin, Beckopox EP 401 from UCB Company was used and from the same a dispersion was prepared in methyl ethyl ketone with commercially available carbon black, Printex alpha from Degussa and a mixture of fullerene C60 and C70 from FCC Company sold as Nanom-Mix The solids content of the polymer amounted to 0.5% by weight, the solids content of carbon black to 0.3% by weight, the solids content of the fullerene mixture to 0.2% by weight, that of the solvent to 99% by weight. The precursor solution was sprayed on the substrate as a polymeric film, tempered by the application of hot air at 350 ° C in ambient air and subsequently the crude weight of the polymeric film was determined, where the coating had a weight in the area surface of approximately 2.5 g / m2. The sample was subsequently examined in a Nikon fluorescence microscope for its inherent fluorescence. The crude coating had no fluorescence. Subsequently, the sample was thermally treated according to DE 202004009060U in a commercial tube reactor. The heat treatment was carried out under a nitrogen atmosphere with a heating and cooling ramp of 1.3 K / min with a holding temperature of 300 ° C and a maintenance period of 30 minutes. Subsequently, the sample was treated in an ultrasonic bath in 10 ml of a 50% ethanol solution at 30 ° C for 20 minutes, washed and dried in a commercial convection oven set at 90 ° C. The gravimetric analysis indicated a contraction after the heat treatment of approximately 30% and a weight in the surface area of the coating composed of an amorphous carbon / pyrolytic carbon similar to glass of 1.75 g / m2. The scanning electron microscope revealed an average porosity of 1 μp ?. Investigation with a fluorescence microscope did not indicate fluorescence of the coating. For the loading of the active agent, first a 1 mM solution of Calcein-AM in DMSO from obitec Company, was diluted to 1: 1000 in acetone and 0.5 mg of the calcein solution was mixed together with 20 mg of poly (DL) - lactide coglycolide) and 2 mg of Paclitaxel in 3 ml of acetone. The resulting solution was added with a constant flow rate of 10 ml / min to a 0.1% solution of Poloxamer 188 (pluronic F68) in 0.05 M PBS buffer while stirring at 400 rpm, and the colloidal suspension was further stirred during 3 h under light vacuum for the evaporation of the solvents and then dried completely for 14 h under total vacuum. The nanoparticles obtained with encapsulated Paclitaxel and in-vivo fluorescence marker were subsequently resuspended in ethanol and by determining the solids content, the concentration of the solution containing particles was obtained. The three posteriorly coated coronary stents were loaded with the particles by immersion and the loaded weight was determined gravimetrically. The average load of coronary stents dried by convection oven amounted to 0.5 g / m2 + 0.05. Subsequently, the stent expanded placed in 6-well plates and incubated with approximately 105 cells / ml, cultured COS-7 cells subcultured three times (37.5 ° C, 5% C02) in DMEM medium in a volume of culture 5 mi. Immediately after the expansion, after 1, 3, 6, 12, 24, 36 as well as also 2, 3, 4, 5, 7, 9, 12, 15, 21 and 30 days in each case the volumes of culture, the amounts released were determined by means of HPLC, and in each case the medium was replaced. In addition, the samples were investigated in the fluorescence microscope and the adherent cells were investigated for fluorescence in the green region. Using the software Lucia de Nikon Company in each case, an area of 0.5 μp? 2 was determined by densitometric measurement of the average color intensity of the fluorescence intensity. The maximum densitometric was observed after 30 days and the intensity of the fluorescence values was determined to be correlated with the release of calcein-AM in percentage against time. The graph of Figure 1 collects the measured values and showing the correlation between the release of the dry particles adsorbed Paclitaxel nanopart encapsulated from the stent and the in vivo activity of the fluorescent dye Calcein-AM. After a period of 35 days, the samples were transferred into new culture vessels and incubated with freshly prepared cell suspension. Paclitaxel could not be identified in the medium nor was there any fluorescence dye from the cell culture. Thus, having described in detail the preferred embodiments of the present invention, it should be understood that the invention defined by the claims below is not limited to particular details set forth in the above description as are possible many apparent variations thereof without depart from the spirit or scope of the present invention.

Claims (56)

1. CLAIMS 1. An implantable medical device or a component thereof, comprises a combination comprising: a) at least one agent for signal generation, which in a physical, chemical and / or biological measurement or verification method leads to detectable signals , b) at least one material for the manufacture of an implantable medical device and / or at least one component of an implantable medical device, c) at least one therapeutically active agent, which in an animal or human organism directly or indirectly satisfies a function therapeutic, d) an adjuvant that allows to control the release of at least one therapeutically active agent and at least one agent for signal generation when the device is exposed to physiological fluids and / or has been implanted in an animal or human organism.
2. 2. The device or components according to claim 1, wherein the therapeutically active agent can be released directly or indirectly in an animal or human organism from the implantable medical device or a component of the implantable medical device.
