EP1087799A1

EP1087799A1 - Method for producing biocompatible surfaces

Info

Publication number: EP1087799A1
Application number: EP98963549A
Authority: EP
Inventors: Franz Herbst; Alexei Kalatchev
Original assignee: Herbst Franz; Kalatchev Alexei
Current assignee: Herbst Franz; Kalatchev Alexei
Priority date: 1998-06-09
Filing date: 1998-12-09
Publication date: 2001-04-04

Abstract

The invention relates to a new and improved method for producing biocompatible surfaces, more particularly, the surfaces of medical objects such as implants. The invention particularly relates to stents with enhanced properties.

Description

METHOD FOR PRODUCING BIOCOMPATIBLE SURFACES

The present invention relates to a novel and improved method for producing biocompatible surfaces - in particular surfaces of medical objects such as implants. The invention particularly relates to so-called "stents" with improved properties.

It is known from the prior art that medical devices or implants that come into contact with body fluids or body tissue - such as e.g. Catheters, electrodes, implants, etc. - can lead to immune defense reactions, thrombus formation, inflammation, etc. In order to suppress these body reactions, the surfaces of the corresponding medical devices are coated with substances which prevent or suppress the reactions mentioned above. The generated biocompatibility should be preserved as long as possible. This can be achieved by covalently binding the substances or biomolecules immobilized on the surface. In the case of covalent bonding, however, care must be taken to ensure that no functional groups which are important for the biocompatible properties of the molecule are destroyed by the chemical crosslinking between the surface and the molecule to be bound. In addition, the free spatial availability of the bound molecule should be guaranteed.

In US Pat. No. 5,049,403 [Lars et al.], A polyamine is ionically adsorbed on the surface to be modified and the molecule to be bound is then covalently bound via a dialdehyde. However, this method has the disadvantage that no covalent bond of the polyamine is built up on the surface to be modified and the complex formed can thus diffuse out in an aqueous environment. In U.S. Patent No. 5,132,108 to Narayanan et. al. the polymer surface to be treated is activated by a radio-induced plasma treatment in an aqueous gas phase. The surface is then treated with a solution of polyethyleneimine (PEI) and 1- (3-dimethylpropyl) -3-carbodiimide (EDC). There is a chemical immobilization of the PEI with the surface via amide bonds. In a further step, the molecule to be bound, which has the biocompatible properties, is bound to the polyethyleneimine via EDC via a further immobilization step. The molecule to be immobilized is then covalently bound to the surface via a polyethyleneimine layer.

However, this method has the restriction that the covalent binding of polyethyleneimine to the surface and to the molecule to be bound requires carboxyl functions, which first have to be created on the surface by plasma treatment. These must be present in the binding molecule by nature or only be introduced by means of appropriate chemical modifications. This method therefore has the further disadvantage that chemical modifications to introduce carboxyl functions have to be carried out, ^* which cause changes in conformation and can therefore lead to a loss of activity. To make matters worse, the native carboxyl functions present in the molecule are blocked by the bridging reaction with EDC and thus the chemical characteristics of a molecule modified in this way are permanently influenced. Carboxyl groups or hydroxyl groups that do not contribute to covalent bonding are also blocked by EDC. In this case, modification to these groups disadvantageously takes place, which can lead to undesired immunological reactions, since new antigenic properties can be introduced into the molecule in this way. This can likewise disadvantageously lead to an undesired loss of activity of the molecule to be bound. In U.S. Patent No. 5,308,641 [Cahalan et. al.] a similar method is described. Here the surface is activated with amino functions. Then PEI is covalently bound to the surface via a dialdehyde. The further bridging of the molecule to be bound with PEI also takes place via a dialdehyde. Here too, amino functions must first be introduced on the surface, which then bind the PEI covalently via a dialdehyde. The binding of the actual biocompatible molecule to the PEI layer takes place here via a dialdehyde function which links amino functions in the molecule to the PEI layer. Here, too, one encounters the same problem of the initial activation of the surface with special functional groups and binding of the biomolecule via introduced or native amino functions in the molecule. Again, as with the Narayanan et. al. undesirable side reactions occur.

