Title of Invention

"PROCESS FOR PREPARING BIOCOMPATIBLE COATINGS ON HOLLOW MOULDINGS"

Abstract

Process for preparing biocompatible coatings on hollow mouldings, with an electrically conductive or metallic surface, which have at least one opening for receiving an electrode, characterized in that the hollow moulding is coated in a low temperature plasma which is produced by a combination of a radiofrequency source which emits in the MHz range and an ultrasound source which emits in the kHz range under reduced pressure, the plasma generating gas or gas mixture containing at least one carbon-containing gaseous compound of the kind such as herein described and optionally a carrier gas, wherein the low temperature plasma coating is carried out under a gas pressure in the range from 0.01 to 1 Torr.

Full Text

The present invention relates to a novel and iproroved process for preparing biocompatible surfaces, particularly th.s surfaces o£ medical objects such as implants. The indention relates particularly to so-called "stents" with improved properties . It is known from the prior art that medical instruments or implants; which come into contact with body fluids or body tissue, such as catheters, 6ilectrod.es, implants, etc., may lead to immune defence reactions, the formation of clots, inflammation, etc. In order to suppress these physical reactions, the surfaces of the medical items in question are coated with, substances which prevent or suppress the above-mentioned reactions- The biocompatibil.ity produced should be maintained for as lone as possible. This can be achieved if the substances or biomolecules immobilised on the surface are covalently bound. In covalertt binding cars must be taken to ensure that no functional groups which are important for the biocompatible properties of the molecule are destroyed by the chemical cross-linking between the surface and the molecule which is; to be bound, In addition, the bound molecule should have free spatial availability. Thus, in U.S. Patent No. 5,049,403 [Lars et al.] a pclyamine is ionically adsorbed on the surface which is to be modified and subsequently the molecule to be bound is ccvalently bound via a di aldehyde. This method does, however, have the disadvantage that there is no covalent binding of the polyamine on the surface which is to be modified and consequently the resulting complex can diffuse away in an aqueous environment. In U.S. Patent No.: 5,132,108 of Narayanan et al. the polymeric surface to be treated is activated by 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). This leads to chemical immobilisation of the PEI with the surface by means of amide bonds. In a further step the molecule to be bound, which has the biocompatible properties, is bound to the •poLyethyleneimine by means of a further immobilisation step with EDC. The molecule to be immobilised is then covaleritly bound to the surface via a layer of polyethyleneimine. However,, this process; does hav« the limitation theit the covalent binding of polyethyleneimine to the surface and to the molecule which is to be bound requires carboxyl functions which first: have to be created on the surface by plasma treatment. In the molecule which is to be bound, these carboxyl functions must occur naturally or 'be introduced by a suitable chemical modification. This process thus has the further disadvantage that chemical modifications have to be carried out to introduce carboxyl functions and such modifications lead to changes in configuration arid may thus :result in a loss of activity. A further detrimental factor is that native carboxyl functions present in the molecule are blocked by the bridging reaction with EDC and thus the chemical characteristics of a molecule thus modified are negatively affected. Carboxyl groups or hydroxyl groups which do not ccntributei to the covalent binding are also blocked'by EDC, Unwanted modification occurs at these groups which mey lead to undesirable immunological reactions, since new antigenic properties may be introduced into the molecule in this way. This may have the detrimental effect of leading to an unwanted loss of a.ctivity of the molecule which is to be bound. U.S. Patent No. 5,308,641 [Cahalan et al.] describes a similar method. Here, the surface is activated with aminof unctions. Then PEI is covalently bound to the surface via a dialdehyde. The molecule to be bound is further bridged with PEI via a dialdehyde. Once again, aminofunctions first have to be introduced onto the surface; and these then bind the PEI covalently via a dialdehyde. The binding of the actual biocompatible molecule to the PEI layer in this case takes place via a dialdehyde function which links aminofunctions in the molecule to the PEI layer. Once again, therms is the same problem of the initial activation of the surface with special functional groups and the binding of the biomolecule via aminofunctions which are either native or to be introduced into the molecule. Once again, as in the patent of Narayanan et al., undesirable side reactions may occur. On the other hand, with regard to the problem described, it is apparent that