Bio-compatible polymeric materials

BIO-COMPATIBLE POLYMERIC MATERIALS This invention relates to bio-compatible polymeric materials and particularly, although not exclusively, provides a bio-compatible polymeric material, a method of producing such a material and the use of such a material in medical treatment, for example in a prosthesis.

Much research is being directed to the provision of materials to meet the growing need for prosthetic devices such as orthopaedic, dental or maxillofacial implants.

For example, nearly half a million patients receive bone implants each year in the US with the majority being artificial hip and knee joints made from titanium or colbalt-chrome alloys. However, these materials are too stiff leading to bone resorption, loosening of the implant and, consequently, have'lifetimes of less than 10 years.

Additionally, medical devices or prostheses such as pacemakers, vascular grafts, stents, heart valves, catheters and dental implants that contact body tissues or fluids of living persons or animals have been developed and used clinically.

A major problem with medical devices such as those described is the susceptibility to foreign body reaction and possible rejection. Consequently, it is of great interest to the medical industry to develop materials from which medical devices can be made which are less prone to adverse biological reactions that typically accompany introduction of medical devices into humans or animals.

It is known to functionalise polymers with biocompatible moieties. However, known functionalised polymers tend to have a relatively low concentration of associated bio-compatible moieties.

It is an object of the present invention to address the above described problems.

According to a first aspect of the invention, there is provided a bio-compatible polymeric material comprising a polymer having functionalised ketone groups in the polymer backbone, wherein ketone groups in the polymer backbone have been functionalised to provide at least two moieties per ketone group which moieties are associated with a part of a bio-compatible moiety.

Except where otherwise stated, throughout this specification, any alkyl, akenyl or alkynyl moiety suitably has up to 8, preferably up to 6, more preferably up to 4, especially up to 2, carbon atoms and may be of straight chain or, where possible, of branched chain structure. Generally, methyl and ethyl are preferred alkyl groups and C2 alkenyl and alkynyl groups are preferred.

Except where otherwise stated in this specification, optional substituents of an alkyl group may include halogen atoms, for example fluorine, chlorine, bromine and iodine atoms, and nitro, cyano, alkoxy, hydroxy, amino, alkylamino, sulphinyl, alkylsulphinyl, sulphonyl, alkylsulphonyl, amido, alkylamido, alkoxycarbonyl, haloalkoxycarbonyl and haloalkyl groups. Preferably, optionally substituted alkyl groups are unsubstituted.

Said functionalised ketone groups may comprise-Cmoieties in the polymer backbone wherein said-C-moieties are functionalised to provide at least two moieties per -C-moiety, each of which two moieties is associated with a part of a bio-compatible moiety.

In the scientific literature there is inconsistency in the use of descriptions such as"bio-compatible","bio-active"and"bio-materials". In the context of the present specification, the term"bio-compatible"has generally been used to refer to a material which is compatible with use in medical applications, for example by not being toxic or otherwise harmful to living materials. It also encompasses materials which have a biological or physiological effect when associated with living materials.

"Rio-compatible moieties"referred to herein suitably refer to moieties which are compatible with use in medical applications, for example by not being toxic or otherwise harmful to living material. Such bio-compatible moieties may be arranged to bond (for example to form ionic or covalent bonds) or otherwise interact with materials present in human or animal bodies in order to improve their integration and acceptance by such bodies.

Preferably, said bio-compatible polymeric material has improved or enhanced bio-compatibility compared to said polymer in the absence of associated bio-compatible moieties.

Bio-compatible moieties suitably include moieties arranged to reduce adverse biological reactions when the polymeric material is introduced into (or otherwise associated with) a human or animal body. For example, adverse biological reactions associated with introduction into a human or animal body of said polymer having said bio-compatible moieties may be less compared to use of the same polymer but which does not include associated biocompatible moieties.

Said polymer having functionalised ketone groups may comprise an aliphatic polyketone wherein ketone groups thereof have been functionalised. Said polymer having functionalised ketone groups may include a polymer back bone which includes moieties of formula EMI4.1 where the starred carbon atoms represent functionalised ketone groups. The proportion of the respective moieties shown may be varied to adjust the properties of the polymer.

Aliphatic ketones which can be functionalised as described herein are sold under the Trade Marks CARILON and KETONEX by Shell and BP respectively.

Preferably, said bio-compatible polymeric material comprises a polymer having phenyl groups, functionalised ketone groups and ether or thioether groups in the polymer backbone.

Preferably, said bio-compatible polymeric material comprises a polymer having a moiety of formula EMI5.1 and/or a moiety of formula EMI5.2 and/or a moiety of formula EMI5.3 wherein the phenyl moieties in units I, II, and III are independently optionally substituted and optionally crosslinked;

and wherein m, r, s, t, v, w and z independently represent zero or a positive integer, E and E' independently represent an oxygen or a sulphur atom or a direct link, G represents an oxygen or sulphur atom, a direct link or a-O-Ph-O-moiety where Ph represents a phenyl group and Ar is selected from one of the following moieties (i) *, (i) **, (i) to (x) which is bonded via one or more of its phenyl moieties to adjacent moieties EMI6.1 EMI7.1

EMI7.2 wherein said polymer includes ketone groups which have been functionalised to provide at least two moieties per ketone group which moieties are associated with a part of a biocompatible moiety.