On the other hand, in view of the problems described, it becomes clear that an essential prerequisite for the successful application of the methods known from the prior art is the presence of chemically reactive groups on the object to be coated. However, this is not the case - for example in the case of an object or a device made of metal, such as the "stents" already mentioned.

In order to increase the biocompatibility of electro-conductive or metal objects with "inert" surfaces, the application of so-called "diamond-like" layers - ie: layers with a diamond-like surface structure - has become established in the prior art. Such a surface is applied as part of a so-called plasma polymerization. - This is mainly carried out in a so-called cold plasma at gas temperatures in a temperature interval of 20 to 80 ° C. The plasma is generally by means of direct current or high-frequency alternating current or by microwaves under pressure Surface layer-producing gaseous reactants carried out from 10 " ² to 1 kPa.

Since the films applied in this way only have a layer thickness of <1 μm, important material properties of a shaped body coated in this way remain unchanged.

For deformable hollow bodies made of an electrically conductive material or with an electro-conductive surface - such as with "stents" made of metal - is it e.g. required that the layer thickness is <10 nm and is particularly preferably between 40 and 80 nm, since otherwise the applied layer becomes brittle when deformed and the effect of metal ion diffusion occurs, which can lead to allergic and other undesirable reactions, and what - naturally - is extremely undesirable, especially in medical devices.

On the other hand, it is known from WO 89/11919 that coating metal hollow bodies as completely as possible presents not inconsiderable problems, since under the plasma conditions described above, a Faraday cage forms in the interior of the metal objects, with the result that that on the inside - if at all - then only an extremely minimal coating can be achieved in terms of area. However, the solution proposed in this laid-open document is unsatisfactory and limited to hollow bodies which have a perforated wall or perforated walls.

The object of the present invention is therefore essentially to overcome the disadvantages of the methods known from the prior art and to provide a method which is capable of molecules - in particular biomolecules - on surfaces which due to their chemical functionality or Reactivity is to be regarded as intrinsically intrinsic, without a chemical functionalization (ie: the incorporation of suitable functional groups) must take place.

In addition, it is a further object of the present invention to provide a person skilled in the art with a method that completely covers metallic objects - in particular hollow metallic bodies - such as e.g. "Stents" - enables.

In particular, the object of the present invention is to create a so-called "stent" - i.e. in the sense of the present invention to provide a medical device for the repair or prevention of vascular occlusions, which is completely covered with a biocompatible layer. Among other things, the "stent" ensures that it can be easily introduced into the vessel, for example by balloon dilatation, and because of its mechanical properties, which - as already mentioned - should remain largely unchanged in the coating - is not disadvantageously deformed during this process. The "stents" known from the prior art deform their ends - usually trumpet-shaped - when placed in the vessel, which is extremely undesirable.

Another object of the present invention is to enable covalent immobilization of the molecules of the biocompatible layer.

These objects are achieved by the in the characterizing part of the claims and by the invention reproduced in the following description.

In order to carry out the present invention, the first step is to produce the complete diamond-like surface on the object to be coated in a so-called plasma polymerization. The General conditions for the construction of the plasma required for this purpose are - as already mentioned at the beginning - known from the prior art [comprehensive polymer. 4, 357-375. 2 Encycl. Polym. Be. Engineering. 11, 248-261; Houben-Weyl E20 / 1, 361-368; gen .: J. Appl. Polym. Be. 38, 741-754 (1989), I. Yasuda, Plasma Polymerization and Plasma Treatment, New York: Wiley 1984, 1. Yasuda, Plasma Polymerization, Orlando, Florida: Academic Press 1986].

The process according to the invention for producing biocompatible coatings on molded hollow bodies with an electrically conductive or metallic surface which has at least one opening for receiving an electrode is characterized in that the hollow mold body is coated in a low-temperature plasma which is produced by a combination of a radio frequency source , which emits radiation with a frequency in the MHz range, and an ultrasound source that emits ultrasound waves in the kHz range - under reduced pressure - is built up, the plasma-producing gas or gas mixture having at least one carbon-containing gaseous compound and possibly a Carrier gas contains

Suitable starting monomers for generating the diamond-like coating in a plasma polymerization are hydrocarbons having 1 to 6 C atoms and halogenated — preferably fluorinated — hydrocarbons, which likewise preferably have 1 to 6 C atoms. The following may be mentioned as preferred examples: tetrafluoroethylene, hexafluoroethane, perfluoropropylene, methane and ethane, of which methane is very particularly preferred.