an essential prerequisite for the successful application of the processes known from the prior art is the presence of chemically reactive groups on the object which ia to be coated. However, ihis is not the case, e.g. in an object or apparatus made of metal, such as the stents mentioned earlier. In order to increase the bioconipatibility of electroconductive or metal objects with "inert" surfaces, the application of so-called diamond-like coatings, i.e. coatings with a diamond-like surface structure, has caught on in the prior art. A surface of this kind is applied by means of so-called plasma polymerisation. This is predominantly carried, out in a so-called cold plaema at gas temperatures in the range from 20 to 80°C. The plasma is produced, inter alia, by means of d.c. current or high frequency a.c. current or by microwaves under pressures of 10-2 to 1 kPa of the gaseous react ants which produce the surface layer. Since the films applied in this! way have a layer thickness of In the case of deformable hollow objects made of electrically conductive material or having an elsctroconductive surface, such as e.g. metal sterits, it is necessary, for example, for the layer thickness to be On the other hand, it is known from WO 89/11919 that the fullest possible coating of hollow metal objects presents considerable problems since a Faraday's cage is produced inside the metal objects under the plasma conditions described above, with the result: that, only extremely minimal coating, if at all, can be achieved on the internal surfaces. The solution proposed in this published application is, however, unsatisfactory and restricted to hollow bodies which have a pierced wall or perforated walls. The aim of the present invention is thus primarily to overcome the disadvantages of the processes known from the art and to provide a process which is capable of binding molecules - particularly biomolecules - to surfaces which should be regarded as inert per se in terms of their chemical functionality or reactivity, without the need for chemical functionalisation (i.e. the incorporation of suitable functional groups). In addition, the invention further sets out to provide the skilled person with a process which makes it possible to cover metal objects, particularly hollow metal objects such as stents, entirely, In particular, the aim of the invention is to provide a so-called stent, i.e.. for the purposes of the present invention a medical device for eliminating or preventing vascular occlusions, which is entirely covered with a biocompatible coating. The stent is intended to ensure that it can easily be introduced into the blood vessel, e.g. by balloon dilatation, and by virtue of its mechanical properties which, as already mentioned, should remain largely unchanged after coating, will not be diaadvantageously deformed during this process. The stents known from the prior art undergo deformation in their endss, usually in a trumpet shape, when placed in the blood vessel, and this is extremely undesirable. A further object of the present invention is to permit covalent immobilisation of the molecules of the biocompatible layer. These objectives are achieved by the invention recited in the characterising clause of the claims and described in the description which follows. In. order to carry out the present invention, first of all in the first step the complete diamond-like surface is created on the object which is to be coated, by so-called plasma polymerisation. The general conditions for forming the plasma required for this purpose are known from the pr:.or art, as mentioned hereinbefore [Comprehensive Polymer Sci. 4, 357-375. 2 Encycl. Polym. Sc:i. Engeniering. 11, 248-261; Houben-Weyl E20/1, 361-368; allg.: J. Appl. Polym. Sci. 38, 741-754 (1989), I. Yasuda, Plasma Polymerization and Plasma Treatment, New York; Wiley 1984, I. Yasuda, Plasma Polymerization, Orlando, Florida; Academic Press 1986]. The. process according to the invention for producing biocompatible coatings on hcllow mouldings, with an electrically conductive or etallic surface, which have at lesst one opening for receiving1 an electrode, is characterised in that the hollow moulding is coated in a low temperature plasma which is, built up by a combination of a radiofrequerncy source which emits radiation with a frequency in the MHz range, and an ultrasound source which emits ultrasound waves in the kHz range, under reduced pressure, the gao or gas mixture which produces the plasma containing at least one gaseouei compound which contains carbon and optionally a carrier gas. The diamond-like coating may be produced in the course of plnsma polymerisation using as starting monorers hydrocarbons having 1 to 6 carbon atoms and balogenated, preferably fluorinated, hydrocarbons which also preferably have 1 to 6 carbon atoms. Preferred examples include: tetrafluoroethylene, hexafluoroethane, perfluoropropylene, methane and ethane, of which methane is moat particularly preferred, In addition, mixtures- of the above monomers with a. carrier gas may also be used, in particular. Noble gases are preferred as the carrier gases, whilst