CA2241483A1

CA2241483A1 - Bioactive coating of surfaces by using cross-linking agents

Info

Publication number: CA2241483A1
Application number: CA002241483A
Authority: CA
Inventors: Roland Kunz; Christine Anders; Peter Ottersbach
Original assignee: Huels AG
Current assignee: Huels AG
Priority date: 1997-06-28
Filing date: 1998-06-26
Publication date: 1998-12-28
Also published as: NO983012D0; JPH1180394A; EP0893164A2; NO983012L

Abstract

Disclosed is a process for coating a polymer substrate, by grafting:
(i) a mixture of (A) a monomer of the general formula Formula I R-(A)a (wherein R stands for an aliphatic unsaturated radical with the valency a; (A) stands for an acid group or a salt thereof; a stands for 1, 2, or 3), and (B) a cross-linking vinyl monomer (B monomer) that contains at least two olefin double bonds or (ii) a mixture of the cross-linking vinyl monomer B and a polymer derived from the (A) monomer (polymer C), onto the polymer substrate, wherein the polymer substrate has been activated prior to the grafting process or an initiator is used and the grafting is initiated by electromagnetic irradiation or thermally. Articles that have been coated according to the present invention are suitable for use in the fields of food and beverage technology, water technology, biotechnology, health and hygiene , and in particular medical technology.

Description

BIOACTIVE COATING OF SURFACES BY USING CROSS-LINKING AGENTS
I. Field of The Invention The present invention relates to a process for bioactively coating a surface of a polymer substrate by grafting with a specific monomer or with a polymer derived therefrom. The most important properties of the coating applied according to the present invention are their bacterio-repellant properties as well as their good compatibility when in contact with body fluids and tissues. Depending on the functionality of the coating monomer or the molar relationship of specific functional groups in the coating, the surface can be made either inhibiting or promoting cellular proliferation.
The present invention also relates to an article having a surface that has been coated in this manner, for use in the fields of food and beverage technology, water technology, biotechnology, health and hygiene and, in particular, in medical technology.
II. Summary of The Invention.
Surprisingly, it has been found that a polymer substrate can be provided with a coating that is powerfully bacterio-repellant and is very adhesive by grafting, initiated by electromagnetic radiation or thermally: (i) a mixture of at least one vinyl monomer (A) of the general formula:
R- (A)a (I) wherein:
R stands for a mono- or di-aliphatically unsaturated organic radical of valency a;
A stands for a carboxyl group -COOH, a sulphuric acid O.Z. 5299 group -OSO2OH, a sulfonic acid group -SO3H, a phosphoric acid group -OPO(OH)2, a phosphonic acid group -PO(OH)2, a phosphorous acid group -OP(OH)2, a phenolic hydroxyl group or a salt of one of the above groups, and a stands for 1, 2, or 3;
providing that if the monomer of formula I has a carboxyl group -COOH or a carboxylate group, this monomer either contains at least one additional radical A with one of values cited for A, other than a carboxyl or carboxylate group, or at least one additional monomer of formula I, in which A has one of the values cited for A, other than a carboxyl or carboxylate group and at least one cross-linking vinyl monomer (B) that contains at least two olefinic double bonds, or (ii) a mixture of a polymer (C) that is produced from at least one monomer (A) and at least one monomer (B), onto the polymer substrate, wherein the polymer substrate is activated prior to the grafting process, or an initiator is used.
Thus, it is possible, either to graft a previously prepared polymer (C) which is not cross linked, together with a cross linking agent (B) or else proceed from the monomer (A) and thereby combine the polymerization and the grafting process. The latter is preferred from the standpoint of process technology.
Of the salts of the groups cited for the monomer (A) in formula (I), physiologically acceptable salts such as alkali salts and in particular sodium salts are preferred.
The common feature of the monomers of formula (I) O.Z. 5299 monomers (A) is that they have 1 or 2 olefin double bonds, and at least one acid group or a salt of an acid group.
The surfaces that have been coated according to the present invention display a noteworthy combination of advantageous attributes and, for this reason, outstanding physiological compatibility. In particular, they display enhanced hemocompatibility and reduce the adhesion and proliferation of bacteria to a greater degree and for longer periods of time, than is the case with coatings known before.
This applies to Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli bacteria, and others. At the same time, in most instances, cellular proliferation, for example of umbilical cord cells, is also inhibited. The particular conditions under which a coating can be bacterio-repellant and at the same time promote cellular proliferation are discussed below. The surfaces of the substrates coated according to the present invention are, optionally after extraction, free of monomer and oligomer fractions that can migrate or be extracted. No undesirable effects caused by the release of foreign substances or by destroyed bacteria were observed.
1. A monomers In the case of the graft (co)polymerisation of monomers, as the A monomer preferred is a mixture of a monomer having a carboxyl group or salt thereof and a monomer having a sulfonic acid group or a salt thereof. Such monomers may have the general formulas:
(CnH2n_q_x)(COOR )x (II) O.Z. 5299 (CnH2n-q-x) (So3Rl)x (III) In the formulas, which are included in the general formula I, n stands, in each case independently, for an integer number from 2 to 6 inclusive;
x stands, in each case independently, for 1 or 2;
stands, in each case independently, for 0 or 2; and the radical R1 stands, in each case independently, for -H
or an equivalent of a metal ion, such as an alkali metal ion.
In keeping with the definitions provided above, the radical (CnH2n_q_x) stands, in each case independently, for a straight-chain or branched monovalent alkenyl radical (q=o, x=1) or an alkadienyl radical (q=2, x=1) or a bivalent alkenylene radical (q=0, x=2), or alkadienylene radical (q=2, x=2).
In place of two A monomers with the formulas II and III, it is also possible to use only one monomer (II+III) that contains both the groups -COOR1 and -SO3R1 within the same molecule.
It is also possible to use A monomers that are derived from benzene of the general formula:

(C6H6_b_C_d)BbR3c(OH)d i.e. ~ R3c (I~

(~E~d (wherein B stands, in each case independently, for a mono- or di-O.Z. 5299 unsaturated straight chain or branched radical of the formula (CnH2n_1_q_y)(COOR1)y or (CnH2n_1_q_y)(-SO3R1)y/ where R1, n and ~ are defined as above, and y stands for 0, 1, or 2);
R3 stands in each case independently for C1_4-alkyl, -NH2, -COOH, -SO3H, -OSO3H, -OPO(OH)2, -PO(OH)2, OP(OH)2, -OPO(O-)OCH2 -CH2-N+(CH3)3, -PO(O )O-CH2-CH2-N+(CH3)3, -OP(O )OCH2-CH2 -N+ (CH3)3, or a salt, in particular an alkali salt, or an ester of the cited groups:
b stands for 1, 2, or 3;
c stands for 0, 1, 2, or 3, and _ stands for 0, 1, 2, or 3:
providing that b + c + _ is not more than 6, preferably not more than 4.
Naturally, apart from the above combination of A
monomers of the formulas II and III, any mixtures of A
monomers of the general formulas I, II, III, and IV can be use for the process according to the present invention.
Other suitable A monomers are compounds according to formula I with sulphuric acid groups or salts of these groups (sulfate groups); sulfonic acid groups or the salts thereof;
phosphonic acid groups, acidic phosphonic acid ester groups or salts of phosphonic acid groups or acidic phosphonic acid ester groups; phosphoric acid groups, acidic phosphoric acid ester groups, or salts of phosphoric acid groups or acidic phosphoric acid ester groups, phosphorous acid groups, acidic phosphorous acid ester groups, or salts of phosphorous acid groups, or acidic phosphorous acid ester groups. These monomers, too, can be used for the process according to the present invention, either mixed together and/or with other A