Thus, preferably, some ketone groups of said polymer are replaced by-C-moieties in the polymer backbone, wherein said-C-moieties include at least two moieties per -C-moiety, each of which two moieties being associated with part of a bio-compatible moiety.

Unless otherwise stated in this specification, a phenyl moiety may have 1,4- or 1,3-, especially 1,4-, linkages to moieties to which it is bonded.

Said polymer may include more than one different type of repeat unit of formula I ; more than one different type of repeat unit of formula II ; and more than one different type of repeat unit of formula III. Preferably, however, only one type of repeat unit of formula I, II and/or III is provided.

Polymers of the type described may be prepared as described in PCT/GB99/02833.

Said moieties I, II and III are suitably repeat units.

In the polymer, units I, II and/or III are suitably bonded to one another-that is, with no other atoms or groups being bonded between units I, II, and III.

Where the phenyl moieties in units I, II or III are optionally substituted, they may be optionally substituted by one or more halogen, especially fluorine and chlorine, atoms or alkyl, cycloalkyl or phenyl groups. Preferred alkyl groups are Cl-lo, especially C14, alkyl groups.

Preferred cycloalkyl groups include cyclohexyl and multicyclic groups, for example adamantyl.

Another group of optional substituents of the phenyl moieties in units I, II or III include alkyls, halogens, CyF2y+l where y is an integer greater than zero, O-Rq (where Rq is selected from the group consisting of alkyls, perfluoralkyls and aryls), CF=CF2, CN, NO2 and OH.

Trifluormethylated phenyl moieties may be preferred in some circumstances.

Preferably, said phenyl moieties are not optionallysubstituted as described.

Where said polymer is cross-linked, it is suitably cross-linked so as to improve its properties. Any suitable means may be used to effect cross-linking. For example, where E represents a sulphur atom, cross-linking between polymer chains may be effected via sulphur atoms on respective chains.. Preferably, said polymer is not optionally cross-linked as described.

Where w and/or z is/are greater than zero, the respective phenylene moieties may independently have 1,4or 1, 3-linkages to the other moieties in the repeat units of formulae II and/or III. Preferably, said phenylene moieties have 1,4- linkages.

Preferably, the polymeric chain of the polymer does not include a-S-moiety. Preferably, G represents a direct link.

Suitably,"a"represents the mole % of units of formula I in said polymer, suitably wherein each unit I is the same ;"b"represents the mole % of units of formula II in said polymer, suitably wherein each unit II is the same; and"c"represents the mole % of units of formula III in said polymer, suitably wherein each unit III is the same.

Preferably, a is in the range 45-100, more preferably in the range 45-55, especially in the range 48-52.

Preferably, the sum of b and c is in the range 0-55, more preferably in the range 45-55, especially in the range 4852. Preferably, the ratio of a to the sum of b and c is in the range 0.9 to 1.1 and, more preferably, is about 1. Suitably, the sum of a, b and c is at least 90, preferably at least 95, more preferably at least 99, especially about 100. Preferably, said polymer consists essentially of moieties I, II and/or III.

Said polymer may be a homopolymer having a repeat unit of general formula EMI10.1 or a homopolymer having a repeat unit of general formula EMI10.2 or a random or block copolymer of at least two different units of IV and/or V wherein A, B, C and D independently represent 0 or 1 and E, E', G, Ar, m, r, s, t, v, w and z are as described in any statement herein.

As an alternative to a polymer comprising units IV and/or V discussed above, said polymer may be a homopolymer having a repeat unit of general formula EMI11.1 or a homopolymer having a repeat unit of general formula EMI11.2 or a random or block copolymer of at least two different units of IV* and/or V*, wherein A, B, C, and D independently represent 0 or 1 and E, E', G, Ar, m, r, s, t, v, w and z are as described in any statement herein.

Preferably, m is in the range 0-3, more preferably 0-2, especially 0-1. Preferably, r is in the range 0-3, more preferably 0-2, especially 0-1. Preferably t is in the range 0-3, more preferably 0-2, especially 0-1.

Preferably, s is 0 or 1. Preferably v is 0 or 1.

Preferably, w is 0 or 1. Preferably z is 0 or 1.

Preferably, said polymer is a homopolymer having a repeat unit of general formula IV. Preferably Ar is selected from the following moieties (xi) *, (xi) **, (xi) to (xxi) : EMI12.1 EMI13.1

In (xi) *, the middle phenyl may be 1,4- or 1,3substituted.

Preferably, (xv) is selected from a 1,2-, 1,3-, or a 1,5- moiety; (xvi) is selected from a 1,6-, 2,3-, 2,6- or a 2,7- moiety; and (xvii) is selected from a 1,2-, 1,4-, 1,5-, 1,8- or a 2,6- moiety.

One preferred class of polymers does not include any moieties of formula III, but suitably only includes moieties of formulae I and/or II. Where said polymer is a homopolymer or random or block copolymer as described, said homopolymer or copolymer suitably includes a repeat unit of general formula IV. Such a polymer may, in some embodiments, not include any repeat unit of general formula V.

Suitable moieties Ar are moieties (i) *, (i), (ii), (iii) and (iv) and, of these, moieties (i) *, (i) and (iv) are preferred. Other preferred moieties Ar are moieties (xi) *, (xii), (xi), (xiii) and (xiv) and, of these, moieties (xi) *, (xi) and (xiv) are especially preferred.