argon is particularly preferred. when using gas mixtures consisting of one or more gases containing carbon with one or more carrier gases, the ratio by volume between the two components is adjusted according to the invention so that the gas mixtures contains the carbon-containing gas or gases and the carrier- gas or gaases in a ratio by volume ranging from 95:1 to 1;:99, preferably in a ratio by volume ranging from 20:80 to 3:97 and moat preferably in a ratio by volume of 5:95. The reaction conditions under which plasma polymerisation tskes place in a low temperature plasma are generally known from the prior art and are not critical. However, a plasma with a high energy density is generally preferred which is usually given by the dimensions joules/kg of 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 arid those in the range from 1 to 10 GJ/kg are particularly preferred. When methane is used as the scle monomer, the energy density should be in the range from 6 to 10, preferably 7 to 9 and moat preferably 8 GJ/kg. When halogenated or fluorinated hydrocarbons are used, the energy density may also be less than 1 GJ/kg, if necessary. When carrying out the process according to the invention, the plasma polymerisation is effected at a gas pressure in the range from 0.02 to l Torr, preferably in the range from 0.02 to 0.1 Torr and most preferably at 0.04 Torr. The radiofrequency source emits radiation in the range from 10 to 15 MHz, preferably radiation in the range from photochemical reaction used consists of generating a carbene which is capable of insserting bonds in C-C, C-H, N-H, S-H, C-0, C==O, C-C, etc. or of adding to them. The polyatnine derivatised with a. photoactive molecule is adsorbed onto the surface in. a first step vie. ionic, hydrophobia or hydrocarbon bridging bonds. The surface is coated with a photoactivatable layer. . Subsequently, the molecule in question is bound to the photoactivatable polyamine layer via ionic, hydrophobia or hydrocarbon bridging bonds. The next step comprises irradiation and hence the generation of reactive carbenes in the polyamine. The carbenes form covalent bridges between the surface, the polyamine and the molecule which is adsorptively bound to the polyamine. It is particularly advantageous if the adsorptively bound molecule carries a fully oppositional charge relative to the polyamine. If this is the case, it is possible to work with very low concentrations of the moleicule to be bound to the PEI layer (polycation) since there is; a powerful ionic concentration effect of the molecule on the pclyamine layer [(also the use of photoactivatable pclyanions) (use of nitrenes, quinones, The present invention relates to a process for preparing biocompatible coatings on hollow mouldings, with an electrically conductive or metallic surface, which have at least one opening for receiving an electrode, characterized in that the hollow moulding is coated in a low temperature plasma which is produced by a combination of a radiofrequency source to is MHz which emits in the MHz range and an ultrasound source which emits in the kHz range from 5 to 100KHZ nder reduced pressure, the plasma generating gas or gas mixture containing at least one carbon-containing gaseous compound of the kind such as herein described and optionally a carrier gas, wherein the low temperature plasma coating is carried out under a gas pressure in the range from 0.01 to 1 Torr. The present invention is illustrated by the Examples which follow. Various other embodiments of the invention and process will become apparent to the skilled person from the description provided. However, it is expressly pointed out that: these Examples and the description associated with them are provided solely as an illustration and must not be regarded as constituting a restriction to the invention. 13 to 14 MHz and most preferably radiation of 13.46 MHz, whilst the ultrasound source emits radiation in the range from 5 to 100 kHz, preferably in the range from 5 to 50 kHz and more preferably radiation in the range from 5 to 25 kHz; most preferably, the. ultrasound source emits ultrasound waves with a frequency of 20 kHz. The present invention also relates to a procedural step in which biomolecules or other molecules can be covalently bound to surfaces; which are, of themselves, chemically inert, without having" to carry out chemical modification of the surface or of the molecule which is to be bound. The term biomoleculee for the purposes of the present invention denotes synthetic or naturally occurring compounds or natural substances which are capable of ensuring cr increasing the biocompatibility of a shaped object in the human or animal body. Examples which may be mentioned include: natural or synthetic sugars, glycosaminoglycans, Eiuch as heparin, endostatin or angiostat in. Other suitable biomolecules are well known to the skilled person from the prior art. After the diamond-like layer has been applied, according to the invention the step of covalently binding the selected molecule takes place: By introducing a photoactive "spacer layer" of PE", first of all, on the one hand, the PEI layer is covalently bound tc the surface and also the molecule is covalently bound tc the PEI layer. There is no need for chemically reactive groups to be present either on the surface or in the molecule to be bound, in order to achieve covalent binding via the photoactivated !?EI molecule. The Process for diamond-like coating of stents in low temperature plasma using ultrasound Example 1 The pla.