WO2005027991A1

WO2005027991A1 - Orthopaedic devices

Info

Publication number: WO2005027991A1
Application number: PCT/GB2004/004000
Authority: WO
Inventors: Mariam Habib; Roger Audley Brooks; William Bonfield; Andrew Lennard Lewis; Peter William Stratford
Original assignee: Cambridge University Technical Services Ltd
Priority date: 2003-09-19
Filing date: 2004-09-17
Publication date: 2005-03-31

Abstract

An orthopaedic implant device, for instance a replacement bone implant, has bone-contacting surfaces formed of osteointegration improving materials which have pendant highly hydrophilic groups, and an overall charge at physiological pH. The highly hydrophilic groups are generally zwitterionic groups, for instance phosphory1choline groups. The surface may be formed by coating a device substrate with a polymer comprising zwitterionic groups and ionic groups, and stabilising this on the surface for instance by crosslinking. Human osteoblasts are shown to adhere to the surfaces.

Description

ORTHOPAEDIC DEVICES The present invention relates to orthopaedic devices for use by implantation in contact with bone. The devices have surfaces formed of materials with improved osteointegrative properties. There have been a number of different approaches taken in order to modify biomaterials that are necessarily required to come into contact with hard or soft tissues, in order to lessen the body's response to these foreign materials. One approach is to attempt to mimic the chemistry or structure of these tissues. The so-called biomimetic or bio-inspired strategy that has been employed to great advantage in orthopaedic areas using hydroxyapatite-based technologies (such as HAPEX) [1 ,2]. Another biomimetic approach has been used in various soft-tissue contacting applications using materials based on the zwitterion, phosphorylcholine (PC) [3], PC materials mimic the outer surface of the cell lipid membrane and have been shown to be effective in improving the biocompatibility of a number of medical devices including soft contact lenses [4] and WO-A-9207885, coronary guidewires [5] WO-A-9301221 and stents [6] and WO98-30615, extracorporeal circuits [7], tympanostomy tubes [8] and vascular grafts [9] to mention but a few. It is believed that the biocompatibility of PC surfaces depends at least in part upon the hydrophilicity of the zwitterionic group. Protein adhesion is the basic first step in a variety of biological processes that would ultimately identify foreign surfaces, resulting in such events as thrombus formation, inflammation and fibrous encapsulation or bacterial adhesion and infection. PC materials have been shown to significantly reduce protein adsorption as their hydrated surfaces are able to interact with proteins without inducing conformational changes in their three dimensional structures, unlike many other hydrogel-type materials [10]. PC- based surfaces are therefore associated with less cellular adhesion, a reduced inflammatory response and lessened fibrous capsule formation [11]. In some applications however, it has been shown that the presence of a bio- inert surface does not necessarily aid in the healing process and hence speed the integration of the implant and tissue. In the case of coronary stents for instance, whilst the presence of a PC coating on the stent could be shown to lessen the chance of stent-related thrombosis [12] and did not induce additional inflammatory events from the vessel wall [6], the injury caused by the process of stent implantation could not be addressed by a bio-inert coating alone, and some element of bioactivity is required to aid in healing and prevent over-excessive scarring around the implant (restenosis of the stented vessel). Hence, the strategy of delivering a suitable drug from the coating that specifically inhibits the processes that result in restenosis is currently enjoying great success in the clinic today [13-15]. An additional approach to obtaining bioactivity is to take the fundamentally bio-inert PC platform and to modify the materials with chemical groups that may be used to serve a particular function or to bring about a specific biological response. In this way, the modified PC surface may be able to reduce non-specific interactions with biomolecules, whilst the modifying group may induce a degree of selectivity. Many biomolecules and cells are known to interact with charged groups and to this end, PC-based materials containing a range of cationic charges have been prepared and characterised [16]. Initial bioevaluation studies of these materials have reported on the interaction of a variety of different cell types (including human granulocytes, monocytes, mouse fibroblasts, rabbit corneal epithelial cells and human vascular endothelial cells) with these charge-modified surfaces, and have indicated that charge can indeed influence cellular responses such as adhesion, these effects being very cell specific [17,18]. In WO01/15752 and US-A-2002/0165617, an orthopaedic implant has a surface carrying a coating comprising at least one phospholipid carrying a charge, in this case, a negative charge. The coatings are shown to induce calcium phosphate precipitation. Phospholipids are believed to play a role in the mineralisation process, probably by virtue of their link with calcium levels within cells. For instance, phospholipids have been detected in calcified nodules, which forms the basis for a mineralisation matrix, by Silvestrini, G. et al in Bone (New York) (1996), 18 (6), 559 to 565. In addition, charged groups have been identified as having an effect on apatite deposition. Negative charges (carboxyl groups and sulphonate groups) can induce apatite deposition, although these apparently need to be precomplexed with calcium ions for this effect to occur. ("Apatite deposition on polyamide films containing carboxyl groups in a biomimetic solution" Miyazaki, T. J. Mat. Sci: Materials in Medicine (2003), 14 (7), 565 to 574 and "apatite deposition on polyamide films containing carboxyl groups in body environment", Miyazaki, T. et al Key Engineering Materials (2002), 218 to 220 (Bioceramics-14), 133 to 136). It would be desirable to produce a material which has improved osteointegration properties, which would be useful to form the surface of an orthopaedic device, which is based on a fundamentally bio-inert material adapted for specific interaction with osteoblasts. A new orthopaedic implant device according to the invention has a surface which in use will contact bone which is formed of osteointegration- improving material, the device being characterised in that the said material comprises a polymer having pendant highly hydrophilic groups and having an overall charge at physiological pH. The highly hydrophilic groups expressed at the surface of the material provide biocompatible properties. Although the hydrophilic groups may be poly(ethylene glycol) moieties, or polyhydroxylated compounds, the highly hydrophilic groups which are believed to confer most biocompatibility should be zwitterionic groups. Zwitterionic groups may have an overall charge at physiological pH. It is possible therefore for the pendant highly hydrophilic groups to confer the overall charge required of the polymer in the new device. Preferably, however, the zwitterionic groups have no overall charge. In this case the overall charge is conferred by other groups on the polymer. Most preferably the zwitterionic group is an ammonium, phosphonium or sulphonium phosphate or phosphonate ester zwitterionic group. Preferably the zwitterionic group has of the general formula II

