WO2002000761A1

WO2002000761A1 - Bio-compatible polymeric material

Info

Publication number: WO2002000761A1
Application number: PCT/GB2001/002785
Authority: WO
Inventors: John Neil Devine; David John Kemmish; Brian Wilson
Original assignee: Victrex Manufacturing Limited
Priority date: 2000-06-24
Filing date: 2001-06-22
Publication date: 2002-01-03
Also published as: GB0015431D0; AU2001274321A1

Abstract

A method of preparing a polymeric material, the method including the steps of: (i) polycondensing at least one compound selected from each of groups (a) to (c) optionally in the presence of a compound selected from group (d) to prepare a polycondensation product, wherein at least one of the compounds selected from groups (a) to (d) is a polymer or a polymerisable monomer and wherein groups (a) to (d) include the following: (a) a compound having an aldehydic or ketonic carbonyl or imine functional group; (b) a compound having an isonitrile functional group; (c) water or a compound having an acid and/or nucleophilic functional group; and (d) ammonia or hydrazine or a compound having a primary or secondary amine functional group or a hydrazine functional group; and (ii) optionally derivatising the polycondensation product.

Description

BIO-COMPATIBLE POLYMERIC MATERIAL

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 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 react functionalised polymeric materials with bio-compatible moieties, to provide bio- compatible materials for prosthetic devices. However, generally, the preparation of known bio-compatible materials involves multiple step treatments for functionalising a base polymer material and/or multiple step treatments of functionalised polymeric materials to associate bio-compatible moieties with the functionalised polymer .

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

According to a first aspect of the present invention, there is provided a method of preparing a polymeric material, the method including the steps of:

(i) polycondensing at least one compound selected from each of groups (a) to (c) optionally in the presence of a compound selected from group (d) to prepare a polycondensation product, wherein at least one of the compounds selected from groups (a) to (d) is a polymer or a polymerisable monomer and wherein groups (a) to (d) include the following:

(a) a compound having an aldehydic or ketonic carbonyl or imine functional group;

(b) a compound having an isonitrile functional group;

(c) water or a compound having an acid and/or nucleophilic functional group; and

(d) ammonia or hydrazine or a compound having a primary or secondary amine functional group or a hydrazine functional group; and

(ii) optionally derivatising the polycondensation product. 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.

Whilst said method may be for preparing any type of polymeric material for any use, said method is preferably a method of preparing a bio-compatible polymeric material. Advantageously, the polycondensation product is pendent from the polymeric chain of the polymer and may improve the bio-compatibility of the polymer.

Group (c) preferably includes water or hydrogen selenide, or a compound having a carboxy, acid anhydride, sulphonic acid, azide, cyanate, cyanamide, thiosulphate, thiocyanate, secondary amine or carbonate moiety and/or functional group.

Where the process includes a compound selected from group (d) , preferably said compound selected from group (a) includes a carbonyl group. In the process a group -NH- of a compound described in group (d) suitably reacts with the carbonyl group to form an imine. Alternatively, an imine may be selected for use in the process, in which case a carbonyl group and a compound from group (d) need not be provided.

In a first embodiment, a compound having a carbonyl group may be selected from group (a) , together with compounds from groups (b) and (c) but not including a compound from group (d) . The nature of the polycondensation product will be affected by the identity of the compound selected from group (c) . In the first embodiment, a compound of type (M⁺)_n(B¹A)^n", especially M⁺(B¹A)^", (wherein the positive and negative charges represent relative charges and not necessarily completely ionic compounds) , may be selected where M represents an alkali metal (especially sodium or potassium) or a hydrogen atom, n represents 1 or 2, B¹ represents the most nucleophilic part of B^XA and suitably A represents the rest of the moiety. Preferably, ( (M⁺)_n(B¹A)^n" is selected from a compound having a -COOM or -S0₂OH moiety or ₂S₂O₃, hydrogen selenide or water.

In a compound having a -COOM moiety, B¹ suitably represents -0- of the -CO-0- part thereof and M preferably represents a hydrogen atom. In a compound having a -S0₂OH moiety, B¹ suitably represents -O- of the -0-S0₂- part thereof. In a compound of formula M₂S₂0₃ M preferably represents sodium, potassium or a hydrogen atom and B¹ suitably represents -S- of a -S-S0₃- part thereof. In hydrogen selenide, B¹ suitably represents -Se- of a -SeH part thereof and, similarly, for water, B¹ suitably represents -0- of a -OH part thereof .