In addition, mixtures of the above can also be used. Monomers with a

Carrier gas are used. Noble gases are preferred as carrier gases, among which argon is particularly preferred. When using gas mixtures consisting of one or more carbon-containing gases with one or more carrier gases, the volume ratio according to the invention is adjusted between the two proportions such that the gas mixture contains the carbon-containing gas (s) and the carrier gas (s) ) in a volume ratio in an interval of 99: 1 to 1:99, preferably in a volume ratio in an interval of 20:80 to 3:97 and particularly preferably in a volume ratio of 5:95.

The reaction conditions under which the plasma polymerization takes place in a low-temperature plasma are generally known from the prior art and are not critical. However, it is generally prefers a plasma with a high energy density, which - usually - is given in the dimension Joule / kg monomer and hydrogen. As is also known from the prior art, this value should be greater than 1 GJ / kg; energy densities in the range from 1 to 20 GJ / kg are preferred and particularly preferably in a range from 1 to 10 GJ / kg. If methane is used as the sole monomer, the energy density should be in the range from 6 to 10, preferably 7 to 9 and particularly preferably 8 GJ / kg. If halogenated or fluorinated hydrocarbons are used, the energy density may also be below 1 GJ / kg if necessary.

When carrying out the process according to the invention, the plasma polymerization takes place under a gas pressure in an interval of 0.02 to 1 Torr, preferably in an interval of 0.02 to 0.1 Torr and particularly preferably at 0.04 Torr. The radio frequency source emits radiation in an interval of 10 to 15 MHz, preferably radiation in an interval of 13 to 14 MHz and particularly preferably radiation of 13.46 MHz, the ultrasound source preferably emitting radiation in an interval of 5 to 100 kHz in an interval of 5 to 50 kHz and particularly preferably radiation in an interval of 5 to 25 kHz emitted; the ultrasound source very particularly preferably emits ultrasound waves with a frequency of 20 kHz.

The present invention additionally relates to a method step in which biomolecules or other molecules can be covalently bonded to surfaces which are chemically inert, without the need to chemically modify the surface or the molecule to be bound.

Biomolecules in the sense of the present invention are synthetic or naturally occurring compounds or natural substances which are capable of ensuring or increasing the biocompatibility of a shaped body in the human or animal body. Examples are:

natural or synthetic sugars, glycosaminoglycans - such as in particular heparin -, endostatin or angiostatin. Other suitable biomolecules are well known to those skilled in the art.

After the diamond-like or the diamond-like layer has been applied, the step according to the invention is followed by the step of covalently binding the selected biomolecule:

The introduction of a photoactive "spacer layer" made of PEI firstly achieves a covalent bond between the PEI layer and the surface, as well as the covalent bond of the molecule to the PEI layer. To do this, chemically reactive groups need not be present on the surface or in the molecule to be bound in order to achieve covalent binding via the photoactivated PEI molecule. The photochemical reaction chosen is the generation of a carbene which is capable of inserting or adding bonds to CC, CH, NH, SH, CO, C = O, C = C, etc. In the first step, the polyamine dehvated with a photoactive molecule is adsorbed on the surface via ionic, hydrophobic or hydrogen bond bonds. The surface is covered with a photoactivatable layer. The corresponding molecule is then bound to the photoactivatable polyamine layer via ionic, hydrophobic or hydrogen bonds. The next step is the irradiation and thus the generation of reactive carbenes in the polyamine. The carbenes form covalent bridges between the surface, the polyamine and the molecule adsorptively bound to the polyamine.