in which the moieties A³ and A⁴, which are the same or different, are - O-, -S-, -NH- or a valence bond, preferably -O-, and W⁺ is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which is preferably a C.,.₁₂- alkanediyl group, preferably in which W⁺ is a group of formula -W¹-N⁺R³ ₃, -W¹-P⁺R ₃, -W¹-S⁺R⁴ ₂ or -W¹-Het⁺ in which: W¹ is alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, which group W¹ optionally contains one or more fluorine substituents and/or one or more functional groups; and either the groups R³ are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenyl, or two of the groups R³ together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R³ together with the nitrogen atom to which they are attached as heteroaromatic ring having 5 to 7 atoms, either of which rings may be fused with another saturated or unsaturated ring to form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R³ is substituted by a hydrophilic functional group, and the groups R⁴ are the same or different and each is R³ or a group OR³, where R³ is as defined above; or Het is an aromatic nitrogen-, phosphorus- or sulphur-, preferably nitrogen-, containing ring, for example pyridine. Generally a group of the formula II has the general formula III

where the groups R⁵ are the same or different and each is hydrogen or C_1-4 alkyl, and m is from 1 to 4, in which preferably the groups R⁵ are the same, preferably methyl. Another class of phosphate or phosphonate ester based zwitterionic groups is a phosphobetaine group which may have the general formula IV

in which A¹⁴ is a valence bond, -O-, -S- or -NH-, preferably -O-; R²¹ is a valence bond (together with A¹⁴) or alkanediyl, -C(O)alkylene- or -C(O)NH alkylene preferably alkanediyl, and preferably containing from 1 to 6 carbon atoms in the alkanediyl chain; W² is S, PR²² or NR²²; the or each group R²² is hydrogen or alkyl of 1 to 4 carbon atoms or the two groups R²² together with the heteroatom to which they are attached form a heterocyclic ring of 5 to 7 atoms; R²³ is alkanediyl of 1 to 20, preferably 1 to 10, more preferably 1 to 6 carbon atoms; A¹⁵ is a bond, NH, S or O, preferably O; and R²⁴ is a hydroxyl, C ₂ alkyl, C ₂ alkoxy, C₇.₁₈ aralkyl, C₇.₁₈ -aralkoxy, C_6-18 aryl or C_6-18 aryloxy group. In compounds comprising a group of the general formula IV, it is preferred that A¹⁴ is a bond; R²¹ is a C_2-6 alkanediyl; W² is NR²²: each R²² is C,.₄ alkyl; R²³ is C₂_₆ alkanediyl; A¹⁵ is O; and R²⁴ is C^ alkoxy. Alternatively, a zwitterion having no overall charge may be a sulphobetaine group, of the general formula XI

where the groups

R²⁵ are the same or different and each is hydrogen or C,.₄ alkyl and w is from

2 to 4. Preferably the groups R²⁵ are the same. It is also preferable that at least one of the groups R²⁵ is methyl, and more preferable that the groups R²⁵ are both methyl. Preferably w is 2 or 3, more preferably 3. Another example of a zwitterionic group has a carboxylate group. One such group is an amino acid moiety in which the alpha carbon atom (to which an amine group and the carboxylic acid group are attached) is joined through a linker group to the backbone of the polymer. Such groups may be represented by the general formula XII

in which A¹⁶ is a valence bond, -O-, -S- or -NH-, preferably -O-, R²⁶ is a valence bond (optionally together with A¹⁶) or alkanediyl, - C(O)alkylene- or -C(O)NHalkylene, preferably alkanediyl and preferably containing from 1 to 6 carbon atoms; and 5 the groups R²⁷ are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or two or three of the groups R²⁷, together with the nitrogen to which they are attached, form a heterocyclic ring of from 5 to 7 atoms, or the three group R²⁷ together with the nitrogen atom to which they are attached form a fused ring heterocyclic structure0 containing from 5 to 7 atoms in each ring. Another example of a zwitterion having a carboxylate group is a carboxy betaine -N^θ(R²⁸)₂(CH₂)_xCOO^θ in which the R²⁸ groups are the same or different and each is hydrogen or C₁.₄ alkyl and x is 2 to 6, preferably 2 or 3.5 Where the zwitterionic pendant groups have no overall charge, or the level of charge requires to be controlled, the polymer has additional ionic groups. Preferably the ionic groups are pendant groups from the backbone of the polymer. Preferably the polymer therefore has pendant highly hydrophilic groups and pendant ionic groups different to the highly 0 hydrophilic groups. Preferably the polymer at the device surface is crosslinked. Additionally or alternatively the polymer may be covalently bound to other components of the material or to underlying components of the device, for instance where the material is a coating on the device. Crosslinked5 materials are found to be particularly stable over extended periods, for instance over long term use of the orthopaedic device. Generally the polymer is obtainable by polymerisation of ethylenically unsaturated monomers including a monomer having a highly hydrophilic substituent group, a monomer having an ionic substituent group, a surface o adherent monomer and a crosslinkable monomer capable of crosslinking after said polymerisation. Preferably the zwitterionic monomer has the general formula I Y B X I in which Y is an ethylenically unsaturated group selected from H₂C=CR-CO-A-, H₂C=CR-C₆H₄-A¹-, H₂C=CR-CH₂A², R²O-CO-CR=CR-CO-O, RCH=CH-CO-O~, RCH=C(COOR²)CH₂-CO-O,

A is -O- or NR¹; A¹ is selected from a bond, (CH₂)A² and (CH₂), SO₃ in which I is 1 to