O.Z. 5299 monomers of the general formulae I, II, III, and IV.
In addition, reference should also be made to monovalent to trivalent (or base) phenols and the salts thereof, which correspond to formula I, as suitable monomers.
These, too, can if necessary be used mixed together and/or with the above cited A monomers.
A combination of monomers I to IV has been found useful for the process according to the present invention;
such a combination results in coatings that have, on the one hand, carboxylic and/or carboxylic groups and, on the other hand, sulfonic acid and/or sulfonate groups. From the standpoint of compatibility or consistency, there are three possible binary combinations of the above groups, namely, carboxyl and sulfonic acid groups, carboxyl and sulfonate groups, and carboxylate and sulfonate groups and, in addition, two tertiary combinations, namely carboxyl, carboxylate, and sulfonate groups, as well as carboxyl, sulfo-acid, and sulfonate groups. All of these combinations describe useful forms of embodiments of the process according to the present invention. Naturally, it is also possible to use monomers whose functional groups can be modified after graft polymerisation. Thus, one can subsequently convert the acrylamide building block to the acrylic acid building block by hydrolysis in an acid medium. In addition, one can transform carboxyl and sulfonic acid groups by neutralisation (e.g., in phosphonic buffers), and carbon ester and sulfo-acid ester groups into carboxylate or sulfonate groups by hydrolysis. In the combination named above, the molar ratio of carboxyl and/or carboxylate groups to sulfonic acid and/or O.Z. 5299 sulfonate groups can vary within very wide limits within the coating. Particularly pronounced cellular proliferation inhibiting properties are achieved if the named ratio amounts to 0.2 to 3, especially 0.4 to 3, and in particular 0.4 to 2.
To a notable extent, the coated surfaces display bacterio-repellent properties as well as cellular proliferation enhancing properties if the stated molar ratio amounts to 2 to 10, especially 3 to 10, and in particular 3 to 5. A coating is similarly proliferation-enhancing in the sense of the present invention if the adhesion and proliferation of mammal cells is enhanced by the coating as compared to uncoated surfaces or is, in any case, affected less than the adhesion and the proliferation of bacteria.
The following can be cited as examples of suitable A
monomers: acrylic acid, methacrylic acid, 4-vinylsalicylic acid, itaconic acid, vinylacetic acid, phenylacrylic acid, 4-vinylbenzoic acid, 2-vinylbenzoic acid, sorbic acid, caffeic acid, maleic acid, methylmaleic acid, crotonic acid, isocrotonic acid, fumaric acid, dimethylfumaric acid, methylfumaric acid, dihydroxymaleic acid, allylacetic acid, and the sodium salts of these acids: sodium vinylsulfonate, sodium allylsulfate, sodium allylsulfonate, sodium methallylsulfate, sodium methallyl sulfonate, sodium styrene sulfonate, sodium vinyltoluene sulfonate; and their acids;
butene-(2)-diol-(1,4)-diphosphoric acid, butene-(2)-diol-(1,4)-diphosphonic acid, as well as the disodium salts of the two phosphoric or phosphonic acids, monoallylphosphite;
2-vinylphenol, 2-allylhydroquinone, 4-vinylresorcinol, m-hydroxystyrene, o-hydroxystyrene, p-hydroxy-styrene, O.Z. 5299 carboxylvinylbenzene sulfonic acid.
In a further embodiment of the process according to the present invention, it is possible to use a mixture of monomers of the general formulas V and VI:

CR1= CHRl CR1= CHRS

(H-l-R3- R4)n COOR6 H-C-R3- R4 (V) ~d ( H

In these formulas:
R1 is hydrogen or methyl;
R2 is a bivalent organic radical, preferably an aliphatic, cycloaliphatic, or aromatic hydrocarbon radical with up to 10 carbon atoms, or a single bond;
R3 is -O- or -NH-R4 is hydrogen or -S03-Na+;

R5 is hydrogen, methyl, or -R2-COOR6;
R6 is hydrogen or Na, and n is 4 or 5, providing that at least one of the R4 substituents is -S03-Na+.

In preferred A monomers of Formulas V and VI, R stands for hydrogeni R2 stands for an alkylene radical with 1 to 4 carbon atoms, a phenylene radical, or a single bond;
R3 stands for -O- or -NH-;

O.Z. 5299 R4 stands for hydrogen or -SO3-Na+;
R5 stands for hydrogen or -R2-COO-Na+;
R6 stands for hydrogen or Na, and n stands for 4.
The A monomers of formula V contain modified sugar radicals that are preferably derived from pentoses and in particular from arabinoses. The sugar radicals contain at least one of the -O-SO3-Na+ ("O-sulfate") or NH-SO3~Na+ ("N-sulfate") radicals, preferably next to the R2 radical. It is preferred that they have 1 - 4 of these radicals. O-sulfate and N-sulfate radicals can exist simultaneously in a sugar radical and it is preferred that the N-sulfate radical is adjacent to the R2 radical. Alternatively, the sugar radical may also contain one type of this radical exclusively, e.g., only O-sulfate radicals. Each of the species referred to (only radicals that contain only O-sulfate as well as radicals that contain N-sulfate) is suitable, in and of itself or together with the other species, as A monomer of Formula V.
Thus, the mixture ratio amounts to 0:100 to 100:0.
The monomers of formula VI are known. The monomers of formula V may for example be prepared as described herein under.
The preparation of monomers V is described by means of a special case starting from D-glucono-1,5-lactone 1 and resulting in a monomer V which is derived from a pentose, namely D-arabinose. However, a person skilled will be able to apply the process without difficulty to other suitable precursors.