It is particularly advantageous if the adsorptively bound molecule carries a total oppositional charge to the polyamine. If this is the case, you can work with very low concentrations of the molecule to be bound to the PEI layer (polycation), since there is a strong ionic concentration effect of the molecule on the polyamine layer [(also use of photoactivatable polyanions) (use of nitrenes , Quinones etc.)].

The present invention is illustrated by the following examples. Various other configurations of the invention and of the methods will become apparent to those skilled in the art from the present description. However, it is expressly pointed out that these examples and the description associated with them are only intended for the purpose of illustration and are not to be regarded as a limitation of the invention. Process for diamond-like coating of stents in low-temperature plasma using ultrasound

example 1

The plasma reactor used for the coating represents a bell-jar chamber with parallel plate electrodes. The lower electrode is connected to a 13.46 MHz radio frequency generator and 20 kHz ultrasound generator. The top electrode is grounded. The reactor is equipped with a backing pump and a turbomolecular pump. Furthermore, the reactor is equipped with a fine valve as a gas inlet, an absolute pressure measuring device and a quartz thickness monitor (QTM), which is attached to the upper electrode.

21 stents are placed in a vertical position on the lower electrode. A Pt / Ir wire (auxiliary electrode), which is firmly connected to the lower electrode, makes electrical contact between the stent and the lower electrode.

The reactor is evacuated to a residual pressure of less than 0.001 torr and pure argon is introduced into the reactor to a pressure of 0.04 torr. A plasma is then generated via the radio frequency generator and the stents are held there for 25 min. pre-treated. The reactor is then charged with a 95/5 mixture of argon / methane with constant pumping. The pressure is kept at 0.04 torr. A plasma is then generated via the radio frequency and the ultrasound generator, with the aid of which the stents are coated. The coating process is carried out until the QTM indicates a layer thickness of 18 nm, which reflects a thickness coating on the stents of 50 nm. Example 2.

The same coating is carried out - as in Example 1 - until the QTM indicates a layer thickness of 65 nm, which corresponds to an average layer thickness on the stents of 200 nm.

Example 3

The same conditions as in Example 1 are chosen. The plasma gas pressure is set to 0.1 Torr here. The average layer thickness on the stents is determined to be 75 nm.

Example 4

The same conditions as in Example 1 are chosen. The argon / methane ratio is set to 90/10.

Example 5

The same conditions are chosen as in Example 1, but instead of an argon / methane ratio of 95/5, a ratio of 83/17 is set.

The preferred layer thickness on the stents is between 10 nm and 80 nm. Under this limit, uncoated zones may be observed on the stent. Cracks and other defects in the coating on the stent can be observed above this limit (FIGS. 1 and 2). Fig. 1 shows a molded body with a homogeneous "diamond-like" coating, which was applied by the method according to the invention and has a layer thickness of about 50 nm after a deformation process. The picture shows a stent after dilation in water at 37 ° C. The figure clearly shows that the coating has not become brittle and has no cracks even after being deformed.

2, on the other hand, shows a corresponding shaped body with a layer thickness of approximately 200 nm. The figure clearly shows the undesirable crack formation after dilatation in water at 37 ° C.

3 graphically represents the release of metal ions from coated and uncoated stents over a period of 48 hours in 1N HCl. It can be clearly seen that the release of metal ions from an uncoated stent takes place with increasing time (t) (curve A), while no release of metal ions is detectable in a stent coated according to the invention (curve B).

Example of covalent binding of heparin to a chemically inert surface

Example 4

Polyethyleneimine (PEI) is chemically linked to the photoactive molecule TRIMID [3-trifluoromethyl-3- (m-isothiocyano-phenyl) diazirine], so that a photochemically active PEI-TRIMID molecule is formed. One PEI molecule carries several covalently bound TRIMID molecules. The coating of an inert surface with heparin is carried out as follows:

A "stent" with a diamond-like is placed in a solution of 60 μg / ml PEI-TRIMID in PBS [phosphate buffer saline: 5 mmol NaH2Pθ4 + 100 mmol NaCI, pH 7.4]