12; A² is selected from a bond, -O-, O-CO-, CO-O, CO-NR¹-, -NR¹-CO, O-CO-NR¹- and NR¹-CO-O-; R is hydrogen or C,.₄ alkyl; R¹ is hydrogen, C_|_₄. alkyl or BX; R² is hydrogen, C,.₄ alkyl or BX; B is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; X is the zwitterionic group. In the monomer of the general formula I, preferably Y is H₂C=CRCOA, most preferably in which A is O and R is selected from hydrogen and methyl, most preferably methyl. Generally B is an alkanediyl group, preferably having 2 to 6 carbon atoms and most preferably being a straight chain alkanediyl group. In the polymer obtainable from ethylenically unsaturated monomers, the monomer having an ionic substituent is preferably a compound of general formula (XII) Y²-B¹-Q (XII) where Y² is an ethylenically unsaturated polymerisable group selected from H₂C=CR⁶-CO-A⁵-, H₂C=CR⁶-C₆H₄-A⁶-, H₂C=CR⁶-CH₂A⁷, R⁷O-CO-CR⁶=CR⁶- CO-O, R⁶CH=CH-CO-O-, R⁶CH=C(COOR²)CH₂-CO-O,

where R⁶ is hydrogen or C_rC₄ alkyl; R⁷ is hydrogen, C,.₄-alkyl or B¹Q; A⁵ is -O- or -NR⁸-, wherein R⁸ is hydrogen or a C_rC₄ alkyl group or R⁸ is a group -B¹-Q; A⁶ is selected from a bond, (CH₂)_nA⁷ and (CH₂)_nSO₃ in which n is 1 to 12; A⁷ is selected from a bond, O, OCO, COO, CONR⁸, NR⁸CO, OCONR⁸ and NR⁸COO; B¹ is a valence bond, a straight or branched alkylene, oxaalkylene or oligo-oxaalkylene group; Q¹ is an ionic group, or, where Y is H₂C=CR⁶COO, H₂C=CR⁶CH₂NR⁸, R⁷OCOCR⁶=COO, or R⁶CH=C(COOR⁷)CH₂COO and B¹ is a valence bond Q may be hydrogen. The ionic substituent may be anionic, in which case the ion is selected from carboxylate, sulphonate, phosphonate and phosphate groups. In such monomers, Q is suitably hydrogen where B¹ is a bond and Y is as indicated, to provide a carboxylate group. Alternatively group B¹ is other than a bond and Q is an anionic group, for instance a carboxylate, sulphonate, phosphonate or phosphate group. Particularly suitably, the ionic group Q is cationic. The group is preferably selected from a group -NR^{Θ 9} ₃ in which each group R⁹ is the same or different, and is hydrogen or alkyl of 1 to 6 carbon atoms two of which groups R⁹ may together from a heterocyclic ring containing from 5 to 7 atoms, preferably hydrogen or methyl, a group N^φHet, where Het is an unsaturated heterocyclic group such as pyridyl, substituted or unsubstituted by one or more alkyl groups of 1 to 4 carbon atoms, and a group -P^ffi R¹⁰ ₃ in which each group R¹⁰ is the same or different and is R⁹ or OR⁹, preferably in which R⁹ is hydrogen or alkyl of 1 to 6 carbons atoms, two of which groups R¹⁰ may together form a heterocyclic ring containing from 5 to 7 atoms, preferably methyl. Where the polymer is, as preferred, a crosslinked material, it is preferred for the crosslinking ability to be conferred by including in the ethylenically unsaturated monomers a monomer having a group capable of crosslinking after polymerisation. This allows the polymer to be applied to the surface and cured after coating to stabilise. Suitable crosslinking monomers have the general formula (IX) Y³-Q¹ (IX) where Y³ is an ethylenically unsaturated polymerisable group selected from H₂C=CR¹¹-CO-A⁸-, H₂C=CR¹¹-C₆H₄-A⁹-, H₂C=CR¹¹-CH₂A¹⁰, R¹²O-CO- CR ¹=CR¹¹-CO-O, R¹¹CH=CH-CO-O-, R¹¹CH=C(COOR¹²)CH₂-CO-O,

where R¹¹ is hydrogen or C_rC₄ alkyl; A⁸ is O or NR¹³; A⁹ is selected from a bond, (CH₂)_PA¹⁰ and (CH₂)_pSO₃ in which p is 1 to

12; A¹⁰ is selected from a bond, O, OCO, COO, CONR¹³, NR¹³CO, OCONR¹³ and NR¹³COO; R¹² is hydrogen, C^-alkyl or Q¹; R¹³ is hydrogen, C,.₄-alkyl or Q¹. Q¹ is a crosslinkable group. Preferably in the crosslinkable monomer, Q¹ contains a group selected from cinnamyl, epoxy, -CHOHCH₂Hal (in which Hal is a halogen atom), methylol, reactive silyl (e.g. alkoxy silyl), an ethylenically unsaturated crosslinkable group, such as an acetylenic, diacetylenic, vinylic and divinylic group, or an acetoacetoxy and chloroalkyl sulfone, preferably chloroethyl sulphone, group. Preferably the crosslinkable monomer is an (trialkoxysilyl) alkyl(meth)acrylate, for instance 3-(trimethoxysilyl) propyl methacrylate. A surface adherent monomer is a compound of general formula (VI) Y¹-Q² (VI) where Y¹ is an ethylenically unsaturated polymerisable group selected from H₂C=CR¹ -CO-A¹¹-, H₂C=CR¹⁴-C₆H₄-A¹²-, H₂C=CR¹⁴- CH₂A¹³, R¹⁶O-CO- CR¹⁴=CR¹ -CO-O, R¹⁴CH=CH-CO-O-, R¹⁴CH=C(COOR¹⁶)CH₂-CO-O,

where R¹⁴ is hydrogen or C,-C₄ alkyl, A¹¹ is -O- or -NR¹⁵- where R¹⁵ is hydrogen or a 0,-0-₄ alkyl group or