An especially preferred class of polymers are polymers which consist essentially of phenyl moieties in conjunction with ketone and/or ether moieties wherein ketone moieties have been functionalised as described. That is, in the preferred class, the polymer does not include repeat units which include-S-,-S02-or aromatic groups other than phenyl. Preferred polymers of the type described include: (a) a polymer consisting essentially of units of formula IV wherein Ar represents moiety (iv), E and E'represent oxygen atoms, m represents 0, w represents 1, G represents a direct link, s represents 0, and A and B represent 1 (i. e. polyetheretherketone).

(b) a polymer consisting essentially of units of formula IV wherein E represents an oxygen atom, E' represents a direct link, Ar represents a moiety of structure (i), m represents 0, A represents 1, B represents 0 (i. e. polyetherketone); (c) a polymer consisting essentially of units of formula IV wherein E represents an oxygen atom, Ar represents moiety (i) *, m represents 0, E' represents a direct link, A represents 1, B represents 0, (i. e. polyetherketoneketone).

(d) a polymer consisting essentially of units of formula IV wherein Ar represents moiety (i), E and E'represent oxygen atoms, G represents a direct link, m represents 0, w represents 1, r represents 0, s represents 1 and A and B represent 1. (i. e. polyetherketoneetherketoneketone).

(e) a polymer consisting essentially of units of formula IV, wherein Ar represents moiety (iv), E and E'represents oxygen atoms, G represents a direct link, m represents 0, w represents 0, s, r, A and B represent 1 (i. e. polyetheretherketoneketone).

Of the aforesaid, the polymers described in (a) and (b) are preferred, with the polymer described in (a) being especially preferred.

In each of the preferred polymers described, at least some ketone groups have been functionalised as described.

Preferably, ketone groups of said polymer at or adjacent to a surface of the bio-compatible material have been functionalised to provide said at least two moieties as described and, suitably, ketone groups within the bulk of said polymer are not functionalised. Thus, preferably, the bulk of said polymer is different compared to a region of the polymer at or adjacent a surface thereof. Thus, the concentration of ketone moieties within the bulk of said bio-compatible polymeric material is preferably greater than the concentration of ketone moieties at or adjacent the surface of said material.

Bio-compatible moieties are preferably associated with the surface of said bio-compatible polymeric material and, suitably, do not substantially penetrate the bulk of the material. The concentration of bio-compatible moieties at a surface of said bio-compatible polymeric material is preferably greater than the concentration in the bulk of the material.

The invention extends to a bio-compatible polymeric material comprising a polymer having bio-compatible moieties associated with its surface and a lower concentration of bio-compatible moieties associated with its bulk, wherein the bulk comprises a polymer having phenyl groups, ketone groups and ether or thioether groups in the polymer backbone. Preferably, the polymer in the bulk and the polymer at the surface of said bio-compatible material are the same except that ketone moieties of said polymer at the surface have been functionalised.

The invention further extends to a bio-compatible polymeric material comprising a polymer having associated bio-compatible moieties, wherein the bulk of said biocompatible polymeric material comprises a polymer having phenyl groups, ketone groups and ether or thioether groups in the polymer backbone and the surface of said biocompatible polymeric material comprises a polymer which has a lower concentration of ketone groups compared to the concentration of ketone groups in the bulk, wherein biocompatible moieties are associated with said polymer at said surface.

Since said polymer having associated bio-compatible moieties is suitably present only at a surface of said bio-compatible polymeric material and is present at a small fraction of the total weight of polymer (the majority of which will not include associated biocompatible moieties) the existence of said bio-compatible moieties may have limited effect on the bulk properties of said bio-compatible polymeric material compared to said polymer in the absence of said associated bio-compatible moieties.

The glass transition temperature (Tg) of said polymer, suitably the bulk thereof, (in the absence of associated bio-compatible moieties) may be at least 135 C, suitably at least 150 C, preferably at least 154 C, more preferably at least 160 C, especially at least 164 C. In some cases, the Tg may be at least 170 C, or at least 190 C or greater than 250 C or even 300 C.

Said polymer, suitably the bulk thereof, (in the absence of associated bio-compatible moieties) may have an inherent viscosity (IV) of at least 0.1, suitably at least 0.3, preferably at least 0.4, more preferably at least 0.6, especially at least 0.7 (which corresponds to a reduced viscosity (RV) of least 0.8) wherein RV is measured at 25 C on a solution of the polymer in concentrated sulphuric acid of density 1.84gcm?3, said solution containing Ig of polymer per 100cm?3 of solution. IV is measured at 25 C on a solution of polymer in concentrated sulphuric acid of density 1.84gcm3, said solution containing 0. 1g of polymer per 100cm3 of solution.

The measurements of both RV and IV both suitably employ a viscometer having a solvent flow time of approximately 2 minutes.

The main peak of the melting endotherm (Tm) for said polymer, suitably the bulk thereof, (if crystalline) may be at least 300 C.

Preferably, said polymer, suitably the bulk thereof, (in the absence of associated bio-compatible moieties) has at least some crystallinity or is crystallisable. The existence and/or extent of crystallinity in a polymer is preferably measured by wide angle X-ray diffraction, for example as described by Blundell and Osborn (Polymer 24, 953,1983). Alternatively, crystallinity may be assessed by Differential Scanning Calorimetry (DSC).

Said polymer, suitably the bulk thereof, (in the absence of associated bio-compatible moieties) may have a number average molecular weight in the range 2000-80000.

Preferably, said molecular weight is at least 14,000. The molecular weight may be less than 60,000.