Coating (coating consists of an inert material, the structure of which is related to diamond) for 30 min. incubated at room temperature. It is then washed 3 times with PBS. The stent, now coated with a layer of PEI-TRIMID, is placed in a solution of 50 μg / ml heparin in PBS for 30 min. at room temperature. Then the stent is applied 2 times with PBS and 1 time with

Washed water and dried in a high vacuum at room temperature. The stent now carries a lower layer made of PEI-TRIMID to which a layer of heparin is ionically bound. In order to covalently bind the layers to the diamond-like surface, the stent is dried in UV for 15 min. exposed at a wavelength of 360 nm. During exposure, a carbene is formed from the TRIMID covalently bound to the PEI, which on the one hand inserts covalently into the diamond-like layer and thus covalently binds the PEI via the TRIMID molecule. On the other hand, the TRIMID also inserts carbene into the heparin molecule and creates a chemical bond between heparin and PEI. The heparin molecule is thus covalently bound to the diamond-like surface via the TRIMID modified PEI linker molecule.

Detection of the binding of heparin via TRIMID-PEI to a diamond-like coated surface

Example 5

The structure of the layers of polyethyleneimine TRIMID and heparin can be observed with the help of a biosensor. To do this, the sensor plate with the coated with the same diamond-like surface as was the case with the stent. The biosensor used is from ASI, Switzerland. The detection principle is based on changes in the refractive index on transparent surfaces when molecules are bound to these surfaces.

FIG. 4 shows a sensogram in which the formation of the first layer of polyethyleneimine TRIMID (B) and the subsequent structure of the heparin layer (D) on the first layer is shown. The same concentrations of polyethyleneimine TRIMID and heparin were pumped over the diamond-like coated sensor plate, as was the case with the coating of the stent.

The individual sections include:

A: Flow of buffer over the sensor, PBS pH 7.4 B: Flow of 60 μg PEI-TRIMID / ml in buffer PBS, pH 7.4 C: Flow of buffer over the sensor, PBS pH 7.4 D: Flow of 40 μg heparin / ml in buffer in buffer PBS, pH 7.4 E: flow of buffer over the sensor, PBS pH 7.4 activity test of the heparin modified surface

5 shows the heparin activity of covalently immobilized heparin on "stents" which were first provided with a "diamond-like" coating to which heparin was covalently bound according to the invention by the process according to the invention.

FIG. 5 shows the activity of uncoated, HSA (Human Serum Albumin) coated and heparin coated "stents" in the diagram. The "stents" were coated according to the above procedure. The uncoated stent was not coated. The stent HSA was made with PEI-TRIMID and then coated with HSA. Stents 1, 2, 3 and 4 were coated according to the above procedure.

The heparin activity is measured using a standard Haemachrom method in the Coacut heparin test. The interaction of antithrombin III with thrombin in the presence of heparin is determined. Non-inactivated thrombin cleaves a chromogenic substrate, which releases a chromophore, the absorption of which can be measured. The size of the absorption of the chromophore is inversely proportional to the heparin activity.

Measurement of stent closure times (TSO) of uncoated, diamond-like coated and diamond-like-heparin coated stents

The in vitro model for measuring stent occlusion times consists of a polyvinyl chloride tube with a total length of 82 cm. The tube segment, which will later accommodate the dilated stent, has an inner diameter of 4 mm. The rest of the hose has a diameter of 3 mm. The stent is inserted into the tube using a balloon catheter and onto one

Diameter of 3 mm dilated. Then 6 ml of platelet-rich plasma are poured into the tube system. Then with a 10 mmol CaCl2

Solution adjusted to physiological concentration of Ca ²⁺ and the plasma at a flow of 8 ml / min. and a flow rate of 2 cm / s pumped in a circle. The temperature is kept at 37 ° C. A control system is operated under the same conditions at the same time without a stent. The time is measured - stent closure time (TSO) - after which plasma can no longer be pumped through the stent. -

6 shows the TSO times of uncoated stents (TSO Steel), of diamond-like coated stents (TSO diamond) and of diamond-like heparin coated stents (TSO diamond + heparin). In the box plot, the y-axis indicates the average stent closure time. It can clearly be seen that the diamond-like or diamond-like + heparin-coated stents have significantly longer shutter speeds than the corresponding uncoated stents.