R¹⁵ is a group Q²; A¹² is selected from a bond, (CH₂)₂ A¹³ and (CH₂)_qSO₃ in which q is 1 to 12; A¹³ is selected from a bond O, OCO, COO, CONR¹⁵, NR¹⁵CO, OCONR¹⁵and NR¹⁵COO; R¹⁶ is hydrogen, C^ alkyl or Q². Q² is (a) a straight or branched alkyl, alkoxyalkyl or (oligo-alkoxy)alkyl chain containing 6 or more, preferably 6 to 24, carbon atoms unsubstituted or substituted by one or more fluorine atoms and optionally containing one or more carbon-carbon double or triple bonds; or (b) a siloxane group -(CR¹⁷ ₂)_r (SiR¹⁸ ₂) (OSiR¹⁸ ₂)_sR¹⁸ in which each group R¹⁷ is the same or different and is hydrogen or alkyl of 1 to 4 carbon atoms or aralkyl, for example benzyl or phenethyl, each group R¹⁸ is alkyl of 1 to 4 carbon atoms, r is from 1 to 6 and s is from 0 to 49. Preferably the surface adherent monomer is a compound in which Q² is an alkyl group of formula -(CR¹⁹ ₂)_tCR¹⁹ ₃ wherein the groups -(CR¹⁹ ₂)- are the same or different, and in each group -(CR¹⁹ ₂)the groups R¹⁹ are the same or different and each group R¹⁹ is hydrogen, fluorine or C,.₄ alkyl or fluoroalkyl and t is from 5 to 23 if Q² contains no fluorine atoms or from 1 to 23, preferably 5 to 23, if Q² contains one or more fluorine atoms; an alkoxyalkyl having 1 to 12 carbon atoms in each alkyl moiety; unsubstituted or substituted by one or more fluorine atoms; or an (oligo-alkoxyl) alkyl group of formula -[(CR²⁰ ₂)_nO]_u (CR²⁰ ₂)_VR²⁰ where the groups -(CR²⁰ ₂)- are the same or different and in each group -(CR²⁰ ₂)- the groups R²⁰ are the same or different and each group R²⁰is hydrogen, fluorine or C,_₄ alkyl or fluoroalkyl and u is from 2 to 6, preferably 3 to 4, and v is from 1 to 12. The ethylenically unsaturated monomers may further comprise comonomers, for instance compounds of the general formula V

in which R²⁹ is selected from hydrogen, halogen, C^ alkyl and groups COOR³³ in which R³³ is selected from hydrogen and C.,.₄ alkyl; R³⁰ is selected from hydrogen, halogen and C₁.₄ alkyl; R³¹ is selected from hydrogen, halogen, C,^ alkyl and groups COOR³³ provided that R²⁹and R³¹ are not both COOR³³; and R³² is a C^o alkyl, a C,.₂₀ alkoxycarbonyl, a mono-or di-(C,.₂₀ alkyl) amino carbonyl, a C₆.₂₀ aryl (including alkaryl) a C_7-20 aralkyl, a C₆.₂₀ aryloxycarbonyl, a C^o -aralkyloxycarbonyl, a C₆.₂₀ arylamino carbonyl, a C₇_ ₂₀ aralkyl-amino, a hydroxyl or a C₂.₁₀ acyloxy group, any of which may have one or more substituents selected from halogen atoms, alkoxy, oligo-alkoxy, aryloxy, acyloxy, acylamino, amine (including mono and di-alkyl amino and trialkylammonium in which the alkyl groups may be substituted), carboxyl, sulphonyl, phosphoryl, phosphino, (including mono- and di- alkyl phosphine and tri-alkylphosphonium), zwitterionic, hydroxyl groups, vinyloxycarbonyl and other vinylic or allylic substituents, and reactive silyl or silyloxy groups, such as trialkoxysilyl groups; or R³² and R³¹ or R³² and R³⁰ may together form -CONR³ CO in which

