Copolymer-modified nanoparticles, especially for use in medical articles

The present invention relates to copolymer-modified nanoparticles, to a process for production thereof, and to applications for the copolymer- modified nanoparticles, especially in medical articles.

The use of nanoparticles has enormous potential, in particular for the development of new polymer-based medical products.

Conventional processes for producing nanoparticles are usually based on chemical production methods. These generate nanoparticles typically by conversion of suitable precursor compounds. For example, the precursor compounds can be reacted with an acid, an alkali, a reducing agent or oxidizing agent to give nanoparticles. An elegant method for production of nanoparticles is that of laser ablation (material removal by laser) in liquids (Amendola et al.: Laser ablation synthesis in solution and size manipulation of noble metal nanoparticles; Phys. Chem. Chem. Phys. 2009, 1 1 , 3805-3821 and Barcikowski et al.: Nanocomposite manufacturing using ultrashort-pulsed laser abla- tion in solvents and monomers; Polimery 2008, 53, nr 9). Nanoparticles are generated here by bombarding substrates immersed into liquid-filled sample vessels with laser radiation. The laser bombardment causes material removal from the substrate surface. The nanoparticles generated are generally the result of nucleation and coalescence phenomena within cavitation bubbles formed above the substrate surface as a result of laser irradiation. A central problem in the generation of nanopartides relates to the agglomeration tendency thereof, as a result of which the further use thereof, especially the incorporation thereof into polymeric materials, can be limited in terms of maximum homogeneity of dispersion. An additional factor is that a rise in agglomeration is generally recorded when nanopartides are subjected to conditions as typically employed in industrial shaping processes, for example extrusion processes. This is especially true with regard to polymeric materials with high processing temperatures.

One approach to suppressing the unwanted agglomeration tendency of nanopartides, in order, for example, to achieve maximum homogeneity of "nano-functionalization", consists in a surface modification of the nanopartides. However, the difficulty is in developing a suitable surface modification. For instance, in the case of a simple hydrophobic modification of nanoparticle surfaces, there is the risk of separation of nanopartides and polymer.

In the case of a slight surface modification, in contrast, there is the risk that the nanopartides form unwanted agglomerates, as a result of which a homogeneous "nano-functionalization" likewise cannot be achieved.

WO 2005/070979 A1 describes a chemical production process, based on what is called emulsion technology, for polymer-modified nanopartides.

Chemical production methods for nanopartides are, however, afflicted with certain disadvantages. For instance, the particle size and the particle size distribution can frequently be controlled only with very great difficulty under the particular chemical conditions. Furthermore, generally time-consuming and costly purification and disposal measures are required for unconverted precursor compounds, reagents and by-products which form. However, impurities are unacceptable especially with regard to medical applications.

The use of laser-generated nanoparticles for production of biologically active devices is known from DE 10 2007 005 817 A1.

It is therefore an object of the present invention to provide modified nanoparticles which avoid the shortcomings known from the prior art and can especially be dispersed very substantially uniformly and homogene- ously in polymers.

This object is achieved in accordance with the invention by copolymer- modified nanoparticles having the features of independent Claim 1. Preferred embodiments of the copolymer-modified nanoparticles are the subject of dependent Claims 2 to 9. Copolymer-modified nanoparticles according to independent Claim 10 likewise form part of the subject- matter of the present invention. A preferred embodiment is the subject of dependent Claim 1 1. A further aspect of the invention relates to a process for producing copolymer-modified nanoparticles having the features of independent Claim 12. A preferred embodiment of the process is the subject of dependent Claim 13. The present invention further comprises a polymer and a semifinished product, finished product or end product according to Claims 14 and 15. Finally, the present invention also provides a medical article having the features of independent Claim 16. Pre- ferred embodiments of the medical article are expressed in dependent Claims 17 and 18. The wording of all claims is hereby incorporated by explicit reference into the content of the present description.

The nanoparticles proposed in accordance with the invention are espe- daily copolymer-modified nanoparticles which are produced or producible (obtained or obtainable) by a process in which nanoparticles are ablated (removed) by means of laser radiation from the surface of at least one, especially one, substrate in a liquid which comprises an amphi- philic, preferably random copolymer.

An amphiphilic copolymer shall be understood in the context of the pre- sent invention to mean a polymer based on at least two different monomer units, at least one monomer unit being a hydrophilic monomer unit and at least one further monomer unit being a hydrophobic and/or fluorophilic monomer unit. In the context of the present invention, a hydrophilic monomer unit shall preferably be understood to mean a monomer unit which has a hydrophilic side group. With regard to the hydrophilic side groups useful in principle, reference is made to the details still to be given on this subject hereinafter.

In the context of the present invention, a hydrophobic or fluorophilic monomer unit shall preferably be understood to mean a monomer unit with a hydrophobic or fluorophilic side group. With regard to hydrophobic or fluorophilic side groups useful in principle, reference is made to the details still to be given on this subject hereinafter.

It has been found that, surprisingly, nanoparticles generated by means of laser ablation (material removal by laser) can be obtained in essentially agglomerate-free form in liquids when the laser ablation is per- formed in the presence of an amphiphilic and preferably random copolymer present in the liquid. The inventive nanoparticles can thus be produced particularly advantageously in a "one-pot process".

The reason for the lack of or greatly reduced agglomeration tendency is based on a surface modification of the nanoparticles, as a result of which the amphiphilic copolymer adds onto the surface of nanoparticles to form copolymer-modified nanoparticles. This results in mutual screen- ing of the nanoparticles, as a result of which the tendency thereof to form agglomerates is lowered or suppressed.

In general, the modification of the inventive nanoparticles is based on noncovalent, especially adsorptive, bonds between the nanoparticles and the amphiphilic copolymer. The bonds are preferably based on Lewis acceptor and Lewis donor interactions. The nanoparticles here generally have Lewis acceptor character. The amphiphilic copolymer preferably has donating atom groups which are generally present in the side chains of the copolymer. The amphiphilic copolymer therefore preferably has Lewis donor character.