In the first embodiment, a product which includes the following moiety may be formed:

B¹

A-0-C*-C-NH-

wherein the starred carbon atom (and the unspecified moieties extending therefrom) represent the residue of the carbonyl compound used in the method.

In a second embodiment, a compound having a carbonyl group may be selected from group (a) , together with compounds from groups (b) and (c) but not including a compound from group (d) . In this case, the compound from group (c) is preferably an azide (N₃ ^~) .

Preferred azides include HN₃ and NaN₃. In the second embodiment, a product which includes the following moiety may be formed:

HO

wherein C* is as described above , In a third embodiment, a compound having a carbonyl group may be selected from group (a) together with compounds from groups (b) and (c) but not including a compound from group (d) . In this case, the compound from group (c) may be selected from a cyanate (i.e. having a moiety OCN^") and the product may be of formula:

/. \

0-C*-C=N- III

I wherein B² represents -CO- H- or -CS- H, wherein the carbon atoms of the aforementioned moieties are bonded to the oxygen atom in structure III.

In a fourth embodiment, a compound having a carbonyl group may be selected from group (a) , together with compounds from groups (b) and (c) and a compound from group (d) which includes an -NH₂ moiety. Where the compound selected from group (c) is of type (M⁺)_n(B¹A)^n" as described above with reference to the first embodiment, the following moiety may be formed in the polycondensation reaction: β'

1 II

A- -N- -C* - C- ^■NH IV

1 1 wherein the starred carbon atom is as described above,

In a fifth embodiment, a compound having a carbonyl group may be selected from group (a) , together with compounds from groups (b) and (c) and a compound from group (d) which includes an -NH₂ moiety. Where the compound selected from group (c) is an azide, a cyanate or a thiocyanate, the product may be of the following formula wherein B² represents -N=N-N-, -CO- H- or -CS-NH-, wherein the carbon atoms of the latter two mentioned moieties are bonded to the nitrogen atom and the starred carbon atom is as described above.

/| \

-N-C*-C=N- V

I

In a sixth embodiment, a compound having a carbonyl group may be selected from group (a) , together with compounds from groups (b) and (c) and a secondary amine compound from group (d) . Where the compound selected from group (c) is of type (M⁺)_n(B¹A)^n" as described above, the following moiety may be formed in the polycondensation reaction: ι

wherein the starred carbon atom is as described above.

In a seventh embodiment, a compound having a carbonyl group may be selected from group (a) , together with compounds from groups (b) and (c) and a secondary amine compound from group (d) . Where the compound selected from group (c) is an azide, the product may be of the following formula where B³ is as described above:

wherein the starred carbon atom is as described above.

In an eighth embodiment, a compound having a carbonyl group may be selected from group (a) , together with compounds from groups (b) and (c) and a secondary amine from group (d) . Where the compound selected from group (c) is of the type R^{1 2} (B* ) ^"K* wherein R¹ and R² independently represent optionally-substituted alkyl or aryl groups and B⁴ represents an electronegative atom, the product may be of the following formula

wherein the starred carbon atom is as described above. Preferably, R¹R²B⁴H is an optionally-substituted dialkylamine.

In a ninth embodiment, a compound having a carbonyl group may be selected from group (a) together with a compound from group (b) . The compounds in groups (c) and (d) may be provided by a single compound which is preferably an amino acid and is preferably an amino acid wherein the amine and carboxy groups are separated by a single carbon atom. Suitably, the amino acid is of formula

AW*. I

R³-CH-COOH

wherein R³ represents an optionally-substituted alkyl group and a specific example of such an amino acid is glutamine. The product of the polycondensation reaction may be as follows: 0 n I II

- H-C-*C-NH-CH-C- IX

wherein the starred carbon atom is as described above and wherein each R³ in the amino acid or in moiety IX may be the same or different. For example, a part of R³ may itself be functionalised in the method. Examples 3 and 6 hereinafter illustrate the ninth embodiment.