3. 3. The device or component according to claim 1, wherein the signal generating agent in addition to its function for signal generation has at least a second function.
4. 4. The device or component according to claim 1, wherein the signal generating agent possesses properties for signal generation without a physical or chemical or biological stimulus or a physiologically conditioned in vivo change.
5. 5. The device or component according to claim 1, wherein the signal generating agent gains its properties for signal generation through a physical, chemical or biological stimulus.
6. 6. The device or component according to claim 1, wherein the signal generating agent gains its properties for signal generation through an in vivo change conditioned physically, chemically or biologically or physiologically.
7. 7. The device or component according to claim 1, wherein the material for the manufacture of an implantable medical device comprises biologically degradable materials.
8. 8. The device or component according to claim 1, wherein the material for the manufacture of an implantable medical device comprises biologically non-degradable materials.
9. 9. The device or component according to claim 1, wherein the material for the manufacture of an implantable medical device comprises a combination of biologically non-degradable materials and biologically degradable materials.
10. 10. The device or component according to claim 3, wherein the second function or other functions is / are those of at least one therapeutically active agent.
11. 11. The device or component according to claim 3, wherein the second function or other functions comprise those of at least one target group.
12. 12. The device or component according to claim 3, wherein in addition to the function for signal generation, at least the function of a therapeutically active agent and the function of at least one target group is present in the device or component.
13. 13. The device or component according to one of the preceding claims, wherein the signal generation agent comprises a first and at least a second unit, which are covalently linked together, wherein the first unit has a function for signal generation and the Second unit or additional units have other functions.
14. 14. The device or component according to one of the preceding claims, wherein the signal generating agent comprises a first and at least a second unit, which are joined together non-covalently, wherein the first unit has a function for signal generation and the second unit or additional units have other functions.
15. 15. The device or component according to claim 13 or 14, wherein the function of the second additional unit or units is that of at least one therapeutically active agent.
16. 16. The device or component according to claim 13 or 14, wherein the function of the second additional unit or units is that of at least one target group.
17. 17. The device or component according to claim 13 or 14, wherein the function of the second unit and at least one additional unit is that of a therapeutically active agent and that of at least one target group.
18. 18. The device or component according to one of the preceding claims, wherein the combination comprises a second agent for signal generation, wherein the second agent for signal generation can be detected with a measurement or verification method, with which the first agent for signal generation is not essentially detectable.
19. 19. The device or component according to one of the preceding claims, wherein the implantable medical device comprises at least one region showing a concentration gradient in the local distribution of at least one agent for signal generation.
20. 20. The device or component according to one of the preceding claims, wherein the implantable medical device comprises a first and a second coating layer, wherein the concentration of the at least one agent for signal generation in the first layer differs from the concentration in the second coating layer.
21. 21. The device or component according to one of the preceding claims, wherein the adjuvants are biodegradable.
22. 22. The device or component according to one of claims 1 to 20, wherein the adjuvants are non-degradable.
23. 23. The device or component according to one of claims 1 to 20, wherein the adjuvants are partially biodegradable.
24. 24. The device or component according to one of claims 1 to 20, wherein the adjuvants are partially biodegradable or comprise mixtures of non-degradable, degradable and / or partially degradable materials.
25. 25. The device or component according to one of the preceding claims, wherein the adjuvant is a retarding agent.
26. 26. The device or component for the manufacture of implantable medical devices according to any of the preceding claims, comprising a first and a second agent for signal generation, which directly or indirectly lead to detectable signals in a method for physical, chemical and physical measurement or verification. / or biological, wherein the first agent in a method, in which the second agent leads to detectable signals is not essentially detectable.
27. 27. The device or component according to claim 26, wherein the first agent for signal generation leads to detectable signals in the methods that include one of the conventional methods of X-rays, the methods of images divided by X-rays similar to computed tomography, neutron transmission tomography, frequent radiomagnetization including magnetic resonance tomography, radionucl-1-based methods that include scintigraphy, computed tomography with a single photon emission (SPECT), positron emission computed tomography (PET), methods Ultrasonics, luoroscopic methods, or methods based on luminescence or fluorescence, including intravasal fluorescence spectroscopy, Raman spectroscopy, fluorescence emission spectroscopy, electrical impedance spectroscopy, colorimetry, optical coherence tomography, or electronic resonance (ESR) , radio recuence (RF), or a microwave laser method.