In the context of the present invention, a donating atom group (donor group) shall be understood to mean an atom group with at least one heteroatom, with at least one free electron pair of the heteroatom able to interact with a Lewis-acidic particle. Suitable donating atom groups can be selected from the group comprising hydroxyl groups, ether groups, amino groups, amine groups, imine groups, oxime groups, diol groups, thioether groups, acyl groups, formyl groups, keto groups, carboxyl or carboxylate groups, amide groups, sulfo or sulfonate groups, phosphoric acid or phosphate groups, phosphonic acid or phosphonate groups, and combinations thereof.

In a preferred embodiment, the nanoparticles are at least partially, pref- erably fully, coated with the amphiphilic copolymer.

The copolymer-modified nanoparticles more preferably have a core-shell structure ("core-shell particles"), in which case the nanoparticles form the core and the copolymer forms the shell of the structure.

In the context of the present invention, nanoparticles shall be understood to mean particles with a dimension in the sub-micrometer range, espe- daily with a dimension of ≤ 100 nm. Due to their small size, nanoparticles have a comparatively large surface area, through which they can release, for example, active ingredients (in the case of metallic nanoparticles, for example, ions). At the same time, the nanoparticles constitute, due to their volume, a considerable reservoir for active ingredients to be released.

The nanoparticles preferably comprise an inorganic material, especially a metal, a metal salt, especially a metal oxide, a metal alloy, a semi- metal, a ceramic, an organic material or a combination thereof.

The nanoparticles preferably comprise biologically active materials. In the context of the present invention, biologically active materials shall be understood to mean materials which can display advantageous effects in a biological system, for example in the body of a patient, in particular from a medical point of view, especially a diagnostic and/or therapeutic point of view. For example, the nanoparticles may comprise antimicrobial, especially antibiotic, disinfecting, inflammation-inhibiting, antithrom- bogenic, cell growth-promoting, cell-differentiating, cell-recruiting, cell- adhering materials or substances or combinations thereof.

The nanoparticles more preferably comprise antimicrobially active metals, metal salts, metal alloys or combinations thereof. In addition, the nanoparticles may, however, also comprise materials with other properties, for example self-cleaning properties (e.g. titanium dioxide), electrical conductivity properties, antistatic properties or UV- protective properties (e.g. zinc oxide). According to the invention, the nanoparticles may comprise a metal selected from the group comprising magnesium, aluminium, copper, zinc, tantalum, titanium, cobalt, iron, palladium, platinum, iridium, silver, gold, salts thereof, especially oxides thereof, and combinations, especially alloys, thereof.

In a further embodiment, the nanopartides comprise metal alloys se- lected from the group comprising nickel-titanium alloys (NiTi), iron-nickel alloys (FeNi), gold-silver alloys (AuAg), silver-copper alloys (AgCu) and combinations thereof.

Examples of ceramic-comprising nanopartides can be selected from the group comprising zirconium dioxide (Zr02), aluminium oxide (AI2O3), silicon oxide (S1O2), titanium carbide, tungsten carbide (WC), boron nitride (BN) and combinations thereof.

According to the invention, the nanopartides may also consist of one of the materials or material combinations described in the preceding embodiments.

In addition, the nanopartides themselves may have a spherical, spheroidal or irregular, for example polygonal, form. Preferably, the nanoparti- cles themselves (without the copolymer modification) have a mean particle size, preferably determined by means of dynamic light scattering or transmission electron microscopy, between 1 and 100 nm, especially 1 and 50 nm, preferably 2 and 40 nm, more preferably 3 and 30 nm, especially preferably 5 and 20 nm.

In a further embodiment, the copolymer-modified nanopartides are present in solid form or as a solid. More particularly, the copolymer-modified nanopartides may be present as a particulate solid, for example as a dry chemical, powder, granules or the like. Since the copolymer-modified nanopartides can also form films themselves, it is also possible in accordance with the invention that the copolymer-modified nanopartides are in the form of a film or foil. In the embodiment described in this para- graph, the copolymer-modified nanopartides may have a proportion between 0.1 and 100% by weight, especially 0.5 and 40% by weight, preferably 1 and 5% by weight, based on the total weight of the particular configuration (powder, granules, film, etc.). According to the invention, it may therefore quite possibly be preferred that the copolymer-modified nanopartides are also present in the form of pure material (proportion of 100% by weight).

In a further embodiment, the copolymer-modified nanopartides are pre- sent together with a liquid dispersant in the form of a dispersion, optionally a dispersion in gel form. The copolymer-modified nanopartides are preferably present in a dispersion as colloids, preferably in homogeneous distribution. Furthermore, the copolymer-modified nanopartides may be present as a gel, in particular hydrogel. With regard to further fea- tures and advantages of the dispersion, especially with regard to suitable dispersants, reference is made completely to the present description.

The amphiphilic copolymer preferably has a weight-average molar mass between 1000 and 1 000 000 g/mol, especially 1000 and 500 000 g/mol, preferably 3000 and 100 000 g/mol.

In a further embodiment, the amphiphilic copolymer is soluble in organic solvents or mixtures thereof, especially in ethyl acetate, methanol, etha- nol, isopropanol, acetone, dioxane, THF, DMF, DMSO, acetonitrile, 4- butyrolactone, dichloromethane, chloroform, carbon tetrachloride, toluene, N-methyl-2-pyrrolidone, perfluorinated solvents, for example per- fluoromethylcyclohexane, perfluoroalkanes, aromatic perfluorinated solvents, or mixtures thereof.

In a preferred embodiment, the amphiphilic copolymer is a fluorophilic or fluorinated copolymer. The copolymer preferably has fluorophilic side groups, i.e. side groups whose hydrogen atoms have been replaced partly or fully (completely) by fluorine atoms. More preferably, the copolymer has perfluorinated side groups, in particular selected from the group comprising perfluorinated alkyl groups, perfluorinated alkenyl groups, perfluorinated alkinyl groups, perfluorinated aryl groups and combinations thereof. Perfluorinated alkyl groups are especially preferred. A perfluorinated side group shall be understood in the context of the present invention to mean a side group whose hydrogen atoms have been fully (completely) replaced by fluorine atoms.