£ima reactor used for the coating is a bell jar chamber with parallel plate electrodes. The bottom electrode is connected to a 13.46 MHz radiofrequency generator and 20 kHz ultrasound generator. The top electrode is earthed. The reactor is equipped with a preliminary vacuum pump and a turbomolecular pump. The reactor is also equipped with a fine valve as the gas inlet, an absolute pressure gauge and a quartz thickness monitor (QTM) which is mounted on the top electrode. 21 Stents are placed vertically on the bottom electrode. A Pt/Ir wire (auxilia.ry electrode) firmly connected to the bottom electrode provides an electrical contact between the stent and the bottom electrode. The reactor is evacuated down to a residual pressure of less than 0,001 Torr and pure argon is introduced into the reactor up to a pressure of 0.04 Torr. Then a pl'aama is produced by means of the radiofrequency generator and the stents are pretreatecl therein for 25 minutes. The reactor is then supplied with a mixture of argon/methane in the ratio 95/5 whilst being continuously pumped out. The pressure is maintained at 0.04 Torr. Subsequently, using the radiofrequency and ultrasound generators, a plasma is generated by means of which the stents are coated. The coating operation is continued until the QTM indicaties a layer thickness of 18 nm, reflecting a coating on the stents with a thickness of 50 nm. The same coating is provided as in Example 1 until the QTM indicates a layer thickness of 65 nm, correspending to an average thickness of coating on the stents of 200 nm. The same conditions are adopted, as in Example 1. The plasma gas pressure is adjusted here to 0.1 Torr. The average coating thickness on the stents is neasured at 75 nm. Example 4 The same conditions are used as in Example l. The argon/methane ratio is adjusted to 90/10. Example-5_. This same conditions are used as in Example 1, except that instead of an argon/methane ratio of 95/5 a ratio of 83/17 is adopted. The preferred thickness of coating on the scents is between 10 nm and 80 nm. Below this limit under certain circumstances uncoated zonea will be observed, on the steint. Above this limit, cracks, and other defects can be observed in the coating of the stent (Figures: l and 2) . Fig. 1 shows a shaped object or moulding with a homogeneous diamond-like coating applied using the process according Co tne invention and. having a coating thickness of about SO nm, after one forming process. The diagram shows a stent after being dilated in water at: 37°C. The Figure clearly shows that even after deformation the coating has not become fragile and has no cracks. Fig. 2, on the other hand, shows a corresponding moulding with a coating thickness of about 200 nm. The Figure clearly shows the undesirable cracking after dilation in water at 37°C. Fig, 3 graphically shows the release of metal ions from coated and uncoated stents over a period of 48 hours in 1 N HC1. It is clear that as the time (t) progresses, metal ions are released from an uncoated stent (curve A), whereas with a stent coated according to the invention there is no detectable relesi.se of metal ions (curve B) . Example of the covalent binding of heparin to a chemically inert surface ExEimr Polyethyleneimine (PEI) is chemically linked to the photoactive molecule TRIMID [3-trifluoromethyl-3-(m-isothiocyano-phenyl) diazirin] sso as to form a photochemically active PEI-TRIMID molecule. A PEI molecule carries a plurality of covalently bound TRIMID molecules. The coating of an inert surface with heparin is carried out as follows: A stent with a diamond-like coating (coating consists of an inert material related to diamond in its structure) is incubated for 30 minutes at ambient temperature in a sclution of 60 µg/ml of PEI-TRIMID in PBS [phosphate buffered saline: 5 mMol NaH2PO4 + 100 mMol Nad, pH 7.4]. It is then washed 3 :x with PBS. The stent, now coated with a layer of PEI-TRIMID, is placed in a solution of 50 µg/ml of heparin in PBS for 30 minutes a™ ambient temperature. Then the stent is washed twice with PBS and once with water and dried under high vacuum e.t ambient temperature. The stent now has a lower layer of PEI-TRIMID onto which a layer oil heparin is ionically bound. In order to bind the layers eovalently to the; diamond-like surface the stent is dried and then illuminated in. UV for 15 minutes at a wavelength of 360 nm. Under illumination, a carbene is formed from the TRIMID covalently bound to the PEI, and this carbene on the one hand covalently inserts into the diamond-like layer and thereby covalently binds the PEI via the TRIMID molecule. On the other hand, the TRIMID also inserts carbene into the heparin molecule and forms a chemical bond between the heparin and