Where a compound having a imine functional group is used in the method, a compound from group (d) is not required. This is because, in processes which include a carbonyl compound from group (a) and a compound from group

(d) , an initial step in the mechanism for forming the polycondensation product is the formation of an iminium ion by reaction of the carbonyl with the compound from group (d) . Accordingly, when an imine is the starting material, it can be used directly, thereby avoiding the initial step. An imine compound selected suitably forms an iminium ion which may be represented by the following resonance structures :

wherein R⁴ and R⁵ represent a hydrogen atom or an optionally-substituted alkyl or aryl group. Where neither R⁴ nor R⁵ represent a hydrogen atom, such that the imine is suitably derived from a carbonyl compound and a secondary amine, the polycondensation products may be compounds VI, VII or VIII as described above when the respective compounds from group (c) are selected as described in the sixth, seventh and eighth embodiments. Where at least one of R⁴ or R⁵ represents a hydrogen atom, such that the imine may be derived from a carbonyl compound and ammonia, a hydrazine or a primary amine, the polycondensation products may be compounds IV or V as described above when the respective compounds from group (c) are selected as described in the fourth and fifth embodiments .

As described above, one of the compounds selected from

(a) to (d) is a polymer or a polymerisable monomer. Some of the functional groups described for the compounds in groups (a) to (d) may be: incorporated into polymer chains (e.g. carbonyl or imine functional groups) ; or be pendent from polymer chains or polymerisable groups (e.g. carbonyl, imine, isonitrile, various of the acid and/or nucleophilic functional groups in group (c) , and primary or secondary amine or hydrazine functional groups of group (d) ) ; or not be capable of incorporation into a polymer (e.g. water and some other acid and/or nucleophilic functional groups in group (c) , ammonia and hydrazine of group (d) ) .

Where at least one of the compounds selected from groups (a) to (d) is a polymerisable monomer, said monomer may be polymerisable in a free radical reaction and/or is preferably ethylenically unsaturated. Examples of such monomers include acrylic or methacrylic acids wherein acid groups thereof participate in the polycondensation reaction and, suitably, thereafter, ethylenically unsaturated moieties in the polycondensation product may be polymerised. Examples of polymers with carbonyl functional groups incorporated into the polymer chains include aliphatic or aromatic polyketones .

Aliphatic polyketones may be prepared by polymerising carbon monoxide, ethylene and one or more hydrocarbons of formula C_xH_y where x is greater than 2 and less than 20 and y is twice x or less and said hydrocarbon contains an olefinically-unsaturated (-CH=CH-) group. US 4 868 282 describes such polymers and the content of the document is incorporated herein by reference .

Preferred aliphatic ketones include moieties of formula o o ii II

-(CH₂-CH₂-C-)~ and - (CHa-CH-C-)-

I

The proportion of the respective moieties shown above may be varied to adjust the properties of a polymer which consists of the moieties. Aliphatic ketones of the type described are sold under the Trade Marks CARILON and

KETONEX by Shell and BP respectively.

Aromatic polyketones may include moieties of formula I^A, II^A and/or III^A as described below, provided that said polymer includes at least one carbonyl group containing moiety of formula I^A or II^A:

The phenyl moieties in units I^A, II^A, and III^A are suitably independently optionally substituted and optionally cross-linked; 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

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^A; more than one different type of repeat unit of formula II^A; and more than one different type of repeat unit of formula III^A. Preferably, however, only one type of repeat unit of formula I^A, II^A and/or III^A is provided.

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

III\

Where the phenyl moieties in units I^A, II^A or III^A 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 Ci-io, especially Cι_₄, 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^A, II^A or III^A include alkyls, halogens, C_yF_2y+i where y is an integer greater than zero, 0-R^q (where R^q is selected from the group consisting of alkyls, perfluoralkyls and aryls) , CF=CF₂, CN, N0₂ and OH. Trifluormethylated phenyl moieties may be preferred in some circumstances .

Preferably, said phenyl moieties are not optionally- substituted 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 1,4- or 1,3-linkages to the other moieties in the repeat units of formulae II^A and/or III^A. 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^A in said polymer, suitably wherein each unit I^A is the same; "b" represents the mole % of units of formula II^A in said polymer, suitably wherein each unit II^A is the same; and "c" represents the mole % of units of formula III^A in said polymer, suitably wherein each unit III^A 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 48- 52. 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^A, II^A and/or III^A.