In a further embodiment, the copolymer comprises at least one repeat monomer unit, preferably two repeat monomer units, with hydrophobic and/or fluorophilic side groups and at least one, preferably one, repeat monomer unit with hydrophilic side groups. The weight ratio of monomer units with hydrophobic and/or fluorophilic side groups to monomer units with hydrophilic side groups may be in the range from 95:5 to 10:90, especially 95:5 to 30:70, preferably 90: 10 to 50:50. The monomer units may in principle also be macromonomers, preference being given to polyolefins, polyacrylates and/or polyethers as macromonomers.

More particularly, monomer units with hydrophobic and/or fluorophilic side groups may have a proportion between 10 and 98 mol%, preferably 50 and 95 mol%, more preferably 75 and 90 mol%, based on 100 mol% of the copolymer.

Monomer units with hydrophilic side groups preferably have a proportion between 2 and 90 mol%, especially 5 and 50 mol%, preferably 10 and 25 mol%, based on 100 mol% of the copolymer. In a further preferred embodiment, the amphiphilic copolymer has hydrophobic and/or fluorophilic side groups which are selected from the group comprising cyclic, branched and/or unbranched alkyl radicals, al- kenyl radicals, alkinyl radicals, haloalkyl radicals, haloalkenyl radicals, haloalkinyl radicals, alkoxy radicals, particularly alkoxy alkyl radicals, alkoxy alkenyl radicals and/or alkoxy alkinyl radicals, aryl radicals and combinations thereof, where preferably one or more hydrogen atoms, especially all hydrogen atoms, of the side groups are replaced by fluorine atoms.

In a further embodiment, the amphiphilic copolymer has hydrophilic side groups which preferably have a hydroxyl radical, hydroxyalkyl radical, especially hydroxymethyl radical, hydroxyethyl radical, hydroxypropyl radical, amino radical, amine radical, ammonium radical, phosphoric acid or phosphate radical, phosphonic acid or phosphonate radical, sulfo or sulfonate radical, carboxyl or carboxylate radical, polyol radical, poly- ether radical, betaine radical or combinations thereof.

The copolymer, especially the backbone thereof, is preferably derived or made from poly-para-hydroxystyrene, polymethacrylate, polyacrylates, polysiloxanes or combinations thereof. In a particularly preferred embodiment, the amphiphilic copolymer corresponds to the formula I:

where - x and y are each the molar proportion of the monomer units in the copolymer,

- R is a hydrogen atom or an alkyl radical, especially a methyl radical,

- M is an aryl radical, especially phenyl radical, and/or an acyl radical or a radical containing an acyl radical, especially formyl radical, keto radical, carboxyl radical or amide radical, preferably carboxyl radical,

- Ri is a hydrophobic or fluorophilic side group, especially a cyclic, branched and/or unbranched alkyl, alkenyl, alkinyl, haloalkyl, haloalkenyl, haloalkinyl, alkoxy, particularly alkoxyalkyl, alkoxyal- kenyl and/or alkoxyalkinyl, and/or aryl radical, in which preferably one or more hydrogen atoms, especially all hydrogen atoms, are replaced by fluorine atoms, and

- R2 is a hydrophilic side group, especially comprising a hydroxyl radical, hydroxyalkyl radical, especially hydroxymethyl radical, hydroxyethyl radical, hydroxypropyl radical, amino radical, amine radical, ammonium radical, phosphoric acid or phosphate radical, phosphonic acid or phosphonate radical, sulfo or sulfonate radical, carboxyl or carboxylate radical, polyol radical, betaine radical, polyether radical or combinations thereof.

In a further embodiment, x is between 10 and 98 mol%, preferably 50 and 95 mol%, more preferably 75 and 90 mol%, and y is between 2 and 90 mol%, preferably 5 and 50 mol%, more preferably 10 and 25 mol%, based in each case on 100 mol% of the copolymer with the formula I.

In a further embodiment, the side group Ri may comprise a carbon chain with at least three carbon atoms, in particular a carbon chain having three to eight carbon atoms. The carbon chain may be a branched, a cyclic or an unbranched carbon chain. In a further embodiment, the side group Ri is selected from the group comprising cyclic alkyl radicals, branched alkyl radicals, unbranched al- kyl radicals and combinations thereof, where the alkyl radicals preferably have a carbon chain with at least three carbon atoms. The side group Ri preferably has alkyl radicals selected from the group comprising propyl radical, isopropyl radical, butyl radical, isobutyl radical, pentyl radical, isopentyl radical, hexyl radical, isohexyl radical, heptyl radical, isoheptyl radical, octyl radical, isooctyl radical and combinations thereof. In a further embodiment, the amphiphilic copolymer is a terpolymer, i.e. a polymer composed of three different, preferably repeat monomer units. The monomer units of the terpolymer are preferably selected from the group comprising hydrophobic, fluorophilic and/or hydrophilic monomer units. More preferably, two monomer units have hydrophobic and/or fluorophilic side groups and one monomer unit has hydrophilic side groups.

More preferably, the amphiphilic copolymer has the formula II below:

x, y and z are each the molar proportion of the monomer units in the copolymer,

R is a hydrogen atom and/or an alkyl radical, especially a methyl radical, - M is an aryl radical, especially phenyl radical, and/or an acyl radical or a radical containing an acyl radical, especially formyl radical, keto radical, carboxyl radical or amide radical, preferably carboxyl radical,

- Ri and R2 are the same or different, preferably different, where preferably

Ri and/or R ₂ are each a hydrophobic or fluorophilic side group, especially selected from the group comprising a cyclic, branched and/or unbranched alkyl, alkenyl, alkinyl, haloalkyl, haloalkenyl, haloalkinyl, alkoxy, particularly alkoxyalkyl, alkoxyalkenyl and/or alkoxyalkinyl, and/or aryl radical, in which preferably one or more hydrogen atoms, especially all hydrogen atoms, are replaced by fluorine atoms, and/or

Ri and/or R ₂ are each a hydrophilic side group, especially comprising a hydroxyl radical, hydroxyalkyl radical, especially hydroxymethyl radical, hydroxyethyl radical, hy- droxypropyl radical, amino radical, amine radical, ammonium radical, phosphoric acid or phosphate radical, phos- phonic acid or phosphonate radical, sulfo or sulfonate radical, carboxyl or carboxylate radical, polyol radical, betaine radical and/or polyether radical, and

- R3 is a hydrophobic and/or fluorophilic side group, especially selected from the group comprising a cyclic, branched and/or unbranched alkyl, alkenyl, alkinyl, haloalkyl, haloalkenyl, haloalkinyl, alkoxy, particularly alkoxyalkyl, alkoxyalkenyl and/or alkoxyalkinyl, and/or aryl radical, in which preferably one or more hydrogen atoms, especially all hydrogen atoms, are replaced by fluorine atoms.