From the above description and the examples it is clear that the method proposed according to the invention is suitable for the production of a large number of shaped articles with a biocompatible surface; however, the method according to the invention is preferably suitable for producing medical devices, implants and surgical instruments and particularly preferably for coating on "stents". The "stents" according to the invention preferably have the structure shown in FIGS. 7 and 8:

7 and 8 show the sectional drawing of the stents according to the invention, which is explained below:

The construction of the stent is chosen according to the invention to solve the problem described in the introduction such that

1. the stent comprises loops (A and B) alone or a combination of loops and joints (C). The loop elements (A, B), like the joint elements (C), can also be connected directly to their closest neighbors via webs.

2. the individual stent segments (loops A and B) have different lengths. The smaller loop segments (A) are at the outer ends of the stent. If the stent has joint elements (C), the smaller loops (A) connected to these elements (C) if not all loops are connected to one another via joints. If all loops are connected with joints, the loops at this point are of type B. The aim of the construction is that the stent does not expand at the ends where the smaller loop segments are located until a higher pressure is applied. As a result, everyone

Expand the loop segments more evenly and there is no trumpet-like or tulip-like expansion at the free ends of the stent.

To further prevent the tulip effect, the individual stentsch runs can be of different strengths. The following principle applies:

Those loops which are located at the two ends of the stent or of the hollow mold body have a greater material thickness than those loops which are arranged more in the direction of the center of the stent or in the center thereof. The material thickness of the loops can change in width or thickness. This ensures that a lower stent counterpressure is counteracted in the center or in the center of the balloon used to dilate the stent than at the outer ends of the stent. According to the invention, an uneven stretching (trumpet or tulip effect) is also avoided. A change in the loop width can be achieved, for example, by simply changing the cut; a change in the loop thickness can e.g. by asymmetrical electropolishing.

Claims

Claims:

1. Shaped body, characterized in that it has a complete diamond-like coating which was applied by means of plasma polymerization in a low-temperature plasma under the action of ultrasound waves and to which a layer of biomolecules is covalently bound.

2. Shaped body according to claim 1, characterized in that the biomolecule is modified with a 3-trifluoromethyl-3- (m-isothiocyanophenyl) diazirine

Linker molecule is bound to the diamond-like layer.

3. Shaped body according to claim 2, characterized in that the linker molecule is polyethyleneimine.

4. Shaped body according to one of claims 1, 2 or 3, characterized in that the biomolecule is a natural or synthetic sugar.

5. Shaped body according to one of claims 1, 2 or 3, characterized in that the biomolecule is a glycosaminoglycan.

6. Shaped body according to claim 5, characterized in that the glycosaminoglycan is heparin.

7. Shaped body according to one of claims 1, 2 or 3, characterized in that the biomolecule is endostatin or angiostatin.

8. Shaped body according to claim 1 to 7, characterized in that it is a stent.

. Stent according to claim 8, characterized in that it has smaller loops (A) and larger loops (B) and articulated elements (C) which are connected either via webs or directly to one another, the smaller loops (A) being at the outer ends of the stent and in the case that not all loops are connected to one another via joints, only the smaller ones

Loops (A) occur in a stent segment and are connected via joint elements (C).

10. Stent according to claim 8, characterized in that it has smaller loops (A) and larger loops (B) and joint elements (C), which either

Bridges or are directly connected to one another, the smaller loops (A) being at the outer ends of the stent.

11. Process for the production of biocompatible coatings on hollow moldings, with an electrically conductive or metallic

Surface which have at least one opening for receiving an electrode, characterized in that the mold hollow body is coated in a low-temperature plasma which is produced by a combination of a radio frequency source which emits in the MHz range and an ultrasound source which emits in the kHz range is built up under reduced pressure, the plasma-producing gas or gas mixture containing at least one carbon-containing gaseous compound and possibly a carrier gas

12. The method according to claim 11, characterized in that the carbon-containing gaseous compound is a hydrocarbon or halogenated hydrocarbon.