Said polymer may be a homopolymer having a repeat unit of general formula

or a homopolymer having a repeat unit of general formula

or a random or block copolymer of at least two different units of IV^A and/or V^A

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^A and/or V^A discussed above, said polymer may be a homopolymer having a repeat unit of general formula

or a homopolymer having a repeat unit of general formula

or a random or block copolymer of at least two different units of IV^A* and/or V^A*, 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^A.

Preferably Ar is selected from the following moieties (xi)*, (xi)**,(xi) to (xxi) :

In (xi)*, the middle phenyl may be 1,4- or 1,3- substituted. 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^A, but suitably only includes moieties of formulae I^A and/or II^A. 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^A. 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. 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^A 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^A 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^A 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^A 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^A, 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. Preferably, said polymer includes an electrophilic carbonyl group which can readily participate in the polycondensation.

The glass transition temperature (T_g) of said aromatic polyketone polymer 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 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 lg 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 O.lg 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 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 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.

Aromatic—ketone-polymers may be prepared 'as described in PCT/GB99/02833.

Examples of polymers with imine functional groups incorporated in the polymer chains include Schiff-base polymers which may be formed by reacting an organic amine or diamine (which term includes hydrazine) with at least one organic ketone, diketone, aldehyde or dialdehyde, provided at least one dialdehyde or diketone and at least one diamine are used. Further details on the type and preparation of Schiff base polymers is provided in US5274070, the content of which is incorporated herein by reference .

In general any functional group (especially -OH, -NH₂, -COOH, -CO- and -NC) may be pendent from any type of polymer, by suitable functionalisation of a polymer. It is preferred, however, that there is not a long series of steps to functionalise a polymer to provide a desired functional group but that either the functional group is prepared directly in a polymerisation reaction or a functional group prepared in a polymerisation reaction is functionalised in a simple derivatisation reaction or reactions . Examples of polymers with pendent groups include: polyacrylic acid or a copolymer thereof; polymethyacrylic acid or a copolymer thereof; or any sulphonated polymer.

Preferably, a compound selected from group (a) is a polymer. In this case, the starred carbon atom and the unspecified moieties bonded thereto in moieties I, II, III, IV, V, VI, VII, VIII and IX may be represented as

R"

C*-

R⁷

wherein R⁶ and R⁷ represent residues of the polymeric backbone .

It will be appreciated that polymers with carbonyl or imine functional groups include a multiplicity of such groups. Consequently, preferably, a multiplicity of carbonyl or imine functional groups (whichever is present) of a polymer may be functionalised to define a polycondensation product in the method described herein.

Preferably, said compound in group (a) does not include any other group which can interfere with the polycondensation reaction. Preferably, said compound in group (a) includes only a single type of functional group which can participate in the polycondensation reaction for preparing said polycondensation product.

A support material may include said polymer. Said support material preferably comprises a major amount of said polymer. Where said support material comprises more than one polymer, the sum of the amounts of respective said polymers preferably represents a major amount.

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

Said support material may include one or more fillers for providing desired properties. Said support material preferably incorporates an X-ray contrast medium. Fillers and/or said X-ray .contrast medium is/are preferably distributed substantially uniformly throughout said support 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 support 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 of X-ray contrast media. Said particulate material is suitably physically held in position by entrapment within the polymer. Most preferably, the compound in group (a) is an aromatic ketone polymer or copolymer and said support material suitably includes such a polymer.

Said support 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, suitably less 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 polyaryetherketone 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.

In some embodiment, a compound may be provided which includes functional groups and/or is of a type such that it falls within more than one of the groups (a) to (d) above. Thus, one compound may provide one functional group described in groups (a) to (d) and another functional group in another group (a) to (d) . An example of this is an amino acid and/or a peptide which may provide a carboxylic acid moiety in group (c) and an amine moiety in group (d) .

Said compound having an isonitrile functional group may be of formula R⁸-NC where R⁸ preferably represents an optional substituent which does not include any functional group which may interfere with the polycondensation reaction. R⁸ could, however, include functionality which aids the bio-compatibility of the polymer prepared in the method or includes functionality which can be derivatised to provide functionality which can aid the bio- compatibility of the polymer or includes functionality which can be associated with bio-compatible moieties which can aid bio-compatibility of the polymer. R⁸ could include a protected functional group, for example a protected amine or, especially, a protected carboxyl group. Suitable protecting groups are well-known (see e.g. TW Green and PGM Wuts, Protective Groups in Organic Synthesis, 2^nd Edition, Wiley, New York 1991) . Example 4 hereinafter describes the preparation of a protected isonitrile compound and Example 5 illustrates its use. Preferably, said compound of formula R⁸NC includes only a single type of functional group which can participate in the polycondensation reaction. Preferably, R⁸ represents an optionally-substituted alkyl, heteroalkyl or cyclic, for example aryl, heteroaryl, cycloalkyl or cycloalkenyl group .