In a further embodiment, x is between 0.1 and 99 mol%, especially 50 and 95 mol%, preferably 80 and 95 mol%, y is between 0.1 and 50 mol%, especially 5 and 35 mol%, preferably 5 and 10 mol%, and z is between 0.1 and 99 mol%, especially 5 and 20 mol%, preferably 5 and 10 mol%, based in each case on 100 mol% of the copolymer represented by the formula II, and especially with the proviso that the sum of x, y and z corresponds to 100 mol% of the copolymer (x+y+z = 100 mol%).

More particularly, x may be between 0.1 and 99 mol%, especially 50 and 95 mol%, preferably 80 and 95 mol%, based on 100 mol% of the co- polymer represented by the formula II, and x and y together may be between 99.9 and 1 mol%, especially 50 and 5 mol%, preferably 20 and 5 mol%, based on 100 mol% of the copolymer represented by the formula II. In a further embodiment, the side groups Ri , R2 and/or R ₃ may comprise a carbon chain with at least three carbon atoms. More specifically, the side groups Ri , R2 and/or R ₃ may have a carbon chain with three to eight carbon atoms. In a further embodiment, the side groups Ri , R2 and/or R ₃ are selected from the group comprising cyclic alkyl radicals, branched alkyl radicals, unbranched alkyl radicals and combinations thereof, where the alkyl radicals preferably have a carbon chain with at least three carbon atoms. The side groups Ri , R2 and/or R ₃ preferably have alkyl radicals selected from the group comprising propyl radical, isopropyl radical, butyl radical, isobutyl radical, pentyl radical, isopentyl radical, hexyl radical, isohexyl radical, heptyl radical, isoheptyl radical, octyl radical, isooctyl radical and combinations thereof. Preferably, the copolymer-modified nanoparticles are present in or within a medical article. Moreover, the copolymer-modified nanoparticles may be present on a surface, in particular an exterior surface, of a medical article, preferably in the form of a coating or, as an alternative, being a component of such a coating. The medical article is preferably a medical or surgical implant, more preferably a vascular, in particular arterial, prosthesis or graft. With regard to further features and advantages of the medical article, reference is made completely to the following description.

The present invention also provides copolymer-modified nanoparticles, wherein the copolymer is an amphiphilic, preferably random copolymer. The copolymer preferably corresponds to the above-described formula II.

In order to avoid unnecessary repetition, with regard to further features and advantages in respect of the copolymer-modified nanoparticles, es- pecially in relation to the nanoparticles themselves and/or the amphiphilic copolymer, reference is made completely to the description so far.

The present invention further provides a process for producing or manufacturing copolymer-modified nanoparticles, in which nanoparticles are ablated by means of laser radiation from the surface of at least one, especially one, substrate in a liquid which comprises an amphiphilic, preferably random copolymer.

The copolymer present in the liquid functionalizes or modifies the sur- faces of the laser-ablated nanoparticles in situ ("in situ functionalization" or "in situ conjugation"). As a result, a dispersion is generally obtained, possibly a dispersion in the form of a gel, in which the copolymer- modified nanoparticles are generally present as colloids, preferably in homogeneous and fine distribution. The dispersions obtained are par- ticularly advantageously notable for exceptionally good storage stability. The amphiphilic copolymer is preferably a copolymer provided in accordance with the invention or a mixture of copolymers provided in accordance with the invention, preferably a copolymer which corresponds to the formula I or II shown in the present description or a mixture thereof.

In a preferred embodiment, the nanoparticles are generated by means of pulsed laser radiation. It is particularly suitable to use short-pulse or ul- trashort-pulse lasers, i.e. lasers with a pulse duration within the nanosecond, picosecond or femtosecond range. In the case of such (ul- tra)short laser pulses, the nanoparticles can particularly advantageously be obtained stochiometrically from the substrate because, due to the shortness of the pulse, thermal action on the substrate is locally limited. A further advantage is that a thermal influence on the liquid surrounding the substrate is avoided. The nanoparticles are preferably generated by means of quality-switched or mode-coupled lasers.

The wavelength of the laser radiation used for ablation or generation of nanoparticles is generally adapted to the absorption spectrum of the solvent and copolymer used, preferably in such a way that the absorption of the copolymer and of the solvent is at a minimum. Suitable wavelengths may, for example, be 532 nm, 800 nm, 1030 nm or 1064 nm. In the case of use of ultrashort pulses, especially at intensities which lead to mul- tiphoton absorption, the laser wavelength should be at least twice the absorption edge of the copolymer.

In general, the liquid used to perform the laser ablation is an organic solvent or a mixture of organic solvents. The liquid is preferably selected from the group comprising ethyl acetate, methanol, ethanol, isopropanol, acetone, dioxane, THF, DMF, DMSO, acetonitrile, 4-butyrolactone, di- chloromethane, chloroform, carbon tetrachloride, toluene, N-methyl-2- pyrrolidone, perfluorinated solvents, for example perfluoromethylcyclo- hexane, perfluoroalkanes, aromatic peril uorinated solvents, and mixtures thereof.

The substrates used may be the materials already mentioned in connec- tion with the nanoparticles in this description, especially metals and/or metal alloys. The substrates may appropriately have an even and preferably flat surface and can be configured, for example, in the form of sheets, slabs or the like. Alternatively, it is also possible to use wires with a diameter corresponding to the laser focus.