PEI. The heparin molecule is thus covalently bound to the diamond-like surface via the TRIMID modified PEI-linker molecule. Evidence of the binding of hepairin via TRIMID-PBI to a surface with a diamond-like coating Example 5 The structure of the layers of polyethyleneinine-TRIMID and heparun can be observed using a biosensor. The sensor plate is coated with the same diamond-like surface as was provided on the stem. The biosensor used in made by Messrs. ASI of Switzerland. The detection principle is based on changes in the refractive index on transparent surfaces when molecules are bound to these surfaces. Fig. 4 is a sensogram showing the formation of the first layer from polyethyleneimine-TRIMID (B) and the subsequent formation of the heparin layer (D) onto the first layer. Equal concentrations of polyethyleneimine-TRIMID and heparin were pumped over the sensor plate with its cliamond-like coating, as was also done when coating the stent. The individual sections contain: 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 into buffer PBS, pH 7 . 4 E: flow of buffer over the sensor, PBS pH 7.4 Activity test of the heparin-modified surface Fig, 5 shows the heparin activity of covalently immobilised heparin on stents which have first been provided, using the process of the invention, with a diamond-like coating ';o which heparin has been covalently bound according to the invention. Fig, 5 shows, in the diagram., the activity of uncoated, HSA (Human Serum Albumin)-coated and heparin-coated stents. The stents ware coatee, using the method described above. The uncoated stent was not coated. The HSA stent was coated with PEI-TRIMID and subsequently with HSA. Stints 1, 2, 3 and 4 were coated using the method described above. The heparin activity was measured by a standard procedure of Messrs. Haemachrom by the Coacut heparin test. The interaction of aritithrombin III with thrombir. was determined in the presence of heparin. Non-activated thrombin cleaves a chromogeriic substrate which releases a chromophore whose absorption can. be measured. The degree of absorption of the chromophore: is in inverse proportion to the heparin activity. Measurement of the stent closure times (TSO) of uncoated stents, stents with a diamond-like coating and atnnts with a diamond-like and heparin coating The in vitro model for measuring the stent closure times consists of a polyvinylchloride tube with a total length of 82 cm. The segment of tube which will later accommodate the dilated atent has an internal diameter of 4 mm. The remainder of the tube has a diameter of 3 mm. The stent is introduced into the tube by means of a be.1 loon catheter and is dilated to a diameter of 3 mm. Then 6 ml of thrombocyte-rich plasma are introduced into the tube system. The medium ia then adjusted to the physiological concentration of Ca2* using a 10 mmolar CaCl2 solution and the plasma is circulated by pumping ;at a rate of: 8 ml/min. at a flow speed of 2 cm/s. The temperature is) maintained at 37oC. A control system is operated under the same conditions and at the same time but without a stent. The time - stent closure time (TSO) - after which no more plasma can be pumped through the stent is measured. Fug. 6 gives the TSO times of uncoated sterits (TSO steel), of diamond-like coated gtents (TSO-diamond) and of stents with a diamond-like and heparin coating (TSO-diamond + heparin) . In the box plot the Y axis shows; the average stent closure time, It is clear that the stents with a diamond-like or diamond-like 4 heparin coating have substantially longer closure times than the corresponding uncoated stents. The foregoing description and Examples show that the process proposed according to the invention is suitable for preparing a multiplicity of different shaped objects with a biocompatible surface; however, the process according to the invention is preferably suitable for producing medical equipment, implants and surgical supplies and most preferably for coating stents. The stents according to the invention preferably have the structure shown in Figs, 7 s.nd 8. Figs. 7 and 8 show a sectional representation of the stents according to the invention, which will be explained hereinafter: The construction of the gterit, as the solution to the objective described hereinbefore, is as follows, according to the invention: 1. the stent consists; of loops (A and B) alone or a combination of loops and joints (C). The loop elements (A, B) ,. as; well as the joint elements (C) , may be connected via webs as well as being directly connected to their nearest neighbour. 