O.Z. 5299 In a first stage, the hydroxyl groups of the lactone 1 are protected by acetalization, for example with acetone, and, at the same time, the (cyclic) lactone is transesterified with methanol to give the (open-chain) methyl ester. An isomer mixture consisting of methyl 3,4j5,6-di-0-isopropylidene-D-gluconate 2 and methyl 2,3j5,6-di-0-isopropylidene-D-gluconate 3 is obtained. This mixture is reduced in a second stage, for example with lithium aluminum hydride, whereby the carboxylic ester functionality becomes a carbinol functionality. Once again, a mixture of isomers is obtained, namely 3,4;5,6-di-0-isopropylidene-D-sorbitol 4 and 2,3;5,6-di-0-isopropylidene-D-sorbitol 5. In a third stage, this mixture of isomers is oxidized with an oxidizing agent such as sodium periodate (NaIO4) with cleavage of the carbon chain to give a single product, the arabinose aldehyde 2,3;4,5-di-0-isopropylidenealdehydo-D-arabinose 6. In the subsequent fourth stage, a vinyl functionality is introduced, for example by a Grignard reaction with 4-vinylphenylmagnesium chloride. A partly protected 4-vinylphenylpentanepentaol, 2,3;4,5-di-0-isopropylidene-1-(4-vinylphenyl)-D-gluco(D-manno)-pentitol 7 is obtained and is referred to as "arasty"
for brevity hereinafter.
This sequence of stages 1 to 4 is illustrated by the following reaction scheme.

O.Z. 5299 CH2OH COOCH3 ~ COOCH3 ~ CH30H, H ~ LA~

HO '~ ~ - OH
_o~ --~~/
_o~ \ --~~\

- OH ~ - OH
- OH - o / CHO
+ ~ 4-c~o- CHOH
0 ~ 0 NaIO4 ~ ~ ~ene , O

- oX - OX - oX OX

The sequence of reactions in stages 1 to 3 (that is to say up to compound 6) has been described by H. Regeling et al., Recl. Trav. Chim. Pays-Bas 1987, (106) 461 and D.Y.
Jackson, Synth. Commun. 1988 (18) 337. Stage 4 (to compound 7) was published for the first time by G. Wulff et al., Macromol Chem. Phys. 1996 (197) 1285.
To prepare a compound corresponding to arasty 7 with an amino group in position 1 it is possible, in a first stage, to oxidize arasty to the corresponding ketone, 2,3j4,5-di-O-isopropylidene-D-arabino 4-vinylphenyl ketone 8. This is converted by reduction in a second stage to 1-amino-1-deoxy-2,3;4,5-di-O-isopropylidene-1-(4-vinylphenyl)-D-gluco(D-manno)-pentitol 9. This sequence of reactions is illustrated by the following formula diagram:

O.Z. 5299 CHOH C=O CHNH2 O I < DMSO/(COcl)2 O

_OX --oX --oX

In the first stage, arasty 7 can be oxidized for example with oxalyl chloride and dimethyl sulfoxide at a temperature <-50~C in an inert solvent. The reductive amination in the second stage is preferably achieved with sodium cyanoborohydride as a reducing agent in the presence of ammonium acetate in a solvent except for water at room temperature.
Compound 7 and 9 are then deprotected (deacetalized) in a first stage and O- and/or N-sulfated in a second stage so that the polymer prepared from them is as far as possible analogous to heparin. The deprotection takes place in acidic medium in which ketals are unstable. The protected compounds are heated, for example, with dilute mineral acid or an acidic ion exchanger to obtain from 7,1-(4-vinylphenyl)-D-gluco(D-manno)-pentitol 10 and from 9,1-amino-1-deoxy-1-(4-vinylphenyl)-D-gluco(D-manno)-pentitol 11. The deprotection and the subsequent sulfation are depicted in the following formula diagram:

O.Z. 5299 CHOH CHOH sufa~on CHOR
O HO- RO --OH -OR
-OH -OR
X OH -OR
--O

R=HorSO3-Na+

0 ~ CHNH2 sufa~on CHNHR
HO- RO--OH -OR
_O X OH -OR
-OH -OR

R=HorSO3-Na+

The two compounds 10 and 11 are sulfated, preferably using a sulfur trioxide/pyridine complex. Because of the preceding deacetalization, the sulfation does not result in a single product with one or more sulfate groups in defined positions. However, the primary hydroxyl groups and the amino groups are preferentially sulfated. The degree of sulfation can be controlled by choice of a suitable molar ratio of sulfur trioxide to hydroxyl and amino groups. It is desired that for more than one sulfate group is introduced on average per molecule, because heparin contains about 2.7 sulfate O.Z. 5299 groups per disaccharide unit.
Sulfation of the deprotected amine compound 11 results in both O-sulfate and N-sulfate groups in the molecule, which is desired in the light of the intended analogy to heparin.
The sulfation is preferably carried out at room temperature in order to avoid premature polymerization. It is nevertheless possible, by a relatively long reaction time, or example up to 100 hours, for the reaction to be continued until all the OH and NH2 groups have reacted completely. It is possible to use as solvent for example excess pyridine or an ether such as tetrahydrofuran. Since the sulfate groups in the reaction products are unstable to acid, it is advisable to add a dehydrating agent, for example molecular sieves, to the precursor solution before adding the sulfur trioxide/pyridine complex. For the same reason it is advisable, after completion of the reaction, to hydrolyze the reaction mixture first by adding water and shortly thereafter a base (which keeps the pH in the alkaline range). An example of a suitable base is a saturated barium hydroxide solution, which also precipitates sulfate ions. Excess barium ions can be precipitated, for example, by passing in carbon dioxide, where appropriate after cautious concentration to remove solvent.
The barium carbonate is filtered off and the filtrate is passed through an ion exchange column in the Na+ form, or treated with the ion exchanger in another way, in order to replace the barium ions by sodium ions. The products, O-sulfated 1-(4-vinylphenyl)-D-gluco(D-manno)-pentitol 12 and N-and O-sulfated 1-amino-1-deoxy-(4-vinylphenyl)-D-gluco(D-O.Z. 5299 manno)-pentitol 13 can be isolated, in each case in the form of the sodium salt, as solid powders by freeze drying the solution which has been concentrated further.
2. Cross l; nk; ng (B) vinyl mo~om~rs Cross linking vinyl monomers (B monomers) have at least 2, preferably 3 to 6 olefin double bonds and generally speaking contain no groups that contribute to the biological action of the coating. Their use leads to coatings that are thicker and more stable with respect to delamination, and brings about a considerable reduction of bacterial adhesion and proliferation under otherwise equal conditions. Cross linking agents with more than two, and in particular those with three to six olefin double bonds are considerably more effective than diolefin cross linking agents. It is also useful to use them if the A monomers contain more than one olefin double bond, and could thus form a network on their own. Naturally, one can also work with two or more different B monomers. In addition to their olefin double bonds, the B
monomers may contain hydrophilic groups such as hydroxyl groups and/or alkyleneoxide groups and are then simultaneously hydrophilizing and cross linking B monomers. The B monomers are preferably used in quantities ranging from 0.01 to 50 mol-~, more preferably from 0.1 to 20 mol-~, especially 1 to 20 mol-~, relative to the A monomers.
Suitable B monomers are, for example, those with two olefin double bonds such as 1, 3-butadiene, isoprene, and chloroprene; (meth)acrylic acid esters such as ethyleneglycol diacrylate, diethyleneglycol dimethacrylate, and polyethyleneglycol (e.g. 10,000) dimethacrylate; and vinyl O.Z. 5299 compounds such as 1, 4-butanediole divinylether, ethyleneglycol divinyl ether and 1, 4-divinylbenzene. Of the cross linking agents with three or more olefin double bonds there are, for example, (meth)acrylic acid esters of polyols having three to six hydroxyl groups such as trimethylolpropane triacrylate, trimethylpropane trimethacrylate and pentaerythritol tetraacrylate; polyvinyl ethers of polyols having three to six hydroxyl groups including glycerine ethylene oxide adduct trivinyl ether such as glycerine-12EO-trivinyl ether and pentaerythritol ethylene oxide adducttetravinyl ether such as pentaerythritol-64EO-tetravinyl ether; carbohydrate derivatives such as (meth)acryloylized hydroxypropyl cellulose with more than two acryloyl groups per molecule, and allyl ether compounds of polyols having three to six hydroxyl groups such as pentaerythritol tetraallyl ether.
3. D Other monomers that can be u~ed In addition to the A monomers that have been described, and which have the groups that render them hemocompatible and bacterio-repellent, which inhibit or enhance cellular proliferation, and the B cross-linking agents, it is also possible to use other olefinically unsaturated monomers (hereinafter referred to as D monomers) which are generally simple and neutral or in any case have only a small effect. These can, for example, be (meth)acrylic acid derivatives, such as esters that may also contain a hydroxyl alkoxy or tertiary amino group, e.g. ethyl acrylate, isobutyl acrylate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, 2-(2'-hydroxyethoxy)ethyl acrylate, 2-hydroxy-1-methylethyl acrylate, 2-N,N-dimethyl- aminoethyl acrylate, n-O.Z. 5299 propyl methacrylate, 2-hydroxyethyl methacrylate, 2-(2'-hydroxyethoxy)ethyl methacrylate, 2-hydroxy-1-methylethyl methacrylate, 2-N, N-dimethylaminoethyl methacrylate, diethyleneglycol mono(meth)acrylate, polyethylene glycol mono(C1-C4)alkyl ether mono(meth)acrylate, (meth)-acrylonitrile; vinyl ketones such as vinylethyl ketone;
olefins and dienes such as 1-butene and 1-hexene; vinyl aromatics such as styrene, and vinyltoluene; and vinylsiloxanes. These monomers can be present in large quantities, e.g., from 0 to 90 mol~, preferably 0 to 30 mol~, based on the total amount of the A, B and D monomers.
4. C polymers of the A and optionally of the D monomer~
Instead of grafting the A, B, and, optionally, the D
monomers as such, it is alternatively possible to polymerize the A monomers and optionally the D monomers in advance and then graft (or graft-polymerize) the polymers (C polymers) obtained in this way together with a cross-linking B monomer.
The C monomers are produced in the usual way by radical-initiated polymerization, most advantageously by solution or emulsion polymerization. Suitable solvents are all known and are for example water; ketones such as acetone, methylethylketone, and cyclonehexanon; ethers such as diethylether, tetrahydrofurane, and dioxane; alcohols, such as methanol, ethanol, n- and iso-propanol, n- and isobutanol, and cyclohexanol; strongly polar solvents such as dimethyformamide, dimethylacetamide and dimethyl sulfoxide;
hydrocarbons such as heptane, cyclohexane, benzole, and toluene; halogenated hydrocarbons such as dichlormethane and trichlormethane; esters such as ethylacetate, propylacetate O.Z. 5299 and amylacetate; as well as nitriles such as acetonitrile; or mixtures of these solvents.
Suitable polymerization initiators are, for example, azonitriles, alkylperoxides, acylperoxides, hydroperoxides, peroxyketones, peroxyesters, and percarbonates, as well as all conventional photoinitiators. Polymerization is initiated thermally, for example by warming to 60 to 100~C or after irradiation at appropriate wavelengths. After the conclusion of the exothermic polymerization reaction, the C polymer may be separated from the solvent in the usual way, for example by precipitation with ether when the polymerization is carried out in an aqueous solution. Polymers produced in emulsion can be extracted by spray-drying. Monomer or oligomer components can be removed by extraction with a suitable solvent.

5. The polymer substrates All polymer plastics such as polyurethanes, polyamides, polyesters, polyethers, polyether block amides and polyorganosiloxanes are suitable as polymer substrates. Also suitable are, for example, polystyrene, polyvinylchloride, polycarbonates, polyolefins, polysulfones, polyisoprene, polychloroprene, polytetrafluorethylene (PFTE), polyacrylates, polymethacrylates, corresponding copolymers and blends, as well as natural and synthetic rubbers with or without radiation sensitive groups. The process according to the present invention can also be used on the surfaces of metal, glass, or wooden bodies with surfaces that are lacquered or coated with plastic in some other way.