Preferably, R⁸ represents an optionally-substituted alkyl group. A preferred such group is of formula

wherein R⁹, R¹⁰ and R¹¹ independently represent a hydrogen atom, an optionally-substituted, especially an unsubstituted, alkyl group, or an optionally-substituted, especially an unsubstituted, phenyl group (but preferably one or fewer of R⁹, R¹⁰ and R¹¹ represent a phenyl group) . An optionally-substituted alkyl group may be substituted by a group which includes a -O-CO-O- moiety, especially an -O-CO-O-R¹² moiety, where R¹² is an optionally-substituted, especially an unsubstituted, alkyl group. Preferably, one or fewer of R⁹, R¹⁰ and R¹¹ is substituted by a group which includes a -O-CO-O- moiety.

Preferably, in products I, II, III, IV, V, VI, VII, VIII, and IX, R⁸ is bonded to the nitrogen atom at the right hand end of the structures shown.

A compound in group (c) having a carboxy functional group may be of formula R¹³COOH, wherein R¹³ represents an optionally-substituted alkyl, heteroalkyl or cyclic, for example aryl, heteroaryl, cycloalkyl or cycloalkenyl group. Where said compound in group (c) is polymerisable, it preferably include an ethylenically-unsaturated group. R¹³ may include functionality which aids the bio- compatibility of the polymer prepared in the method or includes functionality which can be derivatised to provide functionality which can aid the bio-compatibility of the polymer or includes functionality which can be associated with bio-compatible moieties which can aid bio- —compatibility ^~Of^~the^~pσlymer: ^~

R¹³ may include an amine group or a protected amine group. Suitable protecting groups are described in the Greene and Wuts publication referred to above and include carbobenzoxy, tert-butyloxycarbonyl, phthalyl, formyl, tosyl, o-nitrophenyl, sulphenyl and chloroformate groups. Examples 3 and 6 hereinafter include examples of R¹³ including an amine group; and examples 2 and 3 include examples of R¹³ including a protected amine group.

In some embodiments R¹³COOH may be an amino acid or an amino group protected amino acid.

Unless otherwise stated, the term "amino acid" refers to any specie containing amine and carboxylic acid functionality and also oligopeptides having free and available amine and/or carboxyl groups .

In one embodiment, R¹³COOH may include a free amino and a free carboxy functional group suitably separated by a single carbon atom. In this case, both the amine and carboxy functional groups may participate in the polycondensation (and suitably no additional compound selected from group (d) need be included) . The product of such a reaction may be of formula IX as described above.

Preferred compounds in group (c) include carboxylic acids and water, with carboxylic acids being especially preferred.

A compound in group (d) is suitably of general formula R¹⁵-NHR¹⁴ where R¹⁴ and R¹⁵ independently represent a hydrogen atom or an optionally-substituted alkyl, heteroaryl or cyclic, for example aryl, heteroaryl, cycloalkyl or cycloalkenyl group and R¹⁵ may additionally represent a group

where R¹⁶ and R¹⁷ independently represent a hydrogen atom or an optionally-substituted alkyl, heteroaryl or cyclic, for example aryl, heteroaryl, cycloalkyl or cycloalkenyl group. R¹⁴, R¹⁵, R¹⁶ and/or R¹⁷ may independently optionally include functionality which aids the bio- compatibility of the polymer prepared in the method or includes functionality which can be derivatised to provide functionality which can aid bio-compatibility of the polymer or includes functionality which can be associated with bio-compatible moieties which can aid bio- compatibility of the polymer.

If R¹⁴ does not represent a hydrogen atom (and, if relevant, at least one or R¹⁶ and R¹⁷ is not a hydrogen atom) then the products of the polycondensation reactions may be VI, VII and VIII wherein, in the aforementioned products, R¹⁴ and R¹⁵ are bonded to the nitrogen atom at the left hand end of the structures shown. If, on the other hand, R¹⁴ represents a hydrogen atom, then the products of the polycondensation reactions may be IV and V wherein, in the aforementioned products, R¹⁵ is bonded to the nitrogen atom at the left hand end of the structures shown.