Said bio-compatible polymeric material may consist essentially of a single type of polymer with associated bio-compatible moieties (although the bulk of the material may include a polymer which does not have associated biocompatible moieties and/or functionalised ketone groups).

Preferably, the bulk of said bio-compatible polymeric material consists essentially of a single polymer.

Alternatively, said bio-compatible polymeric material, for example the bulk thereof, may comprise a blend of polymers, suitably having different molecular weights.

For example, a blend may comprise a relatively low molecular weight polymer and a relatively high molecular weight polymer.

Where a blend comprises a relatively low molecular weight polymer, the molecular weight of said low molecular weight polymer may be less than 14,000, but preferably greater than 2,000. The relatively high molecular weight polymer may have a molecular weight of at least 14,000 and suitably less than 80,000, especially less than 60,000.

Said bio-compatible polymeric material suitably has a tensile strength (according to ISO R527) of at least 80, preferably at least 90, especially at least 95 MPa. The tensile strength may be less than 360, suitably less than 250, preferably less than 140 MPa. It preferably has an elongate at break (according to ISO R527) of at least 40, preferably at least 50%. It preferably has a tensile modulus (according to ISO R527) of greater than 2.5, preferably greater than 3, especially greater than 3.5 GPa. The tensile modulus may be less than 40, suitably less than 30, preferably less than 20, more preferably less than 10 GPa. It preferably has a flexural strength (according to ASTM D695) of at least 100, more preferably at least 110, especially at least 115 MPa.

The flexural strength may be less than 650, preferably less than 400, more preferably less than 260, especially less than 200 MPa. It preferably has a flexural modulus (according to ISO R178) of at least 3, preferably at least 3.5, especially at least 4 GPa. The flexural modulus may be less than-60, suit-aly-Dess than? 25, preferably less than 20 especially less than 10 GPa. Advantageously, the aforementioned properties can be adjusted by appropriate selection of polymers and/or any reinforcement means included in said support material to suit particular applications. For example, a continuous carbon fibre polyetheretherketone may typically have a tensile strength of about 350 MPa, a tensile modulus of 36 GPa, an elongation of 2%, a flexural modulus of 50 GPa and a flexural strength of 620 MPa.

A polyaryletherketone with 30% of high performance fibres may typically have a tensile strength of 224 MPa, a tensile modulus of 13 GPa, a tensile elongation of 2%, a flexural modulus of 20 GPa and a flexural strength of 250 MPa.

Said bio-compatible polymeric material may include one or more fillers for providing desired properties. Said material preferably incorporates an X-ray contrast medium.

Fillers and/or said X-ray contrast medium is/are preferably distributed substantially uniformly throughout said material.

Where an X-ray contrast medium is provided it suitably comprises less than 25wt%, preferably less than 20wt%, more preferably less than 15wt%, especially less than 10wt% of said bio-compatible material. Where it is provided, at least 2wt% may be included. Preferred X-ray contrast mediums are particulate and preferably are inorganic. They preferably have low solubility in body fluids. They preferably also have a sufficient density compared to that of the polymer to create an image if a compounded mixture of the polymer and contrast medium are X-ray imaged.

Barium sulphate and zirconium oxide are examples. Said particulate material is suitably physically held in position by entrapment within the polymer.

Preferably, said bio-compatible polymeric material includes a major amount of said polymer, especially one having moieties I, II and/or III, described according to said first aspect.

In the context of this specification, a"major"amount may mean greater than 50 wt%, suitably greater than 65 wt%, preferably greater than 80 wt%, more preferably greater than 95 wt%, especially greater than 98 wt% of the referenced material is present relative to the total weight of relevant material present.

Where said bio-compatible polymeric material comprises a blend, said blend preferably includes at least two polymers of a type according to said first aspect. For example, said at least two polymers preferably include moieties I, II and/or III as described above. A said blend preferably includes a major amount of higher (or the highest) number average molecular weight polymer. Said bio-compatible polymeric material preferably includes a major amount of a higher molecular weight polymer.

A said bio-compatible moiety may be selected from an anticoagulant agent such as heparin and heparin sulfate, an antithrombotic agent, a clotting agent, a platelet agent, an anti-inflammatory agent, an antibody, an antigen, an immunoglobulin, a defence agent, an enzyme, a hormone, a growth factor, a neurotransmitter, a cytokine, a blood agent, a regulatory agent, a transport agent, a fibrous agent, a protein-such as?avidtn, a-glycoprotein, a globular protein, a structural protein, a membrane protein and a cell attachment protein, a peptide such as a glycopeptide, a structural peptide, a membrane peptide and a cell attachment peptide, a proteoglycan, a toxin, an antibiotic agent, an antibacterial agent, an antimicrobial agent such as pencillin, ticarcillin, carbenicillin, ampicillin, oxacillian, cefazolin, bacitracin, cephalosporin, cephalothin, cefuroxime,

cefoxitin, norfloxacin, perfloxacin and sulfadiazine, hyaluronic acid, a polysaccharide, a carbohydrate, a fatty acid, a catalyst, a drug, biotin, a vitamin, a DNA segment, a RNA segment, a nucleic acid, a nucleotide, a polynucleotide, a nucleoside, a lectin, a ligand and a dye (which acts as a biological ligand), a radioisotope, a chelated radioisotope, a chelated metal, a metal salt, a sulphonic acid or salt thereof, a steroid, a non-steriod, a nonsteroidal anti-inflammatory, an analgesic, an antihistamine, a receptor binding agent, a chemotherapeutic agent, a hydrophilic polymer (e. g.