28. 28. The device or component according to claim 26 or 27, wherein the second agent for signal generation leads to detectable signals in the methods that include at least one of the conventional methods by X-rays, the methods of divided images based on X-rays including computed tomography, neutron transmission tomography, radiofrequency magnetization including magnetic resonance tomography, radionuclide-based methods including scintigraphy, computed tomography by a single photon emission (SPECT), positron emission computed tomography (PET), ultrasonic-based methods, luoroscopic methods, luminescence or fluorescence-based methods, including intravasal fluorescence spectroscopy, Raman spectroscopy, fluorescence emission spectroscopy, electrical impedance spectroscopy, colorimetry, optical coherence tomography, electronic resonance (ESR), radiofrequency (RF), or a microwave laser.
29. 29. The device or component according to one of claims 26 to 28, wherein at least one of the first or second agent for signal generation is selected from the group consisting of metals, metal oxides, metal carbides, metal nitrides, metal oxynitrides, metal carbonitrides , metal oxycarbides, metal oxynitrides, metal oxycarbonitrides, metal hydrides, metal alkoxides, metal halides, inorganic or organic metal salts including salts and chelates of the group of the lanthanides with the atomic numbers 57-83 or of the transition metals with the atomic numbers 21-29, 42 or 44, metal polymers, metallocenes, or other organometallic compounds, including metal complexes with phthaloe ranins.
30. 30. The device or component according to one of claims 26 to 28, wherein at least one of the first or second agent for signal generation is selected from the group consisting of materials or compounds including those with paramagnetic, diamagnetic, super paramagnetic properties. , ferrimagnetic or ferromagnetic, semi-conductive materials including those of groups II-VI, of groups III-V, or group IV that have absorption properties for radiation at wavelengths ranging from gamma rays to microwave radiation and / or the property of emitting radiation.
31. 31. The device or component according to one of claims 26 to 28, wherein at least one of the first and / or second agent for signal generation is selected from the group of ionic and nonionic halogenating agents including 3-acetylamino-2, 4-acid. 6 - 1 Rhodium benzoic acid, 3,5-diacetamido-2,4,6-triiodobenzoic acid, 2,4,6-triiodo-3,5-dipropionamidobenzoic acid, 3-acetyl-amino-5- ((acetyl-amino) -methyl) ) - 2, 4, 6 - triiodobenzoic acid, 3-acetyl-1-amino-5- (acetylmethyl) -2,4,6-triiodobenzoic acid, 5-acetamido-2,4,6-triiodo-N- ( (methylcarbamoyl) methyl) isofhalamic acid, 5- (2-methoxyacetamido) -2,4,6-lriiodo-N- [2-hydroxy-1 - (meth i -carbamoi 1) -ethyl] -isof-thalamic acid, 5- acetamido- 2, 4, 61riyodo-N-met i 1 i thalamic acid, 5-acetamido-2,4,6- 1 -iiodoido-N- (2-hydroxyethyl) 1-isophthalamic acid, 2 - [[2, 4, 6 - triiodo-3 [(1-oxobutyl) amino] phenyl] methyl] butanoi co, beta- (3-amino-2,4,6-1-rrylophenyl) -α-ethopropionic acid, or yopamidol, yotrolan, yodecimol, iodixanol, yoglucol, yoglucomide, yogulamide, yomeprol, or yopentol.
32. 32. The device or component according to one of claims 26 to 28, wherein at least one of the first or second agent for signal generation is selected from the group consisting of carbon species, including carbides, fullerenes, fullerene metal complexes, or fullerenes endohédricos, containing rare earths including cerium, neodymium, samarium, europium, gadolinium, terbium, dysprosium or holmium, or halogenated fullerenes.
33. 33. The device or component according to one of claims 26 to 28, wherein the first or second agent for generating signal is selected from the group consisting of anionic and / or cationic lipids including anionic or cationic halogenated lipids.
34. 34. The device or component according to one of claims 26 to 28, wherein the first or second agent for signal generation is selected from the group consisting of gases or gas-forming substances in vivo, including air, nitrogen, hydrogen, alkanes or gases of halogenated hydrocarbon including methyl chloride, perfluoroacetone, or perfluorobutane, optionally included in micro-bubbles or microspheres.
35. 35. The device or component according to one of claims 26 to 28, wherein at least one of the first or second agent for signal generation is selected from the group consisting of recombinant or non-recombinant nucleic acids, proteins, peptides or polypeptides, including those that directly or indirectly induce the formation or in vivo enrichment of the agents for signal generation, including nucleic acids, which contain coding sequences for the expression of signal generation agents, including metallo-protein complexes, dicarboxylate proteins, lactoferrin or ferritin, or those that regulate the enrichment and / or homeostasis of the agents for generation of physiologically available signal, including the iron regulatory protein (IRP), the transfrrrin receptor, the 5-aminolevulinate synthase er itroida.
36. 36. The device or component according to one of claims 29 to 35, wherein at least one of the first or second agent for signal generation is provided in the form of nanoparticles or polymeric and / or non-polymeric microparticles, which have an average size from 2 nm to 20 μ ??, or from 2 nm to 5 μt? .