In a further embodiment, the nanoparticles are ablated from the surface of two, three or more substrates, each of which may consist of a different material. In this way, it is particularly advantageously possible to produce copolymer-modified nanoparticles with different properties, for ex- ample antimicrobial, inflammation-inhibiting, antithrombogenic and cell growth-promoting properties. In the case of more than two substrates, the laser can be conducted over the substrates by means of a suitable steering device in random sequence or repeatedly in a fixed, defined sequence. In this way, different nanoparticles can be generated simultane- ously in principle, which especially also leads to very good mixing in the liquid.

After the material removal by laser has ended, the liquid, especially for further use of the copolymer-modified nanoparticles, for example for in- corporation into polymers, can be removed at least partly, for example by applying a reduced pressure or vacuum. In this case, depending on the ablated nanoparticles and the amphiphilic copolymer used and/or the liquid used, dispersions in the form of gels can be obtained. According to the invention, the laser ablation can also be undertaken in a flow chamber with or without recycling of the liquid, as a result of which, depending on the reaction regime, diluted or concentrated copolymer-modified nanoparticles can be obtained.

With regard to further features and advantages of the production proc- ess, especially in relation to the nanoparticles and/or the amphiphilic copolymer, reference is made completely to the description so far.

A further aspect of the present invention relates to a polymer which comprises copolymer-modified nanoparticles according to the present invention.

The copolymer-modified nanoparticles are preferably present in homogeneous distribution or embedded in a matrix or three-dimensional structure of the polymer. In other words, the polymer itself preferably serves as a matrix or a carrier for the copolymer-modified nanoparticles (matrix or carrier polymer).

The copolymer-modified nanoparticles may have a proportion between

0.1 and 99.8% by weight, preferably 0.5 and 40% by weight, more pref- erably 1 and 5% by weight, based on the total weight of the polymer.

The polymer itself is preferably a fluoropolymer or a fluorophilic polymer,

1. e. a polymer whose hydrogen atoms are partly or fully (completely) replaced by fluorine atoms.

The polymer is preferably selected from the group comprising poly(2,3,4,5,6-pentafluorostyrene), poly( 1H, ^' - -heptafluorobutyl meth- acrylate), perfluoroxyalkyl vinyl ether, poly(chlorotrifluoroethylene), polytetrafluoropropylene, polyhexafluoropropylene, polyvinylidene di- fluoride, polytetrafluoroethylene, especially expanded polytetrafluoro- ethylene, homopolymers thereof, copolymers, in particular terpolymers, thereof and combinations or blends thereof. Examples of suitable copolymers include copolymers selected from the group comprising tetrafluoroethylene-perfluorovinyl ether copolymers, ethylene-tetrafluoroethylene copolymers, fluorinated ethylene-propylene copolymers, vinylidene difluoride-hexafluoropropylene copolymers, tetra- fluoroethylene-hexafluoropropylene-vinylidene difluoride terpolymers, tetrafluoroethylene-perfluoromethyl vinyl ether copolymers, ethylene- chlorotrifluoroethylene copolymers and combinations thereof. The fields of use for polymers according to the present invention are extremely varied. In principle, the polymers can be used for production of mouldings, semifinished products, finished products and/or end products, for example of pumps, tanks, vessels, filter housings, pipe valves, collars, flanges, tubes, linings for heat exchange, and for production of filter media.

In the automotive and aviation sectors, inventive polymers can be used, for example, for production of brake hoses, cooling water hoses, transmission and engine parts, sealing rings, sealing collars, sealing flanges, sealing discs, membranes for gasoline or fuel pumps, fuel hoses, tank hoses, outlet seals, and conductive fuel lines and/or gas discharge lines.

In wire and cable technology, it is possible by means of inventive polymers to produce, in particular, refractory, abrasion-resistant, wear- resistant and/or aging-resistant cables or sheathing for wires.

A further possible field of use of inventive polymers relates to the production of seals as typically used in radiators, air conditioning systems and transmission systems.

In the chemical industry, inventive polymers can be used, for example, for production of industrial hoses and pipe linings which are intended, for example, for the transport of chemicals. In order to improve corrosion resistance, it is, for example, also possible to coat pumps, tanks and/or valves with inventive polymers. Also conceivable is use of inventive polymers in the foods industry, for example for production of running rollers and/or crank rollers.

To increase corrosion resistance, inventive polymers can also find use in the architectural sector, for example in roofs, facades and decorative elements.

In addition, the polymers can be used for production of textiles, especially textile fibres, meshes or the like. Quite generally, inventive polymers can be used in the textile industry, preferably for production of sports clothing and/or shoes.

A further possible field of use of the polymers relates to the use thereof for production of membranes, especially for food technology, fluid tech- nology and/or pharmacy.

With regard to further features and advantages of the polymers, especially in relation to the copolymer-modified nanoparticles, the nanoparti- cles themselves and/or the amphiphilic copolymer, reference is made completely to the description so far.

The present invention further provides a coating composition, especially a polymeric coating composition, wherein said composition comprises copolymer-modified nanoparticles according to the present invention.

A coating composition shall be understood in the context of the present invention to mean a composition which is generally provided for coating of shaped bodies, for example mouldings, semifinished products, finished products and/or end products, for example medical articles.

In the coating composition, the copolymer-modified nanoparticles may have a proportion between 0.1 and 99.8% by weight, preferably 0.5 and 40% by weight, more preferably 1 and 5% by weight, based on the total weight of the composition.

With regard to further features and advantages of the coating composi- tion, especially in relation to the copolymer-modified nanoparticles, the nanoparticles themselves, the amphiphilic copolymer and/or possible polymers for the coating composition, reference is made completely to the description so far. A further aspect of the present invention relates to a masterbatch comprising copolymer-modified nanoparticles according to the present invention.

In the context of the present invention, a masterbatch shall be under- stood to mean a polymer additive which may be present, for example, in the form of a powder or granules, said polymer additive having a content of the copolymer-modified nanoparticles which is preferably higher than in the final application, for example in a moulding, semifinished product, finished product or another shaped body, especially medical article. The masterbatch may optionally also be in the form of a dispersion, especially a dispersion in the form of a gel.