poly (ethylene glycol) (PEG), poly (ethylene oxide) (PEO), ethylene oxidepropylene oxide block co-polymers, poly (N-vinyl-2pyrrolidone) (PNVP), poly (2-hydroxyethyl methacrylate) (pHEMA), HEMA co-polymers, poly (vinyl alcohol) (PVA), polyacrylamide, its derivatives, poly (methyl methacrylate) (PMMA), suitably having a PEG chain on each of the side groups, polysiloxanes (e. g. polydimethylsiloxanes (PDMS)), ionic water-soluble polymers like poly (acrylic acid) (PAAc)) and a polyurethane. Examples of some of the aforesaid are provided in US5958430, US5925552, US5278063 and US5330911 and the contents of the aforementioned specifications are incorporated herein by reference.

In one embodiment, said bio-compatibLe ?moi-èties may comprise bone morphogenic protein (BMP) as described in US4563489 and patents cited therein and the contents of the aforesaid are incorporated herein. Said BMP may be provided in combination, for example in admixture, with a physiologically acceptable biodegradable organic polymer and said biodegradable polymer may be associated with at least one of said at least two moieties of said polymer of said bio-compatible polymeric material, for example by being covalently bonded to said at least one of said two moieties. Thus, in this case, the combination of said biodegradable polymer and BMP defines said bio-compatible moieties.

Said biodegradable polymer is preferably a biodegradable polylactic acid; or alternatively, other physiologically acceptable biodegradable organic polymers which are structurally equivalent to polylactic acid can be used as the delivery system for BMP. Examples include poly (hydroxy organic carboxylic acids) e. g. poly (hydroxy aliphatic carboxylic acids), polyglycollic acid, polyglactin, polyglactic acid and poly adonic acids.

In another embodiment, said bio-compatible moieties may be selected from inorganic crystalline structures, inorganic amorphous structures, organic crystalline structures and organic amorphous structures. Preferred bio-compatible moieties are phosphorous based ceramics, for example calcium-phosphorous ceramics. Phosphates in general are suitable but calcium phosphates and calcium apatite are preferred. Especially preferred is hydroxyapatite, a synthetic Ca-P ceramic.

Whilst said bio-compatible moieties may be associated by any suitable means with said ketone group which have been functionalised, for example by covalent bond (s), hydrogen bond (s), encapsulation in a matrix which is bonded to or otherwise interacts with said functionalised groups, or by ionic interaction (s), it is preferred that there are covalent bonds between the bio-compatible moieties and said at least two moieties or there are ionic interactions between said bio-compatible moieties and said at least two moieties.

Ketone groups (-CO-) in said polymer backbone, for example at least one ketone group in moieties I, II and/or III, may be replaced by: EMI24.1 EMI25.1

EMI25.2

VIII wherein L1 and L4 represent linking groups which are disubstituted by moieties K1 and K2 either on the same or different atoms; L2 and L3 independently represent direct links or linking groups which are substituted by moieties K3 and K4 respectively ; or BM1 and BM2 represent biocompatible moieties associated with Kl, K2, K3 and K4, wherein BM1 and BM2 may represent separate moieties or may represent a single moiety which is associated with both K1 and K2 ;

Kl, K2, K3 and K4 represent moieties associated with bio-compatible moieties; and K5 represents a moiety which may, but preferably does not, include a linking group and/or an associated bio-compatible moiety.

Preferably, K5 represents a moiety which is not associated and/or associatable with a bio-compatible moiety, for example a moiety BM1 or BM2. Preferably, K5 represents a hydrogen atom.

It should be appreciated that each moiety L1, LL3 orL4 may be functionalised with further moieties K1,K2,K3,K4 and such further moieties may be associated with biocompatible moieties. Preferably, however, L1, L2, L3 and L4 are substituted only by the number of moieties shown.

Each of Kl,K2, K3 and K4 (and, optionally, K5) may independently include one of the following functional groups or may include the residue of one of the following functional groups (after association with BM1 and BM2) thereby to enable Kl, K2, K3 and K4 (and, optionally, K5) to associate with bio-compatible moieties (e. g.

BM1 and BM2) : -OH, -CHO, -NR102, preferably -NH2 or -NHR10, -SH, @CONHz,-CONHRl ,-COOH,-COC1 or -COOR10 group, a halogen atom, especially a fluorine, chlorine, bromine or iodine atom, -NO2, -SO3M, -SO2R11, -SO2NHR10, -SO2NR102 or-COOM groups, an anhydride, an epoxide, a cyanate,-CN, an isocyanate, a carbon-carbon double bond, for example a group-CRl =CRl 2 or a (Co-Cloalk) acrylate (wherein"alk"refers to an alkyl group) such as-COOC (CH3) CH2 and-COOCHCH2, a carbon-carbon triple bond, for example a group-CR1 or an azide, wherein R1 represents a hydrogen atom or an optionally substituted alkyl group, wherein M represents a hydrogen atom or an alkali metal and R11 represents a halogen,

especially a chlorine, atom.

Each of L1, L2, L3 and L4 may independently include any suitable linking group and such linking groups may include saturated, unsaturated, linear, branched or cyclic moieties. Preferred linking groups include optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl e. g.-Nalkyl, aryl, heteroaryl, e. g. pyridyl, alkylaryl, hetero (aryl) alkyl, e. g.-O-aryl-alkyl, (hetero) heteroaryl e. g.-N-heteroaryl and (hetero) aryl e. g.-0-aryl.