R³⁴ is H or a C^n alkyl group. It is preferred for at least two of the groups R²⁹, R³⁰, R³¹ and R³² to be halogen or, more preferably, hydrogen atoms. Preferably R²⁹ and R³⁰ are both hydrogen atoms. It is particularly preferred that compound of general formula V be a styrene-based or acrylic based compound. In styrene based compounds R³² represents an aryl group, especially a substituted aryl group in which the substituent is an amino alkyl group, a carboxylate or a sulphonate group. Where the comonomer is an acrylic type compound, R³² is an alkoxycarbonyl, an alkyl amino carbonyl, or an aryloxy carbonyl group. Monomers of the general formula V may be used to give the polymer the desired physical or mechanical properties. Particular examples of diluent comonomers include alkyl(alk)acrylate preferably containing 1 to 4 carbon atoms in the alkyl group of the ester moiety, such as methyl (alk)acrylate; a dialkylamino alkyl(alk)acrylate, preferably containing 1 to 4 carbon atoms in each alkyl moiety of the amine and 1 to 4 carbon atoms in the alkylene chain, e.g. 2-(dimethylamino)ethyl (alk)acrylate; an alkyl (alk)acrylamide preferably containing I to 4 carbon atoms in the alkyl group of the amide moiety; a hydroxyalkyl (alk)acrylate preferably containing from 1 to 4 carbon atoms in the hydroxyalkyl moiety, e.g. a 2-hydroxyethyl (alk)acrylate; or a vinyl monomer such as an N-vinyl lactam, preferably containing from 5 to 7 atoms in the lactam ring, for instance vinyl pyrrolidone; styrene or a styrene derivative which for example is substituted on the phenyl ring by one or more alkyl groups containing from 1 to 6, preferably 1 to 4, carbon atoms, and/or by one or more halogen, such as fluorine atoms, e.g. (pentafluorophenyl)styrene. Other suitable diluent comonomers include polyhydroxyl, for example sugar, (alk)acrylates and (alk)acrylamides in which the alkyl group contains from 1 to 4 carbon atoms, e.g. sugar acrylates, methacrylates, ethacrylates, acrylamides, methacrylamides and ethacrylamides. Suitable sugars include glucose and sorbitol. Particularly suitable diluent comonomers include methacryloyl glucose or sorbitol methacrylate. Further diluents which may be mentioned specifically include polymerisable alkenes, preferably of 2-4 carbon atoms, eg. ethylene, dienes such as butadiene, alkylene anhydrides such as maleic anhydride and cyano-substituted alkylenes, such as acrylonitrile. Diluent comonomers may be obtained by conventional known methods. Of the above diluent comonomers some are inert and act simply to modify the physical and mechanical properties of copolymers containing them. Others, and in particular the hydroxyalkyl(alk)acrylates and polyhydroxyl (alk)acrylates have a reactive role in addition to simply modifying physical and mechanical properties. Such comonomers contain functional groups, such as hydroxyl groups, which may react with a crosslinking group or may react with reactive groups in other molecules to attach them to the copolymer. It will also be appreciated that alkyl(alk)acrylates containing 6 or more carbon atoms in the alkyl group may be regarded as either diluent comonomers or as adherent comonomers capable of binding a polymer to a surface by physisorption. The polymers described above, when expressed at the surface of an orthopaedic implant, in particular, polymers having cationic and zwitterionic PC groups, have interesting properties when contacted with human osteoblasts (HOBS). Preliminary results suggest that the presence of charge in the polymer can induce the HOBS to undergo rapid mineralisation as demonstrated by significant calcium presence, alkaline phosphatase expression and lead to mineral-like nodules under scanning electron microscopy. The materials are suitable for application to the surfaces of a variety of materials useful for forming orthopaedic implant devices, such as metals for instance stainless steel and titanium, ceramics, plastics, etc. to form stable coatings. The materials are biocompatible by virtue of the presence of the hydrophilic pendant groups. The polymer appears to increase adhesion of osteoblasts to an implant device coated with the material, increase the rate of mineralisation on the surface of the device and increase the level of expression of alkaline phosphatase in osteoblasts growing on the surface of the device. Implant devices which could make use of this invention include, but are not limited to:- hip implants, knee joints, finger joints, elbow replacements, bone screws and pins, other permanent fixation devices, spinal discs where some integration between disc and vertebral bone is desirable, bone defect filling materials, dental implants, cranio-maxillofacial devices, bone plates, bone and dental cements. In the invention there is also provided a new use of the polymer as defined above in the manufacture of an orthopaedic implant device, wherein the polymer is comprised in material at at least the bone-contacting surface of the device, for increasing the osteointegration of the device, increasing adhesion of osteoblasts to the device, increasing the rate of mineralisation on the surface of the device and/or increasing the level of expression of alkaline phosphatase in osteoblasts growing on the surface of the device. There is also provided a surgical method in which a device of the invention is implanted into an animal whereby the surface formed of the defined material is in contact with bone. There is also provided in the invention a process for manufacturing an orthopaedic implant device, in which a device body is provided on at least a part of its bone-contacting surface with a coating of polymer as defined above. Preferably the process involves coating by contacting the device body with a liquid coating composition comprising a solvent and a coating polymer followed by removal of the solvent to leave the coating polymer on the surface. Preferably the solvent is removed by evaporation. Preferably the coating polymer is cross-linkable and is crosslinked after coating to form the defined polymer. Crosslinking may be by subjecting the polymer to conditions under which the crosslinkable groups form covalent bonds, for instance raised temperature, imposition of radiation, for instance UV radiation or contact with crosslinking agent. Polymers of the five monomers in the ratios exemplified in the worked examples below, have been coated successfully on to a range of materials including stainless steel in our earlier applications WO-A-9822516 and WO- A-0152915. The polymers and coating processes described therein may be used to coat the devices of the present invention. Convenient solvents for use in liquid coating compositions, in which the coating polymer is soluble, are alcohols. Most preferably the solvent is ethanol. The following examples illustrate the invention. Examples: Example 1: Preparation of Phospholipid-based polymers containing charged moieties. The monomer 2-methacyloyloxyethyl phosphorylcholine (MPC) was synthesised and purified and described in US-A-5,741 ,923. Lauryl methacrylate (LMA), hydroxypropyl methacrylate (HPMA) and 3-

(trimethoxysilyl)propyl methacrylate (TMSMA) were purchased from the Aldrich Chemical Company and used as provided. Choline methacrylate (CMA) was purchased as a 70 wt% solution in water that was freeze-dried to a powder and stored at -18°C until required. Polymerisation was conducted using a monomer starved free radical polymerisation method and AIBN as initiator similar to that described by us previously [19]. All polymerisations were conducted under a nitrogen atmosphere at 83°C using isopropyl alcohol (iPA) to solubilise the monomer mixture and isopropyl acetate to dissolve the initiator. The combined monomer/initiator mix was pumped into the reaction vessel over a 2 hr period and refluxed for a further hour. An initiator spike was added and the reaction held at reflux for a further 2 hrs before being recovered by precipitation into a methyl acetate:acetone (7:3) mixture. The resulting 'chippy' polymer was re-dissolved in iPA and precipitated a second time in methyl acetate. All products were collected as fine white powders that were dried for 16 hrs in-vacuo before storing at -18°C. Table 1 outlines the various compositions (shown on a weight % basis) for the range of polymers prepared in this study and also shows a generic structure for the random copolymers produced. Example 2: Confirmation of surface charge. Polymers described in example 1 can be applied to surfaces as a solution in alcohols such as ethanol. Coatings may be applied by conventional methods including dip, spin and spray-coating. The cross- linkable materials must be cured to ensure stability on the substrate surface; this is achieved by, but not limited to, thermal curing, normally above 70°C for at least 4hrs, or by the application of gamma-irradiation (at least =25Kgy), or by both. Typically a 1 % solution is used as for coating. Once cured, the presence of the charged groups can be visualised by staining with an appropriate dye that will interact with the charged groups. The anionic dye amaranth is a suitable choice for visualisation of positively charged polymers (see Figure 1 ). Which shows the visualisation of surface charge by amaranth staining of polymers with varying cationic charge.

MPC LMA CMA HPMA TMSMA wt% (v) (w) (X) (y) (z) 29 51 0 12 5 28 50 5 12 5 27 46 10 12 5 26 42 15 12 5 24 39 20 12 5 22 36 25 12 5 20 33 30 12 5

Table 1 : Generic Structure of Cationically-charged Phospholipid Polymers and their Composition v, w, x, y and z molar represent parts of starting monomers. Analysis Range Polymer yield 57 - 85% Silicon content (by EA) 0.39 - 0.51 wt% Residual monomer content (by HPLC): MPC 0.18-0.34% LMA 0.03-0.17% HPMA 0.025-0.03% TMSMA 0.012-0.055% CMA 0.02-0.14% Molecular weight (by GPC) 131 ,000 - 425,600

Table 2: Analytical Results Obtained from a Range of Cationically Modified Polymers.