6. Grafting onto the polymer substrates 6.1 Grafting onto activated substrate surfaces O.Z. 5299 According to the present invention, the surfaces of the substrates can be activated by several methods. It is expedient that they be first treated in the known way with a solvent in order to free them of oils, greases, and other contaminants.
6.1.1. Activation of standard polymers that have no groups that are sensitive to ultraviolet radiation can best be done by ultraviolet irradiation, e.g., in the range of wavelengths from 100 to 400 nm, preferably from 125 to 310 nm.
A suitable source for this radiation is, for example, an HERAEUS ultraviolet excimer apparatus as manufactured by Noblelight, of Hanau, Germany. However, mercury vapour lamps are also suitable for substrate activation insofar as they emit a considerable proportion of their radiation in the above range. The exposure time generally amounts to 0.1 seconds to 20 minutes, preferably from 1 second to 10 minutes. It has been shown that the presence of oxygen is advantageous. The preferred oxygen vapour pressures lie between 2x10-5 and 2xlO 2. For example, one works in a vacuum of 10 4 to 10 1 bar or by using an inert gas such as helium, nitrogen, or argon, with an oxygen content of 0. 02 to 20 pro mille.
6.1.2 According to the present invention, the activation can also be effected by a high frequency or microwave plasma (Hexagon, Technics Plasma Co., 85551 Kirkheim, Germany) in an air, nitrogen, or argon atmosphere.
Generally speaking, exposure times range from 30 seconds to 30 minutes, and preferably from 2 to 10 minutes. As a rule, in * Trade-mark O.Z. 5299 the case of laboratory equipment, the energy input lies between 100 and 2000W, and preferably between 200 and 1800W.
6.1.3 Corona apparatuses (SOFTAL Co., Hamburg, Germany) can also be used for activation. In this case, exposure times range as rule from 1 second to 10 minutes, and preferably from 1 to 60 seconds.
6.1.4 Activation by electron or gamma radiation (e.g., from a cobalt-60 source) permits short exposure times that as a rule range from 0.1 to 60 seconds.
6.1.5 Flame treatment of surfaces also leads to activation. Suitable equipment, in particular equipment with a barrier flame front, can be built very simply or obtained from ARCOTEC, 712997 Monsheim, Germany. These can be operated with hydrocarbons or hydrogen as the combustion gas. In both cases, it is essential to avoid injurious overheating of the substrate; this can be done easily by close contact with a cooled metal surface on the substrate surface that is remote from the side that is being flame treated. Activation by flame treatment is accordingly limited to relatively thin and flat substrates. Exposure times generally range from 0. 1 seconds to 1 minute, and preferably from 0.5 to 2 seconds, this being done exclusively with roaring flames, the distance from the substrate to the outside flame front amounting to 0.2 to 5 centimetres, preferably 0.5 to 2 centimetres.
6.1.6 Finally, the surfaces of the polymer substrates can also be activated by treatment with strong acids or strong bases. Suitable strong acids are sulfuric acid, nitric acid, and hydrochloric acid. For example, one can treat polyamides O.Z. 5299 for 5 seconds to 1 minute with concentrated sulfuric acid at room temperature. Suitable bases are, in particular, alkali metal hydroxides in water or in an organic solvent. Thus, one can, for example, allow diluted caustic soda to act on the substrate for 1 to 60 minutes at 20 to 80~C. As an alternative, polyamides can be activated if 2~ potassium hydroxide in tetrahydrofurone is allowed to act on the surface for 1 minute to 30 minutes.
In some instances, for example, in the case of highly hydrophobic polymers, it can be useful to activate the surfaces of the polymer substrates by using a combination of two or more of the methods discussed above. Preferred methods of activation are discussed in Paragraph 6.1.1 and Paragraph 6.1.2.
Once the polymer substrates have been pre-treated using one of the methods described in Paragraph 6.1.1 to Paragraph 6.1.6, the activated surfaces can be exposed for 1 to 20 minutes, preferably 1 to 5 minutes, to the effects of oxygen, e.g., in the form of air. Then, coatings solutions are applied to the activated surfaces using known methods such as dipping, spraying, or by brush application. These solutions may be solutions of the A, B, and optionally D
monomers. Alternatively, the solution of a C polymer and a cross-linking B monomer is applied to the activated substrate.
Particularly in the case of hydrophilic monomers or polymers, water and water-ethanol mixtures have been found to be effective solvents, although other solvents can be used to the extent that they have a sufficient dissolving power with respect to the monomers or polymers, and can wet the substrate O.Z. 5299 surfaces sufficiently. Depending on the solubility of the monomers and the desired layer thickness of the finished coating, the concentrations of the monomers or the polymer in the solution can amount to 0.1 to 50 ~-wt. Solutions with monomer or polymer contents from 3 to 10~-wt, for example with approximately 5~-wt, have been found to be effective in practice.
Grafting can be effected by irradiation of the substrate that has been dipped in the coating solution. The substrate can, however, first be removed from the coating solution (or coated by other conventional methods such as spraying, squeegeeing, brushing, or spin-coating) and irradiated after evaporation of the solvent, or even during the evaporation process. Work is best carried out with rays in the short-wave segment of the visible range or in the long-wave segment of the ultraviolet range of electromagnetic radiation. Particularly suitable is the radiation of an ultraviolet excimer in the wavelength range from 250 to 500 nm, preferably from 290 to 320 nm. Here, too, mercury vapour lamps are also suitable insofar as they emit a considerable proportion of their radiation in the above-mentioned ranges.
Generally speaking, exposure times will amount to 10 seconds to 30 minutes, preferably from 2 to 15 minutes.
Alternatively, grafting can be initiated thermally.
To this end, after having been coated with the coating solution, the activated substrate is warmed, in the usual way, e.g., 5 minutes to 4 hours at a temperature that can be between 50 and 100 degrees Celsius.
In some cases, it is useful to repeat the steps O.Z. 5299 described above, including activation, in order to produce a hermetically sealed and/or even thicker coating by means of such a multi-coating technique. As an alternative, it is also possible to dip the activated polymer substrate, optionally after the oxygen treatment described heretofore, in the solution of A and B monomers, and optionally D monomer or the corresponding C polymer, and then irradiate it when it is so immersed. Tests make it easy to establish which radiation times for a given radiation source and which, optionally longer, contact times for the substrate and solution will result in the desired layer thickness.
6.2 Grafting by means of a low-molecular initiator The initiators that are used in this version of the coating process are low-molecular compounds, (i.e., they are not macroinitiators) with a group that decomposes under the action of electromagnetic irradiation or heat, while forming radicals. Both types of initiators are well known in polymerisation technology. These initiators generally have molecular weights less than 1,000.
Azonitriles, alkylperoxides, acylperoxides, hydroperoxides, peroxodisulfates, peroxyketones, peroxyesters, and percarbonates are suitable initiators that break down and form radicals when heated.
Suitable initiators for grafting that is initiated by way of electromagnetic irradiation are all the usual photoinitiators such as benzoines, benzilketales, ~-hydroxyketones, peroxides, azoic compounds, azoxy compounds, diazosulfonates, diazosulfones, diazothioethers, diacyldiazomethanes, diarylsulfides, heteroaromatic O.Z. 5299 substituted disulfides, diaroylsulfides, tetraalkylthiuramdi-sulfides, dithiocarbonates or dithiocarbamates. In particular, benzophenone, acetophenone, fluorenone, benzaldehyde, propiophenone, anthrachinon, carbazol, 3- or 4-methyl- acetophenone, 4,4'dimethoxybenzophenone, allylacetophenone, 2,2'-diphenoxyacetophenone, benzoin-methylether, benzoinethylether, benzoinpropylether, benzoinacetate, benzoinphenyl carbamate, benzoinacrylate, benzoinphenylether, benzoylperoxide, dicumylperoxide, azobisisobutyronitrile, phenyldisulfide, acylphosphanoxides, or chlormethylanthrachinon, and combinations of these, are known. Preferred, photoinitiators that permit especially short radiation times are benzoines, benzoine derivatives, benzil ketales and ~-hydroxyketones.
The polymer substrate is preferably pre-treated with the initiator before grafting. This can be done in that a solution of the initiator is applied to the polymer substrate and the solvent evaporated off. Depending on the substrate and the initiator, suitable solvents are, for example, water, acetone, methylethylketone, butanone, cyclohexanone, diethylether, tetrahydrofurane, dioxane, methanol, ethanol, propanol, butanol, cyclohexanol, dimethylacetamide, dimethylsulfoxide, dimethylformamide, heptane, cyclohexane, benzole, toluene, dichlormethane, trichlormethane, ethylacetate, propylacetate, amylacetate, or acetonenitrile.
The solvent is more preferably one that swells the polymer substrate but not dissolve it, so that close contact is created between the polymer substrate and the initiator.
In the interests of attaining good adhesion of the O.Z. 5299 biologically active coating to the polymer substrate, it is however useful to first pre-treat the polymer substrate with an initiator and at least one monomer, and then graft the A
and B monomers and optionally the D monomer or, alternatively, a C polymer and a B monomer onto the pre-treated polymer substrate. Choice of the initiator and of the monomer will be governed, amongst other things, by the chemical nature of the polymer substrate. The monomer is desired to be able to cause the polymer substrate to swell and thereby permit the initiator to penetrate into the areas of the polymer substrate that are close to its surface. In contrast to this, it makes no difference whether or not the monomer imparts the biological properties that are desired for the pre-treatment.
It is possible to carry out the pre-treatment with one monomer that swells the polymer substrate sufficiently and dissolves the initiator and permits it to penetrate but does not, however, result in the biological properties that are ultimately desired, and use the above-discussed monomers with the biologically effective groups or a polymer therefrom first in the grafting phase. The optimal combinations of polymer substrate, initiator, and monomer for the pre-treatment can be easily determined by means of tests. For example, (meth)acrylic acid and/or its esters combined with the above-discussed preferred photoinitiator are well suited for the pre-treatment of polyamide, polymethane, polyether-blockamide, or polyesteramide or polyesterimide substrates.
It is expedient that the mixture used for pre-treating the polymer substrate is at least for the most part made up of the initiator and at least one monomer. The O.Z. 5299 mixture can consist exclusively of the components named above or smaller quantities, e.g., up to 40, and preferably up to 20~-wt of a solvent. The latter can, for example, be the case if the monomer and the initiator cannot be mixed to form a homogeneous mixture or solution, or cannot be mixed well enough, or if the substrate swells excessively with the monomer alone. Examples of suitable solvents are the solvents mentioned above for the initiator. Shorter irradiation times of the process according to the present invention can be attributed essentially to the fact that the solvents in the mixture for the pre-treatment of the polymer substrates are present in smaller quantities.
The treatment of the polymer substrate with the initiator and the monomer, when applied, should be such that the surface of the polymer substrate swells slightly. The duration of the treatment will depend on the particular combination of polymer substrate, initiator, and monomer, and on the temperature. It need only amount to 1 to 10 seconds and amounts advantageously from 1 to 5 seconds. The optimal temperatures and treatment times can be determined very easily by way of simple tests. It is preferred that the treatment of the polymer substrate with the initiator and the aliphatic unsaturated monomer be effected at a temperature from 10 to 200~C, in particular from 20 to 80~C, and in particular 30 to 60~C
The mixture that contains the initiator and is used to treat the polymer substrate can be applied to the substrate by the usual application techniques, such as spraying, brushing, or dipping.