Examples of groups of formula VI (excluding BM1 and BM2) include EMI27.1

Examples of groups of formula VII (excluding BM1 andBM2) include EMI27.2 EMI28.1

Examples of groups of formula VIII (excluding BM1 and BM2)include EMI28.2

According to a second aspect of the invention, there is provided a method of making a bio-compatible polymeric material for use in medical applications, the method include the steps of: selecting a polymer having ketone groups in the polymer backbone; and (ii) functionalising ketone groups in said polymer to provide at least two moieties per ketone group which are associated with a bio compatible moiety or which moieties are in themselves bio-compatible moieties.

Said polymer selected in step (i) may be as described in any statement herein. It is preferably a polymer having phenyl groups, ketone groups, optionally sulphone groups, and ether or thioether groups. For example, it may include moieties I, II, III, IV, IV*, V or V*, suitably prior to functionalisation of any ketone groups thereof and provided of course that the polymer includes ketone groups.

Preferably, the moieties produced in step (ii) are not, in themselves, bio-compatible; preferably, ketone groups are functionalised to provide said at least two moieties and bio-compatible moieties are then associated with said at least two moieties.

Preferably, the method involves functionalising ketone groups in said polymer which are present at or adjacent a surface thereof, and, suitably, ketone groups within the bulk of said polymer are not functionalised in the manner described. Thus, the method preferably includes the step of functionalising said polymer so that the concentration of ketone moieties within the bulk of the polymer is greater than the concentration of ketone moieties at or adjacent the surface of said polymer.

Preferably, said polymer is presented as a solid, suitably shaped so as to represent at least part of a device for use in medical applications, and functionalised in the method. For example, said device may be a component of an implant for a human or animal body, for example an orthopaedic or dental implant or vascular graft. Said solid may be provided in a desired shape by any suitable means, for example by injection or compression moulding or by film formation techniques or extrusion.

Ketone groups in said polymer may be functionalised to provide said at least two moieties in a single treatment.

Example 1 hereinafter is of this type. Alternatively and preferably, the method may include a series of treatments to provide said at least two moieties. Examples 2,3,5, and 7 hereinafter are of this type. Preferably, functionalisation of ketone groups involves an initial step wherein said ketones groups are functionalised to form hydroxy groups. Hydroxy groups may be functionalised in subsequent treatments or may aid substitution or reaction of another group linked to the same carbon atom which carries a hydroxy group. Thus, functionalisation of ketone groups may include a step comprising treatment of said ketone groups to form hydroxy groups.

The method preferably includes the step of treating said polymer after functionalisation of ketone groups to provide said at least two moieties with a material for providing bio-compatible moieties (hereinafter"BCM material"). Said BCM material may be arranged to provide any of the bio-compatible moieties described herein. Said polymer may be provided as a solid. Suitably, said bio compatible moieties are caused to become associated with a surface of said solid, preferably with said at least two moieties at a surface of said solid. Said solid is preferably shaped so as to represent at least a part of a device for use in medical applications, as described above.

Preferably, after association with said biocompatible moieties, the bio-compatible polymeric material is not engineered or otherwise treated in a manner which may result in substantial depletion of the bio-compatible moieties associated with its surface.

Association of bio-compatible moieties with said at least two moieties may be effected in any suitable way which will depend on the nature of the BCM material and/or the identity of said at least two moieties formed by functionalising ketone groups of the polymer. In some embodiments, the method may include causing covalent bond formation between the polymer and said bio-compatible moieties. In other embodiments, association of said at least two moieties and bio-compatible moieties may be effected by other means, for example by ionic interactions. Bio-compatible moieties could be built up in a series of steps.

BCM material may include any suitable functional group that is arranged to become associated with functional groups resulting from functionalising ketone groups in the polymer backbone and may be selected from any of the functional groups referred to above for Kl,K2, K3, K4 and/or K5 provided that a selected functional group is capable of becoming associated with, suitably reacting, with a said functional group resulting from functionalising ketone groups in the polymer backbone.

In some cases BCM material may be provided by reaction of one or more functional groups resulting from functionalising ketone groups in the polymer backbone with more than one functional group. For example said biocompatible moieties may include a polyurethane which may be prepared: when one or more functional groups resulting from functionalising ketone groups in the polymer backbone is/are hydroxy groups and BCM material provides a diisocyanate and a diol; or when one or more functional groups resulting from functionalising ketone groups in the polymer backbone include isocyanate groups and BCM material provides a diisocyanate and a diol. Thus, in both cases, BCM material may be provided by use of two different compounds.

Preferably, ketone groups in said polymer are functionalised to: EMI32.1 a group IX EMI32.2 agroup X EMI33.1 or a group XI wherein L',L2,L3 and L4 are as described above; il, J2, J3 and J4 represent groups which can be associated with biocompatible moieties; and J5 represents a moiety which may be but is preferably not adapted to be associated with bio-compatible moieties.

J5 preferably represents a hydrogen atom.

J1, J2, J3 and J4 may independently represent any of the functional groups described above for Kl,K2,K3 and K4.