Example 3: Culture of human osteoblasts (Hobs) on polymer surfaces and analysis by staining. Tissue culture flasks (25ml) were coated with 1 wt% ethanolic solution of polymers containing 0, 5 & 20% CMA and cured at 72°C for 72 hours. Uncoated tissue culture flasks were used as controls. Human osteoblasts (Hobs) were seeded into flasks at a density of 1x10⁴/cm² and cultured in McCoy's medium containing 10% foetal calf serum, 1 % glutamine and 30μg/ml vitamin C. Images of cells on polymer and control surfaces were captured using an optical microscope and 3-chip colour camera connected to a computer with frame grabber and image analysis software.

Mineralisation and alkaline phosphatase (ALP) activity were measured by staining with Alizarin red and Fast Red TR respectively: a) Mineralisation: Dissolve Alizarin red in water, adjust pH to 4.2 with ammonium hydroxide. Stain cells for 1-5 min at room temperature. Rinse in acetone, followed by xylene-acetone (1 :1 ). Final wash in xylene. b) ALP Activity: Stock solution of 0.2mg/ml napthol AS-MX phosphate (dissolved in N,N dimethylformamide) diluted in 0.1 M Tris buffer at pH 9.2. Add 1 mg/ml Fast Red TR Salt to stock solution & sterile filter before immediate use. React with fixed cells for 2 min at room temperature. Hobs expressed distinct morphologies on PC and control surfaces

(Figure 2). On CMA 0 there was little cell adhesion, while on CMA 5 adherent cells were mostly rounded with some spreading at the edges. Cells were fully spread on CMA20 and control surfaces. At the 48 hour time point large numbers of nodules staining positive for alizarin red were visible on CMA 20 (Figure 3a) compared to the control

(b). On CMA 20 a larger number of cells were ALP positive Fig. 3(c) compared to control (tissue culture plastic). Figure 2 shows an image of Hobs on CMA(O)(a), CMA5(b), CMA20(c) and control (d). The scale bar is 100 μm and N in (c) signifies a mineral nodule. The results show that PC surfaces are capable of inducing specific morphologies in Hobs. Cell adhesion and spreading increases with cationic charge. There is also the early deposition of mineral in granular modules which showed positive staining for calcium.

References:

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Optimising HAPEX topography influences osteoblast response. Tissue Eng. 2002; 8: 453-467.

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Histopathology of biocompatible hydroxyapatite-polyethylene composite in ossiculoplasty. ORL J Otorhinolaryngol Relat Spec. 2002; 64: 173-179.

[3] Lewis AL. Phosphorylcholine-based polymers and their use in the prevention of biofouling. Coll Surf B: Biointerfaces 2000; 18: 261-275.

[4] Lemp MA, Caffery B, Lebow K, Lembach R, Park J, Foulks G, Hall B,

Bowers RJW, McGarvey S, Young G. Omafilcon A (Proclear) soft contact lenses in dry eye population. CLAO Journal 1999; 25(1 ): 40-47.

[5] Gobeil F, Juneau C, Plante S. Thrombus formation on guide wires during routine PTCA procedures. A scanning electron microscopic evaluation. Can J Cardiol 2002; 18: 263-269. [6] Whelan DM, van der Giessen WJ, Krabbendam SC, van Vliet EA, Verdouw OD, Serruys PW, van Beusekom HMM. Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries. Heart 2000; 83(3): 338-345. 5 [7] De Somer F, van Belleghem Y, Caes F, Francois K, Arnout J, Bossuyt X, Taeymans Y, van Nooten G. Phosphorylcholine coating offers natural platelet preservation during cardiopulmonary bypass. Perfusion 2002; 1 : 39- 44. [8] Berry JA, Biedlingmaier JF, Whelan PJ. In-vitro resistance to bacterial0 biofilm formation on coated fluoroplastic tympanostomy tubes. Otolaryngol Head Neck Surg 2000; 123: 246-251. [9] Chen C, Lumsden AB, Ofenloch J, Beverly N, Campbell EJ, Stratford PW, Yianni YP, Taylor AS, Hanson SR. Phosphorylcholine coating of ePTFE grafts reduced neointimal hyperplasia in canine model. Ann Vase Surgery5 1997; 11 (1 ): 74-79. [10] Ishihara K, Nomura H, Mihara T, Kurita K, Iwasaki Y, Nakabayashi, N. Why do phospholipid polymers reduce protein adsorption? J Biomed Mater Res 1998; 39: 323-330. [11 ] Goreish HH, Lewis AL, Long S, Lloyd AW. The effect of o phosphorylcholine (PC) coated materials on the inflammatory response and fibrous capsule formation- in-vitro and in-vivo observations. J Biomed Mater Res 2003; 68A:231 -250. [12] Lewis AL, Stratford PW. Phosphorylcholine-coated stents. J Long Term Effects Med Implants 2002: 12, 231-250.5 [13] Guagliumi G, Musumeci G, Vassileva A, Tespili M, Valsecchi O. Through the drug-eluting stent labyrinth. Ital Heart J 2003; 4(4): 236-45. [14] Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. A randomized comparison of a sirolimus-eluting stent with a standard stent for 0 coronary revascularization. N Engl J Med. 2002; 346(23): 1773-80. [15] Grube E, Gerckens U, Muller R, Bullesfeld L Drug eluting stents: initial experiences. Z Kardiol. 2002; 91 (3): 44-8.

[16] Lewis AL, Berwick J, Davies MC, Wang JH, Small S, Dunn A, Redman R. and Jones, SA: Synthesis and charactiersation of cationically-modified phospholipid polymers Biomaterials 2004; 25(15):5125-5135. [17] Long SF, Lewis AL, Hanlon GW, Lloyd AW. Differential cell adhesion to phosphorylcholine polymers with varying cationic charge. Eur Cells Materials 2001; 2(Suppl 1); 50.