37. 37. The device or component according to one of claims 29 to 36, wherein at least one of the first or second agent for signal generation is provided in the form of microspheres, macro spheres, micelles or liposomes, or encapsulated in linings. polymeric
38. 38. The device or component according to one of claims 29 to 35, wherein at least one of the first or second agent for signal generation is provided in the form of biological vectors, for example, transfection vectors such as, for example, virus particles. or viruses, preferably adenoviruses, viruses associated with adenoviruses, herpes simplex viruses, retroviruses, alphaviruses, poxviruses, sand-viruses, vacciniaviruses, influenza viruses or polioviruses.
39. 39. The device or component according to one of claims 29 to 35, wherein at least one of the first or second agent for signal generation is selected in the form of agents for signal generation or vectors containing cells, cell cultures, organized cell cultures , tissues, organs of any desired species, and non-human organisms that contain recombinant nucleic acids with coding sequences for signal generating agents.
40. 40. The device or component according to one of claims 29 to 39, wherein at least one of the first or second agent for signal generation is provided in the form of a solution, a suspension, an emulsion or dispersions or a solid material or any mixtures thereof.
41. 41. The device or component according to one of claims 26 to 28, wherein the first agent for signal generation is covalently linked to the second agent for signal generation.
42. 42. The device or component according to one of claims 26 to 28, wherein the first agent for signal generation binds non-covalently to the second agent for signal generation.
43. 43. The device or component according to any of the preceding claims, wherein the implantable medical device or component thereof is formed of a material in at least one of the methods for imaging applied in medical technology can not be represented.
44. 44. The device or component according to claim 43, wherein the material comprises at least one of the polymers selected from the group consisting of polyurethane, collagens, albumin, gelatin, hyaluronic acid, starch, cellulose including methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose -phthalate, casein, dextran, polysaccharides, fibrinogen, poly (D, L-lactide), poly (D, L-lactide-glycolide), poly (glycolides), poly (hydroxybutylate), poly (alkyl carbonates), poly (orthoesters), polyesters, poly (hydroxyvaleric acid), polydioxanone, poly (ethylene terephthalate), poly (malic acid), poly (tartronic acid), polyanhydrides, polyphosphohazenes, poly (amino acids), or copolymers thereof.
45. 45. The device or component according to claim 43, wherein the material comprises at least one non-polymeric material, selected from the group consisting of ceramic, glass, metals, alloys, bone, stone or minerals.
46. 46. The device or component according to claim 43, wherein the material comprises a mixture of non-polymeric and polymeric materials.
47. 47. The device or component according to claim 43, wherein the material comprises an organic, inorganic or inorganic-organic composite material mixed.
48. 48. An implantable medical device or component thereof, according to any of the preceding claims, comprising magnesium and / or zinc.
49. 49. The device according to the claim 48, which is a stent.
50. 50. The device according to claim 49, wherein the stent is at least partially coated with a coating comprising magnesium and / or zinc particles, or alloy particles comprising magnesium and / or zinc.
51. 51. The device according to the claim 49, wherein the stent or a portion thereof is produced from a material comprising magnesium and / or zinc or an alloy of any of these metals.
52. 52. The device according to any one of the preceding claims, comprising agents for generating signal in a porous crosslinked network that can be loaded with therapeutically active agents.
53. 53. The device according to any of the preceding claims, wherein the combination is in the form of a coating.
54. 54. A method for determining the degree of release of an active agent from an implantable medical device or component thereof as defined in any of claims 1 to 53 comprising: providing a fully or partially degradable implantable medical device or a complete degradable component or partially thereof, the device comprises at least one agent for signal generation, which leads directly or indirectly to detectable signals in a method for physical, chemical and / or biological measurement or verification, including a method for imaging, and less a therapeutically active agent that will be released into a human or animal organism, wherein the device at least partially releases the therapeutically active agents together with the signal generating agents at the time of device degradation after insertion of the device into a human or animal organism, determined The degree of release of therapeutically active agents is detected by detecting the signal generating agents released with the use of non-invasive methods for imaging.
55. 55. A method for determining the degree of release of an active agent from an implantable medical device or a component thereof as defined in any of claims 1 to 53 comprising: providing a non-degradable implantable medical device or a component thereof, the device comprises at least one agent for signal generation, which leads directly or indirectly to detectable signals in a method for physical, chemical and / or biological measurement or verification, especially in a method for imaging, and at least one agent therapeutically active that will be released into a human or animal organism, wherein the device at least partially releases the therapeutically active agents together with the signal generating agents after insertion of the device into a human or animal organism, determining the degree of release of therapeutically active agents by detecting the agents for Generation of signal released with the use of non-invasive methods for imaging.
56. 56. The method according to any of claims 54 to 56, wherein at least one signal generating agent is covalently or non-covalently bound to at least one therapeutically active agent.