The method may include the step (s) of treating a polymer which includes groups IX, X or XI with a material *BM1 and/or *BM2 arranged to supply bio-compatible moieties BM1 and/or BM2 as described above such that, after said treatment (s), said groups IX, X, XI define groups VI, VII and VIII described above respectively. Alternatively, BM1 and/or BM2 may be built up in a series of steps and, in this case, a polymer which includes group IX, X or XI may be treated with a material *BM1 and/or *BM2 arranged to supply parts of bio-compatible moieties BM1 and/or BM2, with other parts thereof being supplied in subsequent treatment (s).

Where no covalent or ionic bonds are formed in the treatment (s), *BM1 and *BM2 may be the same as BM1 and BM2 respectively; and Jl,J2, J3 and J4 may be the same as Kl,K2,K3 and K4 respectively.

*BM I and *BM2 may include any functional groups arranged to become associated with Jl,J2, J3 or J4 and may be selected from any of the functional groups described above for K1, K2, K3 and K4 provided that a selected functional group is capable of becoming associated with, suitably reacting, with a selected functional group provided by J1, J2, J3 and J4 *BM1 and *BM2 may be the same or different.

Advantageously they are the same. In some cases *BM1 and *BM2 may be respective parts of a single entity, for example a single chemical compound, whereby after treatment with IX, X or XI said single entity may provide a bridge between Jl and J2 ; or J3 and J4. Preferably, however, *BM1 and *BM2 are not respective parts of a single entity.

Polymers described herein may be prepared as described in PCT/GB99/02833.

According to a third aspect of the present invention, there is provided a device for use in medical applications, wherein said device includes a biocompatible polymeric material according to said first aspect or made in a method according to said second aspect.

Said device is preferably a prosthetic device, for example an implant such as an orthopaedic, dental or maxillofacial implant or a component thereof; or a device, for example a catheter, which is arranged to be temporarily associated with a human or animal body. Said device is preferably a prosthetic device as described. An orthopaedic device may be an implant for a body joint, for example a hip or knee joint or spine fusion device.

A said device may include a part or parts made out of said bio-compatible polymeric material-and a part or part made out of other materials. Suitably, however, said device includes at least 50wt%, preferably at least 65wt%, more preferably at least 80wt%, especially at least 95wt% of said bio-compatible polymeric material. In some embodiments said device may consist essential of said biocompatible polymeric material.

According to a fourth aspect, there is provided a method of making a device according to the third aspect, the method comprising: forming a material into a shape which represents or is a precursor of a device or a part of a device for use in medical applications wherein said material comprises a polymer; and treating material in said shape (preferably the surface thereof) thereby to functionalise ketone groups in said polymer to provide at least two moieties per ketone group which are associated with a bio-compatible moiety or which moieties are themselves bio-compatible moieties.

The invention extends to the use of a polymer having carbon atoms (suitably derived from ketone groups) in its polymer backbone which carbon atoms include one or more pendent groups which is/are associated with respective parts of one or more bio-compatible moieties, wherein at least two parts of one or more pendent groups of a respective said carbon atom are associated with at least two part (s) of one or more bio-compatible moieties.

Any feature of any aspect of any invention or embodiment described herein may be combined with any feature of any aspect of any other invention or embodiment described herein.

Specific embodiments of the invention will now be described by way of example.

The following material is referred to hereinafter: PEEK (Trade Mark)-polyetheretherketone obtained from Victrex Plc of England.

All chemicals referred to were used as received from Sigma-Aldrich Company, Dorset, U. K., unless otherwise stated.

All PEEK films used were approximately 120Am thick.

Film samples were prepared from samples of Victrex PEEK (Melt Viscosity 0.45 kNgm-2 at 1000 sec-1 at 400 C) powder which was compression moulded between metal plates using a Moore laboratory hot press at 400 C for 5 to 10 minutes.

The PEEK melt was quenched in ice-cold water in order to obtain 120Am thick amorphous samples. The film samples were refluxed in acetone for 72 hours prior to use.

Example 1 Reaction of PEEK'film with 4lithiobenzonitrile.

To a three necked round bottomed flask equipped with a magnetic stirring bar and nitrogen inlet was added 4bromobenzonitrile (3.0g, 16.50mol). To this solution was added (10.3ml, 16.50mmol) of 1.6M n-butyl lithium at -78 C. The reaction solution was then stirred at-78 C for lh. The reaction solution was transferred via cannulae to a test tube containing PEEK films (lcm x 5cm) under a nitrogen atmosphere. The solution was then allowed to warm to room temperature and stirred for a further 24 hours. The films were then removed and washed with isopropanol (3 x 50ml), methanol (3 x 50ml) and acetone (2 x 50ml) before being dried at room temperature for 24h.

Example 2 Complete hydrolysis of the nitrile group of a modified PEEKTM film A film from example 1 was placed in a 250ml round bottomed flask fitted with a reflux condenser. To the flask was added 80ml of a 10% aqueous sodium hydroxide and 15ml of ethanol in order to facilitate complete hydrolysis of the nitrile to the carboxylic acid. The solution was heated to reflux for 12-24 hours in order to ensure complete hydrolysis. The solution was cooled and the film removed and placed in a solution of glacial acetic acid followed by washing with 2M HC1 and distilled water. The sample was dried at room temperature overnight.

Example 3 Partial hydrolysis of the nitrile group of a modified PEEKs film A film from example 1 was placed in a 250ml round bottomed flask fitted with a reflux condenser. To the flask was added 65ml of ethanol followed by 5ml of 25% sodium hydroxide. The solution was stirred whilst 50ml of 27.5% hydrogen peroxide was run into the flask via dropping funnel. The addition took place such that the temperature of the reaction solution was within the 4050 C range. When the exothermic reaction was complete the reaction mixture was heated to 50 C for 24h. The film was then removed from the solution and washed with 2M HC1 solution followed by distilled water.