O.Z. 5299 According to the present invention, the A and the B
monomers and optionally the D monomers or the C polymer and the cross-linking agent B may be grafted onto the polymer substrate that is provided with an initiator. This process may be induced either photochemically or thermally. During the grafting process, the monomers or the C polymer can come into contact with the polymer substrate as a substance or more expediently dissolved in a solvent. Depending on the type of the monomer or of the C polymer, the solvents that are suitable for the pre-treatment are also suitable for the pre-treatment. Generally speaking, the solutions contain 2 to 50~-wt monomers or C polymer. The polymer substrate can be dipped or coated with the solution of the monomers or of the polymer using one of the application techniques referred to above.
Photochemical grafting can be initiated by electromagnetic radiation in the wavelength range from 180 to 1200 nm, preferably from 200 to 800 nm, and in particular from 200 to 400 nm. Radiation in this range of wavelengths is relatively soft and does not as a rule attack the polymer substrate. As an example, one can use an excimer ultraviolet radiator (HERAEUS, D-63801 Neuostheim) with continuous irradiation, for example with XeCl or XeF as the radiating medium. In principle, mercury vapour lamps with a wide ultraviolet spectrum and radiation in the visible range or in the above named ranges can also be used. Exposure times generally amount to 60 to 300 seconds. The exposure times will depend, amongst other things, on the geometry of the irradiated substrate. Objects having distinctly three-O.Z. 5299 dimensional characteristics must be rotated, and will require longer irradiation times.
Alternatively, grafting can also be induced thermally. To this end, the polymer substrate coated with A
and B monomers and optionally C monomer, or with the C polymer and a B monomer, is warmed to a temperature at which the initiator that is being used breaks down while forming radicals and the grafting proceeds. Generally speaking, this is the case if the polymer substrate is warmed for a period of 5 to 240 minutes to a temperature in the range from 50 to 100~C, depending on the initiator, the A and B monomers and optionally the D monomer or the C polymer and the B monomer.
After grafting (as in Paragraph 6.1 and Paragraph 6.2) groups that have been introduced can be converted in the usual way to derivatives, either wholly or in part. Carboxyl groups can be converted to carboxylate groups (i.e., salts) or sulfonic acid groups can be neutralised to sulfonate groups, (i.e., salts), carbonester groups can be saponified to hydroxyl or carbonate acid groups and carbonamide or nitrile groups can be saponified to carboxyl groups. The formation of further derivatives of polymer substrates modified according to the present invention can be undertaken according to common procedures (H. Beyer, Lehrbuch der organischen Chemie [A
Textbook of Organic Chemistry], S. Hirzel Verlag, Stuttgart, 1988, p. 260 et seq.) If, in particular in the case of applications in the field of medical technology, it is important that the grafted coatings be free of soluble monomers or oligomers, these undesirable components can be extracted, for example with hot O.Z. 5299 water. Since the coating is bonded covalently onto the polymer substrate, when this is done it will not be dissolved, damaged, or be degraded with respect to its biological effectiveness.