R¹⁵ may include a carboxy group or a protected carboxy group' wherein^{^} protecting ^~group^~s^~may^~be^~ as"described in the aforementioned Green and Wuts publication. In some embodiments, R^1Ξ-NHR¹⁴ may be an amino acid or carboxy group protected amino acid. In some embodiments, R¹³COOH and R¹⁵-NHR¹⁴ may represent the same amino acid.

Preferred compounds in group (d) include primary and secondary amines and ammonia.

Step (i) of the method may be carried out in a protic or aprotic solvent. The solvent is preferably organic. Preferred protic solvents are methanol and 2,2,2- trifluoroethanol. Preferred aprotic solvents include tetrahydrofuran, chloroform, methylenechloride, dimethylformamide, ethylether, ethylene chloride and acetonitrile. A mixture of a protic and an aprotic solvent could be utilised. In the method compounds, from groups (a) , (b) , (c) and (d) (if included) may be added to the selected solvent and caused to react. The reaction may be undertaken at ambient temperature. Preferably, the polymer amongst the reactants is a solid. Advantageously, isolation of the desired product simply involves removal of the functionalised polymer from the solvent, followed by washing and/or drying as may be required.

The derivatisation (e.g. in step (ii)) of the polycondensation product could occur during the polycondensation reaction and/or by reaction with a compound in addition to those described in groups (a) to

(d) or after the polycondensation reaction. For example, the solvent (e.g. an alcoholic solvent, such as methanol) may participate in the reaction by reaction with an intermediate in the polycondensation, as in Example 3 hereinafter. Alternatively, the solvent may be selected so that it does not react, but a compound (e.g. a polysiloxane) may be added which can participate in the reaction by reaction with an intermediate in the polycondensation, as in Example 6 hereinafter.

Where derivatisation is undertaken after the polycondensation reaction, this could be in addition to derivatisation, for example of the type described above, which takes place during the polycondensation reaction.

Any desired derivatisation may be undertaken. A preferred reaction involves treatment with one or more peptides

(e.g. RGDS or KRSR) in order to attach bio-compatible moieties to the polymer used in the method.

In general terms, the method may be regarded as a method of associating bio-compatible moieties with a 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 avidin, 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 argent such^{" " "}as^"'"^eΗcil^in ^{~^}t carcillin, ^~"ca^"rbenicillin, 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 non- steroidal anti-inflammatory, an analgesic, an anti- histamine, a receptor binding agent, a chemotherapeutic agent, a hydrophilic polymer (e.g. poly (ethylene glycol) (PEG), poly (ethylene oxide) (PEO) , ethylene oxide- propylene oxide block co-polymers, poly (N-vinyl-2- pyrrolidone) (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 moieties 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— o±ymer-may be associated with ends of said polymer of said bio-compatible polymeric material, for example by being covalently bonded to end groups .

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. In one embodiment, a polyurethane may be associated with a polymeric material prepared in the method. For example, a polymer having hydroxy functional groups may be prepared in the method and this may be treated with a diisocyanate and a diol to prepare a polyurethane; or a polymer prepared may have isocyanate groups and these may be treated with a diisocyanate and a diol to prepare a polyurethane .

— Where said method of the first aspect uses a polymer

(rather than a polymerisable monomer) in solid form, the method preferably involves polycondensing functional groups present at or adjacent the surface of the polymer so that, suitably, a polycondensation product is not formed in the bulk of the material. Thus, suitably, polymeric chains of said polymer at the surface thereof are different compared to chains within the bulk. The concentration of a polycondensation product at the surface of the polymer is preferably greater than in the bulk.

According to another aspect of the present invention, there is provided a device for use in medical applications, wherein said device comprises a polymeric material as described herein.

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 or tubing, 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 polymeric material and a part or parts 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 polymeric material. In some embodiments said device may consist essential of said polymeric material.

According to a further aspect, there is provided a method of making a device for use in medical applications, 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 selected from one of groups (a) to (d) described above; and treating material in said shape (preferably the surface thereof) with other compounds in groups (a) to (c) and optionally (d) thereby to cause formation of a polycondensation product, suitably at or near the surface of said polymer.