Example 4 Reaction of modified PEEKs film with lithium aluminium hydride Freshly dried diethyl ether (50ml) was added to a 250ml three necked round bottomed flask containing a sample of PEEK film from example 1 and lithium aluminium hydride (3.8g, 100mmol). The solution was then gently refluxed for 48h. The PEEK film sample was removed, washed with ice-cold dilute sulphuric acid solution, followed by exhaustive washing with distilled water before being dried at room temperature overnight.

Example 5 Reaction of a modified PEEK film with paminobenzoic acid.

A sample of PEEKTM film from example 4 was placed in a 100ml Schlenk flask and the flask placed under a nitrogen atmosphere. A 5% w/v solution of p-aminobenzoic acid solution in acetic acid (50ml) was added to the flask and the reaction mixture stirred at room temperature for 72h.

The film was then removed and washed with acetic acid followed by distilled water and acetone, before being dried at room temperature overnight.

Example 6 Surface reduction of PEEK film Dimethylsulfoxide (300ml) and sodium borohydride (2.4g, 63.5mmol) were introduced to a 500ml reaction flask and the solution stirred at 120 C. A PEEK film sample (2 x 10cm) was totally immersed in the reaction solution and stirred at 120 C for 6h. The film was then removed ana'washed successively'with methanol, water and ethanol.

The sample was then dried at room temperature overnight.

Example 7 Reaction of PEEK film with triaminopyrimidine A sample of PEEKTM film was immersed into a solution of 2,4,6-triaminopyrimidine (5.4g, 43.2mmol) in ethanol (15ml) and water (3ml). Sodium hydroxide (1.8g, 45mmol) was then added portionwise over 30 minutes. The reaction mixture was then heated to 40 C and stirred for 24h before being stirred at reflux for 72h. The film sample was then removed and washed successively with 10% aqueous HC1, water, methanol and hexane. The sample was then dried at room temperature overnight.

Example 8 Reaction of modified PEEKTM film with glutamic acid A lcm x 4cm strip of modified PEEKTM film from example 6 was immersed into a 3% (w/v) solution of glutamic acid in acetic acid containing H2SO4 (0.5%) as a catalyst. The reaction mixture was heated to 90-110 C and stirred for 72h, before being removed and rinsed with methanol (5 x 30ml), water (3 x 30 ml) and ethanol (3 x 20ml). The sample was then dried at room temperature overnight.

Example 9 Reaction of surface modified PEEKw containing carboxylic acid groups with the peptide GRGDS A surface modified PEEK film from Example 8 was stirred at 10 C for 1 hr under an atmosphere of nitrogen in an aqueous solution of the water soluble carbodiimide, l-ethyl-3- (3-dimethylamino propyl)-carbodiimide)(0.4g) -dissolved in buffer at pH 4.5 (0.1M 2- (N- morpholino) ethanesulphonic acid) (40ml). The sample of PEEK was removed and washed with buffer solution.

The sample was stirred at 20 C for 24 hr under an atmosphere of nitrogen in a solution of the peptide GRGDS (160mg) in phosphate-buffered saline solution (40ml)(Na2HP04, 1.15g; KH2PO4, 0.2g; NaCl. 8g; KCl, 0.2g; MgCl2, 0. 1g ; CaCl2. O. lg in 1 Litre of distilled water). The functionalised PEEK was washed successively with phosphate buffer and distilled water. Each carboxyl group of the functionalised PEEK reacts with a separate peptide.

Example 10 Reaction of surface modified PEEk' containing amino groups with the peptide GRGDS A modified PEEK sample from example 7 was placed in a 250ml round-bottomed flask fitted with a magnetic follower and a nitrogen inlet and outlet and containing N, N-dimethylacetamide (60ml), and disuccinimidylsuberate (300mg). The contents were stirred under an atmosphere of nitrogen at room temperature for 2hrs. The specimen was removed, washed with ether and dried in vacuo for lOhrs at 50 C. The dried sample was stirred at 20 C for 24 hr under an atmosphere of nitrogen in a solution of the peptide GRGDS (160mg) in an aqueous buffer solution (40ml), pH 9.

The functionalised PEEK was washed successively with the buffer solution and ether. Each amine group of the functionalised polymer reacts with a separate peptide.

Example 11 Reaction of surface modified PEEK containing amino groups with multiple antigenic peptide.

A modified PEEKTM sample from example 7 was placed in a 250ml round-bottomed flask fitted with a magnetic follower and a nitrogen inlet and outlet and containing N, N-dimethylacetamide (60ml), and disuccinimidylsuberate (lOOmg). The contents were stirred under an atmosphere of nitrogen at room temperature for 2hrs. The specimen was removed, washed with ether and dried in vacuo for lOhrs at 50 C. The dried sample was stirred at 20 C for 24 hr under an atmosphere of nitrogen in a solution of a commercially available multiple antigenic peptide [ (Lys) 4 (Lys) 2-Lys-ss-Ala-] (50mg) in an aqueous buffer solution (40ml), pH 9.

The functionalised PEEK was washed successively with the buffer solution and ether.

The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

The invention is not restricted to the details of the foregoing embodiment (s). The invention extend to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.