7. Use of the coated substrates Coated polymer substrate that have been manufactured according to the present invention are suitable for producing articles or are themselves utility articles, in particular in the areas of foodstuffs and beverage technology, water technology, biotechnology, health and hygiene and, in particular, medical technology. Such items, which can be either totally or partly coated according to the present invention, also constitute an object of the present invention.
Examples of these are textiles, furniture and appliances, hoses and tubes, floor coverings, wall coverings, and ceiling coverings, storage bins, packaging, window frames, telephones, toilet seats, door handles, handles and restraining belts used in public transportation and medical equipment, articles used in medical technology, such as, for example, implants or aids such as drains, guide wires, cannulae, intraoccular lenses, contact lenses, stents, vascular prostheses, joint prostheses, bone replacement materials, ligament prostheses, dental prostheses for plastic surgery, blood bags, dialysis membranes, suture materials, dressings, non-woven mat products, and surgical instruments preferred use for the materials according to the present invention is for manufacturing catheters.
The present invention will be described in greater detail below but without limiting its area of application as O.Z. 5299 defined in the patent claims.
Examples 1 to 6 In Examples 1 and 2, polymers are grafted; monomers are grafted in Examples 3 to 6.
Example 1 1-mol solutions of sodium 4-styrenesulfonate (NaSS), maleic acid (MS), and polyethyleneglycol-1000-monomethylether monoacrylate (PEG-100-MeO-MA; Polyscience Europe GmbH, Heidelberg) were combined at a ratio of 5: 5: 1 by volume and mixed with 1 mol% K2S208 relative to the total of the monomers. The batch was heated to 60~C for four hours whilst being stirred, cooled, and poured slowly and whilst being stirred into a 5-times greater volume of ethanol. The precipitated copolymer was filtered off, washed with ethanol, and dried for 10 hours at 55~C in a convection-type drying cabinet. A 10~-wt aqueous solution of the copolymer was made up for the coating tests. This solution was mixed with as much diethyleneglycol dimethacrylate (DEGDMA; Polyscience Europe GmbH, Heidelberg), so that its concentration amounted to 20~-wt.
Example 2 The same procedure as in Example 1 above was followed. However, the volumetric ratio of the solutions amounted to 50:50:1; the solution that was produced was 1~-wt and the cross-linking agent used was polyethyleneglycol-1000 dimethacrylate (PEGlOOODMA; Polyscience Europe GmbH, Heidelberg) at a concentration of 20~-wt.
Examples 3 to 6 Monomers of NaSS and maleic acid (MS) or acrylic O.Z. 5299 acid, respectively, were dissolved in water at the concentrations set out in the table. The type and the concentration of the cross-linking agent are also set out in the table (PETAE = pentaerythritol triallylether, PETA =
pentaerythritol tetraacrylate; Polyscience Europe GmbH, Heidelberg).
Polymer substrates and activation thereof In each case, the substrate material was a 0. 1-mm thick polyamide, 12-film (Type L2101, Huls AG). Prior to coating, the film was activated as follows:
Example 1 The polyamide film was immersed for 5 seconds in a solution of 40 g 2, 2'-dimethoxy-2-phenylacetophenone ("ultraviolet initiator") warmed to 70~C and air dried.
Examples 2 to 6 In each instance, the polyamide films were exposed to excimer radiation of 702 nm wavelength at a pressure of 1 bar. The radiation was generated by an excimer ultraviolet radiator (Heraeus, Kleinostheim, Germany) with a power output of 1. 7 kW, set at a distance of 4 cm from the sample.
Graft polymerization Example~ 1 to 6 The activated polyamide (PA) 12-films were immersed in the coating solutions and, when still immersed, were exposed to excimer ultraviolet irradiation at a wavelength of 308 nm for the times given in the Table. Once again, the radiation was generated by an excimer ultraviolet radiator (Heraeus, Kleinostheim, Germany) with a power output of 1. 7 kW set at a distance of 4 cm from the sample.

O.Z. 5299 Measurement of bacterial adhesion of coated standard foil using adenosine triphosphate (ATP) (static) Bioluminometric methods that are customary in the technology were used. After adsorption of Klebsiella pneumoniae bacterial cells on the PA 12-films that were either untreated or had been treated according to the present invention, the non-adhering bacteria were rinsed off using sterile PBS buffer solution. The bacterial content of adenosine triphosphate (ATP)was extracted from the bacteria adhering to the film and determined in a bioluminometric test using a commercially available test combination. The number of light pulses measured is proportional to the number of adhering bacteria.

O.Z. 5299 CA 0224l483 l998-06-26 Table: Test conditions and results - coating tests Example Polymer or monomer Activation Cross- Grafting Bacterial mixture for grafting linking method adhesion agent (1) 1 Poly(NaSS-co-MS-co- Ultraviolet DEGDMA W 308 25 PEG 1000-MeO-MA initiator 20~-wt nm for 5:5:1 15 min 10-% aqueous solution 2 Poly(NaSS-co-MS-co- W 172 nm PEG1000- W 308 37 PEG 1000-MeO-MA 5 minutes DMA nm for 50:5:1 20~-wt 15 min 10-~ aqueous solution 3 NaSS/MS 3/2.4~-wt in W 172 nm PEG1000- W 308 50 water 5 minutes DMA nm for 0.5~-wt 15 min 4 NaSS/MS 3/2.4~-wt in W 172 nm PEG1000- W 308 38 water 5 minutes DMA nm for 0.5~-wt 15 min NaSS/MS 0.5/4.5~-wt W 172 nm PETAE W 308 3 in water 5 minutes 0.005~- nm for WT 15 min 6 NaSS/MS 0.5/4.5~-wt W 172 nm PETA W 308 1 in water 5 minutes 0.005~- nm for WT 15 min (1) As compared to an uncoated PA 12-film O.Z. 5299

Claims

1. A process for coating a polymer substrate hemocompatible, to form a polymeric surface coating layer thereon that is bacteria-repellant and adhesive to the polymer substrate, which process comprises:
grafting, initiated by electromagnetic radiation or thermally:
(i) a mixture of at least one vinyl monomer (A monomer) of the general formula:
R-(A)a (I) (wherein:
R stands for a mono- or di-aliphatically unsaturated organic radical having the valency a A stands for a carboxyl group -COOH-, a sulphuric acid group -OSO2OH, a sulfonic acid group -SO3H, a phosphoric acid group -OPO(OH)2, a phosphonic acid group -PO(OH)2, a phosphorous acid group -OP(OH)2, a phenolic hydroxyl group, or a salt of one of the above cited groups, and a stands for 1, 2, or 3 provided, however, that when the monomer of Formula I has a carboxyl group -COOH or a carboxylate group, then either this monomer contains at least one additional A radical that is other than a carboxyl or carboxylate group or at least one additional monomer of Formula I is used, in which A is a value that is other than the carboxyl or carboxylate group); and at least one cross-linking vinyl monomer (B monomer) that contains at least two olefinic double bonds, or (ii) a mixture of at least one cross-linking vinyl monomer (B monomer) mentioned above and a polymer produced from at least one (A) monomer (polymer C), onto the polymer substrate, wherein the polymer substrate is activated prior to the grafting process, or an initiator is used in the grafting process.

2. A process as defined in claim 1, wherein the vinyl (A) monomer is at least one member selected from the group consisting of:
(a) a carboxylic acid or a physiologically acceptable salt thereof, where the carboxylic acid is acrylic acid, methacrylic acid, 4-vinylsalicylic acid, itaconic acid, vinylacetic acid, phenylacrylic acid, 4-vinylbenzoic acid, 2-vinylbenzoic acid, sorbic acid, caffeic acid, maleic acid, methylmaleic acid, crotonic acid, isocrotonic acid, fumaric acid, dimethylfumaric acid, methylfumaric acid, dihydroxymaleic acid, or allylacetic acid;
(b) a sulfonic acid or a physiologically acceptable salt thereof, where the sulfonic acid is allylsulfonic acid, vinylsulfonic acid, styrenesulfonic acid or vinyltoluenesulfonic acid;
(c) a sulfuric acid or a physiologically acceptable salt thereof, where the sulfuric acid is allylsulfuric acid or methallylsulfuric acid;
(d) butene-(2)-diol-(1,4)-diphosphoric acid or disodium salt thereof, butene-(2)-diol-(1,4)-diphosphonic acid or disodium salt thereof or monoallylphosphite; and (e) 2-vinylphenol, 2-allylhydroquinone, 4-vinylresorcinol, m-hydroxystyrene, o-hydroxystyrene or, p-hydroxystyrene.