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Claims

CLAIMS 1. An orthopaedic implant device having a surface which will, in use, contact bone formed of osteointegration-improving material characterised in that the said material comprises a polymer having pendant highly hydrophilic groups

5 . and having an overall charge at physiological pH. 2. A device according to claim 1 in which the highly hydrophilic groups are zwitterionic groups. 3. A device according to claim 2 in which the zwitterionic groups have no overall charge at physiological pH.0 4. A device according to claim 3 in which the zwitterionic group is an ammonium, phosphonium or sulfonium phosphate or phosphonate ester zwitterionic group. 5. A device according to claim 4 in which the zwitterionic group has the general formula II

in which the moieties A³ and A⁴, which are the same or different, are -O-,0 -S-, -NH- or a valence bond, preferably -O-, and W^" is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which is preferably a C.,_₁₂-alkanediyl group, preferably in which W⁺ is a group of formula -W¹-N⁺R³ ₃, -W¹-P⁺R⁴ ₃, -W¹-S⁺R ₂ or -W¹-Hef in which:5 W¹ is alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, which group W¹ optionally contains one or more fluorine o substituents and/or one or more functional groups; and either the groups R³ are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenyl, or two of the groups R³ together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R³ together with the nitrogen atom to which they are attached as heteroaromatic 5 ring having 5 to 7 atoms, either of which rings may be fused with another saturated or unsaturated ring to form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R³ is substituted by a hydrophilic functional group, and the groups R⁴ are the same or different and each is R³ or a group OR³,0 where R³ is as defined above; or Het is an aromatic nitrogen-, phosphorus- or sulphur-, preferably nitrogen-, containing ring, for example pyridine. 6. A device according to claim 5 in which the zwitterionic group has the general formula III

where the groups R⁵ are the same or different and each is hydrogen or C^0 alkyl, and m is from 1 to 4, in which preferably the groups R⁵ are the same preferably methyl. 7. A device according to any preceding claim in which the polymer has pendant ionic groups different to the pendant highly hydrophilic groups. 8. A device according to any preceding claim in which the polymer is5 crosslinked in the material. 9. A device according to any preceding claim in which the polymer is obtainable by polymerisation of ethylenically unsaturated monomers including a monomer having a highly hydrophilic substituent group, a monomer having an ionic substituent group, a surface adherent monomer and a crosslinkable o monomer capable of crosslinking after said polymerisation. 10. A device according to claim 9 in which the zwitterionic monomer has the general formula I Y B X I in which Y is an ethylenically unsaturated group selected from H₂C=CR-CO-A-, H₂C=CR-C₆H₄-A¹-, H₂C=CR-CH₂A², R²O-CO-CR=CR-CO-O, RCH=CH-CO-O-, 5 RCH=C(COOR²)CH₂-CO-O,

A is -O- or NR¹; A¹ is selected from a bond, (CH₂)A² and (CH₂), SO₃- in which I is 1 to 12; A² is selected from a bond, -O-, O-CO-, CO-O, CO-NR¹-, -NR¹-CO, O-CO-NR¹-, and NR¹-CO-O-;5 R is hydrogen or C_M alkyl; R¹ is hydrogen, C^. alkyl or BX. R² is hydrogen or C_M alkyl; B is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine0 substituents; X is the zwitterionic group. 11. A device according to claim 10 in which Y is H₂C = CR-CO-A-, preferably in which A is O and R is selected from hydrogen and methyl. 12. A device according to claim 10 or claim 11 in which B is an5 alkanediyl group, preferably having 2 to 6 carbon atoms, preferably being straight chain. 13. A device according to any of claims 9 to 12 in which the monomer having an ionic substituent is a compound of general formula (XII) Y²-B¹-Q (XII) o where Y² is an ethylenically unsaturated polymerisable group selected from H₂C=CR⁶-CO-A⁵-, H₂C=CR⁶-C₆H₄-A⁶-, H₂C=CR⁶-CH₂A⁷, R⁷O-CO-CR⁶=CR⁶-CO-O, R⁶CH=CH-CO-O-, R⁶CH=C(COOR⁷)CH₂-CO-O,

where R⁶ is hydrogen or C C₄ alkyl; R⁷ is hydrogen, C^-alkyl or B¹Q; A⁵ is -O- or -NR⁸-, wherein R²⁷ is hydrogen or a C_rC₄ alkyl group or R⁸ is0 a group -B¹-Q; A⁶ is selected from a bond, (CH₂)_nA⁷ and (CH₂)_nSO₃ in which n is 1 to 12; A⁷ is selected from a bond, O, OCO, COO, CONR⁸, NR⁸CO, OCONR⁸ and NR⁸COO; B¹ is a valence bond, a straight or branched alkylene, oxaalkylene or5 oligo-oxaalkylene group; Q is an ionic group, or, where Y is H₂C=CR⁶COO, H₂C=CR⁶CH₂NR⁸, R⁷OCOCR⁶=COO, R⁶CH=C(COOR⁷)CH₂COO and B¹ is a valence bond Q may be hydrogen. 14. A device according to claim 13 in which the said ionic substituent0 is is anionic and is selected from the group consisting of carboxylate, sulphonate, phosphonate and phosphate. 15. A device according to claim 13 in which the ionic group Q is cationic, and is preferably selected from a group -NR⁹ ₃ ^Θ in which each group R⁹ is the same or different, and is hydrogen or alkyl of 1 to 6 carbon atoms two of5 which groups R⁹ may together from a heterocyclic ring containing from 5 to 7 atoms, preferably hydrogen or methyl, a group N^ΘHet, where Het is an unsaturated heterocyclic group such as pyridyl, substituted or unsubstituted by one or more alkyl groups of 1 to 4 carbon atoms, and a group -PR¹⁰ ₃ ^Θ in which each group R¹⁰ is the same or different and is hydrogen or alkyl of 1 to 6 o carbons atoms, two of which groups R³¹ may together form a heterocyclic ring containing from 5 to 7 atoms, preferably methyl.