With regard to further features and advantages of the masterbatch or polymer additive, especially in relation to the copolymer-modified nanoparticles, the nanoparticles themselves, the amphiphilic copolymer and/or possible polymers for the masterbatch, reference is likewise made completely to the description so far. The present invention further provides a liquid dispersion comprising a liquid dispersant, and nanoparticles modified with an amphiphilic, preferably random copolymer. The dispersion may optionally be present as a dispersion in the form of a gel. In other words, it may be preferred that the dispersion is a gel, in particular a hydrogel.

The dispersant is generally an organic solvent or a mixture of organic solvents which is preferably selected from the group comprising ethyl acetate, methanol, ethanol, isopropanol, acetone, dioxane, THF, DMF, DMSO, acetonitrile, 4-butyrolactone, dichloromethane, chloroform, carbon tetrachloride, toluene, N-methyl-2-pyrrolidone, perfluorinated solvents, for example perfluoromethylcyclohexane, perfluoroalkanes, aromatic perfluorinated solvents, and mixtures thereof.

The copolymer-modified nanoparticles are preferably in colloidal distribution in the liquid dispersant.

The copolymer-modified nanoparticles are preferably copolymer- modified nanoparticles according to the present invention.

With regard to further features and advantages of the liquid dispersion, especially with regard to the copolymer-modified nanoparticles, the nanoparticles themselves and/or the amphiphilic copolymer, reference is likewise made to the details so far.

A further aspect of the present invention relates to a process for producing a polymer comprising copolymer-modified nanoparticles, in which copolymer-modified nanoparticles according to the present invention are incorporated into a raw polymer. In the context of the present invention, a raw polymer shall preferably be understood to mean a polymer which is at least free of copolymer- modified nanoparticles. Possible raw polymers include, for example, the polymers already mentioned in the present description.

In a preferred embodiment, the copolymer-modified nanoparticles are incorporated into the raw polymer by producing a mixture of the raw polymer, the copolymer-modified nanoparticles and optionally additional additives. For this purpose, the raw polymer can be provided as a liquid dispersion, suspension, solution or melt. The copolymer-modified nanoparticles are preferably provided in the form of a liquid dispersion or in the form of a masterbatch.

With regard to further features and advantages of the process, especially in relation to the copolymer-modified nanoparticles, the nanoparticles themselves and/or the amphiphilic copolymer, reference is again made to the details given above.

A further aspect of the present invention relates to a semifinished product, finished product (component prefabricated from raw material or semifinished product, which is used in an end product without further processing) or end product, comprising nanoparticles modified with an amphiphilic, preferably random copolymer, or a polymer comprising nanoparticles modified with an amphiphilic, preferably random copolymer. The copolymer-modified nanoparticles are preferably copolymer- modified nanoparticles according to the present invention. In a preferred embodiment, the copolymer-modified nanoparticles are present in homogeneous dispersion in the semifinished product, finished product or end product. Alternatively, the semifinished product, finished product or end product may also have a coating with the copolymer- modified nanoparticles.

The copolymer-modified nanoparticles preferably have a proportion be- tween 0.1 and 99.8% by weight, preferably 0.5 and 40% by weight, more preferably 1 and 5% by weight, based on the total weight of the semifinished product, finished product or end product.

With regard to further features and advantages of the semifinished prod- uct, finished product or end product, especially in relation to the copolymer-modified nanoparticles, the nanoparticles themselves and/or the amphiphilic copolymer, reference is made completely to the description so far. In addition, the present invention also encompasses a process for producing an inventive semifinished product, finished product or end product, in which nanoparticles modified with an amphiphilic, preferably random copolymer, preferably copolymer-modified nanoparticles according to the present invention, are incorporated into a raw polymer and then the raw polymer is shaped together with the incorporated copolymer- modified nanoparticles to give a semifinished product, finished product or end product.

The raw polymer is preferably shaped together with the incorporated co- polymer-modified nanoparticles by means of extrusion, especially strand extrusion, fibre extrusion or film extrusion, spinning, especially fibre spinning, pressing, especially hot pressing, punch pressing, especially micro punch pressing, embossing, rolling, casting, especially injection moulding, or blowing, especially extrusion blowing, to give the semifin- ished product, finished product or end product. In an alternative production process, a semifinished product, finished product or end product is at least partly, preferably fully (completely), coated with nanoparticles modified with an amphiphilic, preferably random copolymer, preferably with inventive copolymer-modified nanoparti- cles.

To coat the semifinished product, finished product or end product, it is especially possible to use an inventive coating composition. In principle, it is possible to coat interior and/or exterior surfaces of the semifinished product, finished product or end product.

With regard to further features and advantages of the process, reference is likewise made to the description so far.

Finally, the present invention also relates to a medical article, especially a medical, preferably surgical implant or a part thereof, comprising nanoparticles modified with an amphiphilic, preferably random copolymer or a polymer which comprises nanoparticles modified with an am- phiphilic, preferably random copolymer.

In a particularly preferred embodiment, the copolymer-modified nanoparticles are copolymer-modified nanoparticles according to the present invention, i.e. producible or obtainable by a process in which the nanopar- tides are ablated by means of laser radiation from the surface of a substrate in a liquid comprising an amphiphilic, preferably random copolymer.

The abovementioned polymer is likewise preferably a polymer according to the present invention. The copolymer-modified nanopartides are present in the medical article preferably in homogeneous distribution or dispersion. Alternatively, the medical article may also have a coating with the copolymer-modified nanopartides or the polymer. The coating may be formed on an interior and/or exterior surface of the medical article.

In a further embodiment, the nanopartides, especially in the case of a purely surface coating of the medical article, are released over a period of one week to 10 years, especially 6 weeks to 7 years, preferably 6 months to 3 years, to a physiological environment, especially after implantation of the article into the body of a patient to the body region surrounding the article.

The copolymer-modified nanopartides preferably have a proportion be- tween 0.01 and 50% by weight, especially 0.05 and 10% by weight, more preferably 0.05 and 5% by weight, especially 0.5 and 3% by weight, especially preferably 0.1 and 3% by weight, particularly 0.1 and 1 % by weight, based on the total weight of the medical article. In a further embodiment, the medical article is formed from a polymer, preferably a fluorine-containing, fluorinated or fluorophilic polymer. For example, the medical article may be produced or made from a polymer selected from the group comprising perfluoroxyalkyl vinyl ether, poly(chlorotrifluoroethylene), polyvinylidene difluoride, polytetrafluoro- ethylene, polyhexafluoropropylene, polytetrafluoroethylene, especially expanded polytetrafluoroethylene, homopolymers thereof, copolymers, in particular terpolymers, thereof and combinations or blends thereof.