3. A process as claimed in claim 2, wherein the vinyl (A) monomer is a mixture of the carboxylic acid or salt thereof (a) and the sulfonic acid or salt thereof (b).

4. A process as claimed in claim 2 or 3, which employs, together with the (A) monomer, (D) an olefinically unsaturated monomer which is neutral, is not cross-linking and has no substantial effect on hemocompatibility and bacteriarepellency of the resulting polymeric surface coating layer, wherein the olefinically unsaturated monomer is employed in an amount of up to 90 mol% based on the total amount of the (A), (B) and (D) monomers and is selected from the group consisting of a (meth)acrylic acid ester which may also contain a hydroxyl, alkoxy or tertiary amino group; (meth)acrylonitrile;
a vinyl ketone; an olefin; a vinyl aromatic; and a vinylsiloxane.

5. A process as claimed in claim 4, wherein the olefinically unsaturated monomer (D) is polyethylene glycol mono(C1-C4)alkyl ether mono(meth)acrylate.

6. A process as claimed in claim 3, 4 or 5, wherein the carboxylic acid or salt thereof (a) is acrylic acid, methacrylic acid or maleic acid; and the sulfonic acid or salt thereof (b) is sodium 4-styrenesulfonate.

7. A process as defined in claim 1, which employs in addition to the (A) and (B) monomers, (D) an olefinically unsaturated monomer which is neutral or in any case only slightly effective in terms of hemocompatibility and bacteriarepellency of the resulting polymeric surface coating layer.

8. A process as defined in claim 1 or 7, wherein the (A) monomer is a mixture of monomers of the general formula II
and III:
(CnH2n-q-x) (COOR1)x (II) (CnH2n-q-x) (SO3R1)x (III) (wherein n stands, independently in each case, for an integer of from 2 up to and including 6;
x stands, independently in each case, for 1 or 2;
stands, independently in each case, for 0 or 2; and R1 stands, independently in each case, for -H, for an equivalent of a metal ion, a radical of an aliphatic, cycloaliphatic, or araliphatic alcohol).

9. A process as defined in Claim 1 or 7, wherein the (A) monomer is a benzene derivative of Formula IV:

(wherein B stands, independently in each case, for a mono- or di-unsaturated straight chain or branched radical of the formula (CnH2n-1-q-y)(COOR1)y or (CnH2n-1-q-y)(SO3R1)y' R1 stands, independently in each case, for -H, for an equivalent of a metal ion, a radical of an aliphatic, cycloaliphatic, or araliphatic alcohol.
n stands for an integer of from 2 to 6;
q stands for 0 or 2;
y stands for 0, 1, or 2;
R3 stands, independently in each case, for C1-4-alkyl, -NH2, -COOH, -SO3H, -OSO3H, -OPO(OH)2' -PO(OH)2' OP(OH)2' -OPO(O-)OCH2-CH2-N+(CH3)3, -PO(O~)O-CH2-CH2-N+(CH3)3, -OP(O~)OCH2-CH2-N(CH3)3, or a salt, or an ester of the cited groups:
b stands for 1, 2, or 3;
c stands for 0, 1, 2, or 3, and d stands for 0, 1, 2, or 3;
providing that b + c + d is not more than 6).

10. A process as defined in Claims 1 or 7, wherein the A
monomer is a mixture of monomers of the general formulae V and VI, and (wherein R1 stands for hydrogen or methyl;
R2 stands for a bivalent organic radical or a single bond;
R3 stands for -O- or -NH-;
R4 stands for hydrogen or the -SO3-Na+;
R5 stands for hydrogen, methyl or -R2-COOR6;
R6 stands for hydrogen or Na, and n stands for 4 or 5, providing that at least one of the R4 substituents is - SO3-Na+).

11. A process as defined in Claim 8, wherein that the A
monomers of Formulae (II) and (III) are so selected that the grafted polymeric surface coating layer contains carboxyl and sulfonic acid groups, carboxyl and sulfonate groups, carboxylate and sulfonate groups, carboxyl, carboxylate and sulfonate groups, or carboxyl, sulfoacid and sulfonate groups.

12. A process as defined in Claim 11, wherein the molar ratio of carboxyl and/or carboxylate groups to sulfonic acid and/or sulfonate groups is 0.2 to 3.

13. A process as defined in Claim 11, wherein the molar ratio of carboxyl and/or carboxylate groups to sulfonic acid and/or sulfonate groups is 2 to 10.

14. A process as defined in Claim 11, wherein the molar ratio of carboxyl and/or carboxylate groups to sulfonic acid and/or sulfonate groups is 3 to 5.

15. A process as defined in any one of Claims 1 to 14, wherein the cross-linking vinyl monomer (B monomer) has 3 to 6 olefin double bonds.

16. A process as defined in Claim 15, wherein the (B) monomer contains no groups that contribute to the biological effect of the coating.

17. A process as defined in Claim 15 or 16, wherein the crosslinking vinyl monomer (B monomer) is (1) a (meth)acrylic acid ester of a polyol having three to six hydroxyl groups, (2) a polyvinyl ether of a polyol having three to six hydroxyl groups, (3) a polyallyl ether of a polyol having three to six hydroxyl groups or (4) a (meth)acrylized carbohydrate.

18. A process as defined in any one of Claims 1 to 17, wherein the polymer (C) produced from the (A) monomer is grafted onto the polymer substrate together with the (B) monomer.

19. A process as defined in any one of Claims 1 to 18, wherein the substrate surfaces has been activated by ultraviolet irradiation, plasma processing, corona processing or with a strong acid or a strong base, prior to the grafting step.

20. A process as defined in Claim 19, wherein the grafting is effected by radiation in the range from 250 to 500 nm.

21. A process as defined in any one of Claims 1 to 18, wherein the grafting is carried out by means of an initiator which breaks down when acted upon by electromagnetic radiation or heat, forming a radical, and with which the polymer substrate has been treated prior to the grafting process.

22. A process as defined in Claim 21, wherein the (A) and (B) monomers are grafted on the polymer substrate according to process variant (i).

23. A process as defined in any one of claims 1 to 21, wherein the polymer substrate is for use in foodstuffs or beverage technology, water technology, biotechnology, or health and hygiene.

24. An article which has been coated, either wholly or in part, according to the process of any one of Claims 1 to 22, for use in foodstuffs or beverage technology, water technology, biotechnology, or health or hygiene.

25. An article as defined in Claim 24, which is textile, furniture and appliance, hose and tube, floor covering, wall covering, ceiling covering, storage bin, packaging, window frame, telephone, toilet seat, door handle, handle restraining belt used in public transportation, or medical equipment.

26. An article as defined in Claim 25, for use in medical technology selected from the group consisting of drains, guide wires, cannulae, intraoccular lenses, contact lenses, stents, vascular prostheses, joint prostheses, bone replacement materials, ligament prostheses, dental prostheses for plastic surgery, blood bags, dialysis membranes, suture materials, dressings, non-woven mat products, surgical instruments, and catheters.