16. A device according to any of claims 9 to 15 in which the crosslinkable monomer has general formula (IX) Y³-Q¹ (IX) where Y³ is an ethylenically unsaturated polymerisable group selected from H₂C=CR¹¹-CO-A⁸-, H₂C=CR¹¹-C₆H₄-A⁹-, H₂C=CR¹¹-CH₂A¹⁰, R¹²O-CO- CR¹¹=CR¹¹-CO-O, R¹¹CH=CH-CO-O-, R¹¹CH=C(COOR¹²)CH₂-CO-O,

where R¹¹ is hydrogen or C,-C₄ alkyl; A⁸ is O or NR¹³; A⁹ is selected from a bond, (CH₂)_pA¹⁰ and (CH₂)_pSO₃ in which p is 1 to 12; A¹⁰ is selected from a bond, O, OCO, COO, CONR¹³, NR¹³CO, OCONR¹³ and NR¹³COO; R¹² is hydrogen, C_1-4-alkyl or Q¹; R¹³ is hydrogen, C₄₁_-alkyl or Q¹. Q¹ is a crosslinkable group. 17. A device according to claim 16 in which Q¹ contains a group selected from cinnamyl, epoxy, -CHOHCH₂Hal (in which Hal is a halogen atom), methylol, reactive silyl (e.g. alkoxy silyl), an ethylenically unsaturated crosslinkable group, such as an acetylenic, diacetylenic, vinylic or divinylic group, acetoacetoxy and chloroalkyl sulfone, preferably chloroethyl sulphone, group. 18. A device according to claim 17 in which the crosslinkable monomer is 3-(trimethoxysilyl)propyl methacrylate. 19. A device according to any of claims 9 to 18 in which the surface adherent monomer is a compound of general formula (VI) Y¹-Q² (VI) where Y¹ is an ethylenically unsaturated polymerisable group selected from H₂C=CR¹⁴-CO-A¹¹-, H₂C=CR¹⁴-C₆H₄-A¹²- H₂C=CR¹⁴-CH₂A¹³, R¹⁶O-CO- CR¹⁴=CR¹⁴-CO-O, R¹⁴CH=CH-CO-O-, R¹⁴CH=C(COOR¹⁶)CH₂-CO-O,

where R¹⁴ is hydrogen or C C₄ alkyl, A¹¹ is -O- or -NR¹⁵- where R¹⁵ is hydrogen or a C_rC₄ alkyl group or R¹⁵ is0 a group Q²; A¹² is selected from a bond, (CH₂)_q A¹³ and (CH₂)_qSO₃ in which q is 1 to 12; A¹³ is selected from a bond O, OCO, COO, CONR¹⁵, NR¹⁵CO, OCONR¹⁵ and NR¹⁵COO;5 R¹⁶ is hydrogen, C^ alkyl or Q². Q² is (a) a straight or branched alkyl, alkoxyalkyl or (oligo-alkoxy)alkyl chain containing 6 or more, preferably 6 to 24, carbon atoms unsubstituted or substituted by one or more fluorine atoms and optionally containing one or more carbon-carbon double or triple bonds; or0 (b) a siloxane group -(CR^17a ₂)_r (SiR¹⁸ ₂) (OSiR¹⁸ ₂)_sR¹⁸ in which each group R¹⁷ is the same or different and is hydrogen or alkyl of 1 to 4 carbon atoms or aralkyl, for example benzyl or phenethyl, each group R¹⁸ is alkyl of 1 to 4 carbon atoms, r is from 1 to 6 and s is from 0 to 49. 20. A device according to claim 19 in which Y¹ is H₂C=CR¹⁴ COA¹¹-, in5 which A¹¹ is preferably O, and R¹⁴ is preferably selected from hydrogen and methyl. 21. A device according to claim 19 or claim 20 in which Q² is an alkyl group of formula -(CR¹⁹ ₂)_tCR¹⁹ ₃ wherein the groups -(CR¹⁹ ₂)- are the same or different, and in each group -(CR¹⁹ ₂)the groups R¹⁹ are the same or different and o each group R¹⁹ is hydrogen, fluorine or C_1-4 alkyl or fluoroalkyl and t is from 5 to 23 if Q² contains no fluorine atoms or from 1 to 23, preferably 5 to 23, if Q² contains one or more fluorine atoms; an alkoxyalkyl having 1 to 12 carbon atoms in each alkyl moiety; unsubstituted or substituted by one or more fluorine atoms; or an (oligo-alkoxyl) alkyl group of formula -[(CR²⁰ ₂)_nO]_u (CR²⁰ ₂)_VR²⁰ where 5 the groups -(CR²⁰ ₂)- are the same or different and in each group -(CR²⁰ ₂)- the groups R²⁰ are the same or different and each group R¹⁸ is hydrogen, fluorine or C_M alkyl or fluoroalkyl and u is from 2 to 6, preferably 3 to 4, and v is from 1 to 12. 22. A device according to any preceding claim in which the material is0 in the form of a coating on a device body, wherein the body is formed of stainless steel, titanium, ceramics or plastics. 23. A device according to claim 22 which is selected from hip implants, knee joints, finger joints, elbow replacements, bone screws and pins, permanent fixation devices, spinal discs, bone defect filling materials, dental5 implants, cranio-maxillofacial devices, bone plates, bone and dental cements. 24. Use of a polymer in the manufacture of an orthopaedic device having said polymer in the material of the surface of the device which will in use contact bone to increase the osteointegration of the device, increase adhesion of osteoblasts to the device, increase the rate of mineralisation on the surface of o the device, or increase the level of expression of alkaline phosphatase in osteoblasts growing on the surface of the device, in which the material comprises a polymer as defined in any preceding claim. 25. A surgical method in which an orthopaedic device according to any of claims 1 to 23 is implanted into an animal in contact with bone.5 26. A process of manufacturing an orthopaedic device in which a device body is provided at least on a part of its bone-contacting surface with a coating of a polymer as defined in any of claims 1 to 21. 27. A process according to claim 26 in which the coating is provided by contacting a liquid coating composition comprising a solvent and a coating o polymer and removing the solvent to leave the coating polymer on the surface. 28. A process according to claim 27 in which the solvent is removed by evaporation. 29. A process according to claim 27 or claim 28 in which the coating polymer is cross-linkable and is cross-linked after coating, preferably by heating. 30. A process according to any of claims 27 to 29 in which the solvent is an alcohol, preferably ethanol.