In a preferred embodiment, the medical article is selected from the group comprising prosthesis, especially vascular prosthesis, stent, stent graft, stent lining, shunt, catheter, trocar, surgical instruments, cardiovascular implant, heart valve prosthesis, heart valve flaps, venous sheath, wound dressing, haemostatic, surgical suture material, anastomosis ring, medical meshes, especially hernia meshes, incontinence meshes and/or prolapse meshes, dental implant, epitheses and ortheses. In a particularly preferred embodiment, the medical article is a hollow implant, preferably a tubular implant, especially a vascular prosthesis, preferably an arterial vascular prosthesis. The tubular implant is preferably produced or made from polytetrafluoroethylene (PTFE), especially expanded polytetrafluoroethylene (ePTFE).

Particularly advantageously, the wall thickness of a medical article configured as a hollow implant is not influenced by the presence of the co- polymer-modified nanoparticles. A medical article configured as a hollow implant preferably has a wall thickness between 0.05 and 1 mm, espe- daily 0.2 and 0.8 mm, preferably 0.3 and 0.6 mm.

In addition, the medical article is preferably sterilized, especially by means of ethylene oxide. With regard to further features and advantages of the medical article, especially in relation to the copolymer-modified nanoparticles, the nanoparticles themselves, the amphiphilic copolymer and possible polymers from which the article can be produced, reference is made completely to the description so far.

A further aspect of the present invention relates to a process for producing or manufacturing a medical article, in which nanoparticles modified with an amphiphilic, preferably random copolymer, preferably inventive copolymer-modified nanoparticles, are incorporated into a raw polymer, and then the raw polymer is shaped together with the incorporated nanoparticles to give a medical article. In an especially preferred embodiment, the copolymer-modified nanoparticles are ablated by means of laser radiation from the surface of a substrate in a liquid comprising an amphiphilic, preferably random copolymer.

The raw polymer is preferably shaped together with the incorporated nanoparticles by means of extrusion, especially strand extrusion, film extrusion or fibre extrusion, spinning, especially fibre spinning, pressing, especially hot pressing, embossing, rolling, punch pressing, especially micro punch pressing, casting, especially injection moulding, or blowing, especially extrusion blowing, to give the medical article.

An alternative production process for a medical article consists in at least partly, preferably fully (completely), coating an already prefabri- cated medical article with nanoparticles modified with an amphiphilic, preferably random copolymer, preferably with inventive copolymer- modified nanoparticles.

In principle, both interior and exterior surfaces of the medical article can be coated with the copolymer-modified nanoparticles.

To coat the medical article, it is also possible to use a coating composition which comprises copolymer-modified nanoparticles. The coating composition may, for example, be an inventive coating composition.

The copolymer-modified nanoparticles are also preferably incorporated into the raw polymer in the form of a liquid dispersion or of a master- batch. For this purpose, preference is given to employing inventive dispersions or masterbatches. With regard to further features and advantages of the production processes for the medical article, reference is likewise made completely to the description so far. The advantages of the present invention will be summarized once more hereinafter as follows.

The inventive copolymer-modified nanoparticles exhibit essentially no agglomeration tendencies and are therefore outstandingly suitable for homogeneous incorporation into polymeric materials. Homogeneous distribution or dispersion of the copolymer-modified nanoparticles particularly advantageously brings about a likewise homogeneous development of the properties imparted thereby in the materials. Thus, by means of the inventive copolymer-modified nanoparticles, medical articles in par- ticular can be produced with homogeneously highly developed medical, especially diagnostic and/or therapeutic, properties.

The selection or production of the amphiphilic copolymer to be used for modification of the nanoparticles can be matched in a particularly advan- tageous manner to the polymers into which the copolymer-modified nanoparticles are to be incorporated. For example, preference is given to copolymers with fluorophilic side groups when the copolymer-modified nanoparticles are to be incorporated into fluorinated polymers, for example polytetrafluoroethylene.

The amphiphilic copolymer-based modification of the nanoparticles is particularly advantageously sufficiently stable that it is not destroyed under the customary conditions of industrial shaping and forming processes, for example extrusion processes.

The production of the copolymer-modified nanoparticles, which is based on laser ablation and simultaneous in situ functionalization or in situ con- jugation of the laser-ablated nanoparticles with an amphiphilic, preferably random copolymer, also constitutes a high-purity operation. Complex and especially environmentally polluting purification and disposal steps are dispensed with.

A further advantage is that the production of the copolymer-modified nanoparticles may not be dependent on chemical precursor compounds or stabilisators, thus yielding the copolymer-modified nanoparticles in a higher degree of purity. This is especially advantageous in respect of a subsequent usage of the nanoparticles, such as in semifinished products, finished products or end products, in particular medical articles.

A further advantage relates to the possibility to achieve a higher in situ functionalisation or in situ conjugation of the laser-ablated nanoparticles with an amphiphilic, preferably random copolymer.

Depending on the type and number of substrates which are subjected to the laser ablation, it is possible in principle to produce more or less simultaneously copolymer-modified nanoparticles with different properties.

A further advantage relates to the possibility of what is called in-process control, for example by means of UV-VIS spectroscopy, of the in situ functionalization of the laser-ablated nanoparticles. A further advantage, finally, is also that there is no limitation whatsoever with regard to the nanoparticles. Instead, it is possible by means of laser ablation as a continuous operation to produce a desired amount or concentration of copolymer-modified nanoparticles. Further features and advantages of the invention are evident from the description of preferred embodiments which follows, with reference to examples. In this context, individual features may each be implemented alone or in combination with others. The examples which follow are intended to illustrate the invention in detail without restricting it.