2. The individual stent segments {loops A and B) are of different lengths. The smaller loop segments (A) are located at: the outer ends of the stent. If the stent has joint elements (C), the smaller loops (A) are connected to these elements (C), if not all the loops are interconnected by joints. If all the loops are connected by joints the loops at this point are type B. The purpose of the construction is that the stent will only expand under elevated pressure at the ends where the smaller loop segments are located. As a result, all the loop segments will expand more evenly and there will be no trumpet-shaped or tulip-shaped expansion at the free ends of the stent . To prevent the tulip effect still further, the individual stesnt loops may be of different thicknesses. The following principle applies: those loops which are located at both ends of the stent or hollow moulding have a graater material thickness than those loops which are arranged more towards the centre of the stent: or actually in its centre. The thickness of the material of the loops may vary in width or thickness. This ensures! that the balloon which is used to dilate the stent encounters less counterpressure from the stent in the middle or in its centre ths.n at the outer ends of the stent. According to the invention, this also prevents uneven expansion (trumpet or tulip effect). The width of the loop can be changed, for example, by simply changing the cut; a change in the thickness of the loop may be obtained for example by asymmetric electric grinding. WE CLAIM; 1. Process for preparing biocompatible coatings for bonding of biomolecules on hollow mouldings, with an electrically conductive or metallic surface, which have at least one opening for receiving an electrode, characterized in that the hollow moulding is coated in a low temperature plasma which is produced by a combination of a radiofrequency source which emits in the MHz range from 10 to 15 MHz and an ultrasound source which emits in the kHz range from 5 to 100 kHz under reduced pressure, the plasma generating gas or gas mixture containing at least one carbon-containing gaseous compound of the kind such as herein described and optionally a carrier gas, wherein the low temperature plasma coating is carried out under a gas pressure in the range from 0.01 to 1 Torr. 2. Process as claimed in claim 1, wherein the carbon-containing gaseous compound is a hydrocarbon or halohydrocarbon. 3. Process as claimed in claim 2, wherein the carbon-containing gaseous compound is a hydrocarbon or fluorohydrocarbon having 1 to 6 carbon atoms. 4. Process as claimed in claim 3, wherein the hydrocarbon is methane. 5. Process as claimed in one of claims 1 to 4, wherein the carrier gas is a noble gas. 6. Process as claimed in claim 5, wherein in the carrier gas is argon. 7. Process as claimed in one of claims 1 to 6, wherein the gas mixture contains the carbon-containing gas or gases and the carrier gas or gases in a ratio by volume ranging from 99:1 to 1: 99. 8. Process as claimed in claim 7, wherein in that the gas mixture containing the carbon-containing gas or gases and the carrier gas or gases in a ratio by volume ranging from 20:80 to 3:97. 9. Process as claimed in claim 8, wherein the gas mixture contains the carbon-containing gas or gases and the carrier gas or gases in a ratio by volume of 5:95. 10. Process as claimed in one of claim 1, wherein the low temperature plasma coating is carried out under a gas pressure in the range of from 0.02 to 0.1 Torr. 11. Process as claimed in claim 10, wherein the low temperature plasma coating is carried out under a gas pressure of 0.04 Torr. 12. Process as claimed in claim 1, wherein the radiofrequency source emits radiation in the frequency range from 13 to 14 MHz. 13. Process as claimed in claim 12, wherein the radiofrequency source emits radiation with a frequency of 13.46 MHz. 14. Process as claimed in claim 1, wherein the ultrasound source; emits ultrasound waves in a frequency range from 5 to 50 kHz. 15. Process as claimed in claim 14, wherein the ultrasound source emits ultrasound waves in a frequency range from 5 to 25 kHz. 16. Process as claimed in claim 15, wherein the ultrasound source emits ultrasound waves at a frequency of 20 kHz. 17. Process as claimed in claim 1, wherein the said biomolecule is covalently bound by means of a photochemically activated molecule to a moulding with a chemically inert surface. 18. Process as claimed in claim 17, wherein the biomolecule is bound to the diamond-like coating via a linker molecule modified with 3- trifluoromethyl-3-(m- isothiocyanophenyl) diazirine. 19. Process as claimed in one of claims 17 or 18, wherein the polyethyleneimine is used as the linker molecule. 20. Process as claimed in one of claims 17 to 19, wherein a natural or synthetic sugar is used as the biomolecule. 21. Process as claimed in one of claims 17 to 20, wherein a glycosaminoglycan is used as the biomolecule. 22. Process as claimed in claim 21, wherein herapin is used as the glycosaminoglycan. 23. Process as claimed in any one of the preceding claims, wherein endostatin or angiostatin is used as the biomolecule. 24. Process for preparing biocompatible coatings on hollow mouldings substantially as herein described with reference to the foregoing description.

Documents:

1657-del-1998-abstract.pdf

1657-del-1998-claims.pdf

1657-del-1998-correspondence-others.pdf

1657-del-1998-correspondence-po.pdf

1657-del-1998-description (complete).pdf

1657-del-1998-drawings.pdf

1657-del-1998-form-1.pdf

1657-del-1998-form-13.pdf

1657-del-1998-form-19.pdf

1657-del-1998-form-2.pdf

1657-del-1998-form-4.pdf

1657-del-1998-form-6.pdf

1657-del-1998-gpa.pdf