13. The method according to claim 12, characterized in that the carbon-containing gaseous compound embodies a hydrocarbon or fluorocarbon with 1 to 6 carbon atoms.

14. The method according to claim 13, characterized in that the hydrocarbon is methane.

15. The method according to any one of claims 1 1 to 14, characterized in that the carrier gas is a noble gas.

16. The method according to claim 15, characterized in that the carrier gas is argon.

17. The method according to any one of claims 1 1 to 16, characterized in that the gas mixture or the carbon-containing gas (s) and the or

Contains carrier gas (s) in a volume ratio in an interval of 99: 1 to 1:99.

18. The method according to claim 17, characterized in that the gas mixture contains the carbon-containing gas (s) and the carrier gas (s) in a volume ratio in an interval of 20:80 to 3:97.

19. The method according to claim 18, characterized in that the gas mixture contains the carbon-containing gas (s) and the carrier gas (s) in a volume ratio of 5:95.

20. The method according to any one of claims 1 1 to 19, characterized in that the low-temperature plasma coating is carried out under a gas pressure in an interval of 0.01 to 1 Torr.

21. The method according to claim 20, characterized in that the

Low temperature plasma coating takes place under a gas pressure in an interval of 0.02 to 0.1 Torr.

22. The method according to claim 21, characterized in that the

Low temperature plasma coating takes place under a gas pressure of 0.04 Torr.

23. The method according to any one of claims 11 to 22, characterized in that the radio frequency source emits radiation in a frequency interval from 10 to

15 MHz emitted.

24. The method according to claim 23, characterized in that the radio frequency source emits radiation in a frequency interval of 13 to 14 MHz.

25. The method according to claim 24, characterized in that the radio frequency source emits radiation with a frequency of 13.46 MHz.

26. The method according to any one of claims 1 1 to 25, characterized in that the ultrasound source emits ultrasound waves in a frequency interval of 5 to 100 kHz.

27. The method according to claim 26, characterized in that the ultrasound source emits ultrasound waves in a frequency interval of 5 to 50 kHz.

28. The method according to claim 27, characterized in that the

Ultrasound source emits ultrasound waves in a frequency interval of 5 to 25 kHz.

29. The method according to claim 28, characterized in that the

Ultrasonic source emits ultrasonic waves with a frequency of 20 kHz.

30. Device for coating moldings which have an electro-conductive or metallic surface in a low-temperature plasma, characterized in that they have at least one device for emitting a radio frequency in the MHz range and at least one device for emitting ultrasound in the kHz range and one or has several devices for evacuating and for filling with gaseous compounds.

31. Molded hollow body, characterized in that it was produced by a method according to claims 11 to 29.

32. Molded hollow body according to claim 31, characterized in that it embodies an expandable tubular stent.

33. Molded hollow body according to one of claims 31 or 32, characterized in that the diamond-like coating has a thickness of 2.5 to 100 nm.

34. Molded hollow body according to claim 33, characterized in that the diamond-like coating has a thickness of 10 to 80 nm.

35. Molded hollow body according to one of claims 31 to 34, characterized in that the wall thickness or the strength of the loops have a greater material thickness at the ends of the hollow mold body or stent than in the center thereof.

36. A process for the production of biocompatible surfaces on molded articles with chemically inert surfaces, characterized in that a biomolecule is covalently bound to a molded article with a chemically inert surface by means of a photochemically activated molecule.

37. The method according to claim 36, characterized in that the biomolecule is bonded to the diamond-like layer via a linker molecule modified with 3-trifluoromethyl-3- (m-isothiocyanophenyl) diazirine.

38. The method according to any one of claims 36 or 37, characterized in that polyethylene imine is used as the linker molecule.

39. The method according to any one of claims 36 to 38, characterized in that a natural or synthetic sugar is used as the biomolecule.

40. The method according to any one of claims 36 to 38, characterized in that a glycosaminoglycan is used as the biomolecule.

41. The method according to claim 40, characterized in that heparin is used as the glycosaminoglycan.

42. The method according to any one of claims 36 to 38, characterized in that endostatin or angiostatin is used as the biomolecule.