1. Materials and analytical methods

All reagents and solvents were purchased commercially, unless stated otherwise. 2-Ethylhexyl methacrylate (EHMA) and trimethylsilyl-2- hydroxyethyl methacrylate (TMS-HEMA) were dried over calcium chlo- ride and distilled before use. 1 - 1 - -Perfluorooctyl methacrylate (FOMA) was filtered through a column packed with active alumina. Poly(ethylene oxide)methacrylate (PEOMA, M approx. 360 g mo ¹ ) was used as obtained. Poly-p-hydroxystyrene was purchased from Polysciences, Inc. Varrington, PA (M _w = 9000 to 1 1 000 g mol ^"1 - PDI about 3).

NMR analyses were conducted on a Bruker 250 or 300 MHz spectrometer. Gel permeation chromatography was conducted at 30°C using MZ- Gel SDplus 10E6, 10E4 and 500 columns, an ERC RI-101 differential refractometer detector, and THF as an eluent.

Transmission electron micrographs were obtained by means of a Tech- nai F20 microscope. The samples were prepared by means of ultrami- crotomy. Dynamic light scattering measurements were conducted by means of an ALV 5000 correlator, ALV-SP81 goniometer laser (krypton ion laser 647.1 nm - Spektra Physics Model Kr2025 - avalanche photodiode module). 2. Preparation of amphiphilic random copolymers

. Preparation of an amphiphilic random copolymer of the formula III below

Formula

Copolymer III was prepared by substitution of poly(p-hydroxystyrene) with 1-octyl bromide and 1 -,1 --perfluorooctyl bromide. In the copolymer obtained, 50 mol% of the monomer units had an n-octyl side chain in the p position, and 15mol% of the monomer units a 1 -,1 --perfluorooctyl unit.

2.2. Preparation of an amphiphilic random copolymer of the formula IV below

Formula IV

Copolymer IV was prepared by means of a free-radical polymerization of 2.6 mmol of EHMA, 0.4 mmol of PEOMA and 1 .3 mmol of FOMA in 1 1 .5 ml of 1 ,4-dioxane in the presence of 0.03 mmol of AIBN as an initiator at 65°C over 16 hours. Subsequently, the product was precipitated twice in methanol and then dried under reduced pressure. The resulting copolymer with the formula IV had a molecular weight Mn = 45900 g/mol ^"1 (PDI = 1.9) with 58 mol% of EHMA, 7 mol% of PEOMA and 35 mol% of PFOMA.

3. Preparation of matrix polymers

3.1. Preparation of poly(2,3,4,5,6-pentafluorostyrene) (PFS)

PFS was prepared by a free-radical polymerization of 1 ml of 2,3,4,5,6- pentafluorostyrene in 1 ml of THF at 60°C over 5 hours in the presence of 1.8 x 10 ^~5 mol of AIBN as an initiator. Subsequently, the product was precipitated twice in methanol and dried under reduced pressure.

3.2. Preparation of poly(1 - , 1 - -heptafluorobutyl methacrylate) (PFBA) PFBA was prepared by a polymerization of 3.1 mmol of 1 H, 1 H-hepta- fluorobutyl methacrylate in the presence of 1 .3 x 10 ^~5 mol of AIBN as initiator. The polymerization was conducted at 70°C over one hour. Subsequently, the product was precipitated twice in methanol and dried under reduced pressure.

4. Production of copolvmer-modified nanoparticles

The generation of nanoparticles was conducted by means of a nanosec- ond laser system (New wave Gemini PIV) which provided laser pulses with a pulse duration of 3 to 5 nanoseconds at a central wavelength of 532 nm. The laser system generated laser pulses with a pulse energy of up to 0.1 joule with a repetition rate of 15 Hz. The laser beam was fo- cussed through focussing lenses (focal length 40 mm) onto the surfaces of a silver and copper substrate. All experiments were conducted with a pulse energy of 7 mJ and with a 1 mm offset of the substrates in relation to the focus.

The silver and copper substrates were each placed separately onto the base of a sample vessel. Subsequently, the sample vessels were each filled with 2 ml of a solution containing THF and one of the copolymers prepared under 2., such that the substrates were in each case fully immersed into the solution. In this way, the copolymers were present during the generation of copper and silver nanoparticles and brought about in situ functionalization of the nanoparticles during the generation thereof.

The nanoparticles generated in the THF solution were characterized by means of dynamic light scattering (DLS) and transmission electron microscopy (TEM) and energy-dispersive x-ray spectroscopy (EDX). The dispersions obtained after conducting the laser ablation did not give any signs of precipitation. In addition, conduction of the abovementioned methods for characterization of the nanoparticles generated by means of laser ablation showed that they were present coated with the copolymer and hence separately from one another, as a result of which flocculation, precipitation or sedimentation tendencies were successfully suppressed.

5. Incorporation of the copolymer-modified nanoparticles into polymers

For incorporation of nanoparticles produced under 4., the matrix poly- mers PFS and PFBA were selected. For this purpose, 10 mg in each case of the matrix polymer were dissolved in 1 ml of THF. Subsequently, 0.8 ml of the dispersion produced as under 4. was added. The resulting mixture was heated to 55°C over one hour. Subsequently, the THF solvent was removed under reduced pressure.

6. Production of an ePTFE prosthesis with copolymer-modified nanoparticles

Pure PTFE powder was used to produce a pasty, PTFE-containing dis- persion by addition of a liquid lubricant, for example of odourless petroleum spirit or naphtha. This dispersion was admixed with copolymer- modified silver nanoparticles according to Example 4 and homogenized by means of stirring. The concentration of the copolymer-modified nanoparticles used was 1 .0% by weight, based on the total weight of the PTFE used. The homogeneous mixture obtained was then preshaped to a cylindrical blank with a pressure of 3000 kPa (kilopascals). The preshaped blank was then extruded to a tube with an internal diameter of 6 mm. The resulting extrudate was expanded at a temperature of 325°C and converted to a tubular shape. Subsequently, the extrudate was sin- tered above the expansion temperature at 350°C in order to crystallize the extruded structure. Finally, the extruded prosthesis was rinsed in or- der to remove adhering non-integrated copolymer-modified silver nanoparticles. Finally, the prosthesis was cut to the desired length.