The invention extends to the use of a polymeric material as described herein in the manufacture of a device for use in a medical treatment, for example in surgery.

The invention extends to a polymeric material, preferably for use in medical applications, wherein said material comprises a polymer wherein a surface of said material comprises an optionally derivatized polycondensation product, prepared as described according to said first aspect and wherein the bulk of said material comprises said polymer without an associated polycondensation product .

Preferably, the bulk of said material is an aromatic polyketone polymer or copolymer as described herein. In this case, preferably, the said polymer at the surface includes -C- moieties incorporated into the polymer chain - that is carbonyl groups have been replaced by two single bonds extending from the former carbonyl carbon atoms.

The invention extends to a functionalised polymeric material, preferably a bio-compatible polymeric material, wherein the bulk of said material comprises a polymer (suitably as described herein) of a type which includes, in the polymer backbone, the following:

(A) phenyl moieties;

(B) carbonyl and/or sulphone moieties; and (C) ether and/or thioether moieties;

wherein a surface of said material comprises a functionalised derivative of said polymer present in the bulk which derivative has a lower concentration of carbonyl moieties compared to the concentration of carbonyl moieties in the bulk.

Since said functionalised polymeric material is suitably only functionalised at or adjacent its surface and functionalised polymer represents only a small fraction of the total weight of the polymer, the existence of functionalised polymer may have a limited effect on the bulk properties of the polymeric material. Preferably, said surface includes a greater concentration of functionalised carbonyl moieties compared to the concentration of functionalised carbonyl moieties in the bulk.

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 herein:

PEEK (Trade Mark) -polyetheretherketone obtained from Victrex Pic and/or prepared as described herein.

In the following examples, polyaryletherketone films of approximately 5cm x 5cm x 120μm thick were used. The film samples were prepared from samples of Victrex PEEK™

(Melt Viscosity 0.45kNsm^"2, at lOOOsec^"2 at 400°C) powder which was compression moulded between metal plates using a Moore Laboratory hot press at 400°C for between 5 and 10 minutes. The PEEK™ melt was quenched in ice-cold water in order to obtain 120μm thick amorphous samples. The film samples were refluxed in acetone for 72h prior to use.

All chemicals referred to herein were used as received from Sigma-Aldrich Chemical Company, Dorset, U.K, unless otherwise stated. Example 1 Surface Reaction of PEEK™ with N-protected glycine in the presence of benzyl isocyanide.

A solution of methanol (30ml) and triethylamine (1.39ml, lOmmol) was added to a 100ml three neck round bottomed flask. A sample of PEEK™ film was immersed in the solution and the solution stirred for 5 minutes at room temperature. To this solution was added benzyl isocyanide (1.22ml, lOmmol) followed by tert- butoxycarbonylglycine (1.75g, lOmmol). The mixture was stirred for 72 hours at room temperature. The film sample was then removed and washed with methanol, IM HCl and distilled water and was then dried at room temperature overnight .

Example 2 Surface Reaction of PEEK™ with carboxyl protected glycine, N-protected glycine and benzyl isocyanide.

Glycine methyl ester hydrochloride (1.26g, lOmmol) was added to a stirred solution of triethylamine (1.39ml, lOmmol) in methanol (30ml) at room temperature. A sample of PEEK™ film was immersed in the reactive solution followed by benzyl isocyanide (1.22ml, lOmmol) and tert- butoxycarbonyl glycine (1.75g, lOmmol). The solution was stirred at room temperature for 72 hours before the film was removed and washed with methanol, IM HCl and distilled water and was then dried at room temperature overnight.

Example 3 Surface Reaction of PEEK™ with L-glutamine and n-butylisocyanate. A solution of L-glutamine (1.46g, lOmmol) and triethylamine (1.39ml, lOmmol) in methanol (100ml) was cooled to -30° and stirred for 1 hour. A sample of PEEK™ film was added to the solution followed by a 10ml solution of n-butyl isocyanide (1.04ml, lOmmol) in methanol. The mixture was stirred for 72 hours at room temperature. The film sample was then removed and washed with methanol, IM HCl and distilled water and was then dried at room temperature overnight .

Example 4 Synthesis of [ (2-isocyano-2-methyl) -propyl-1- methylcarbonate.

1.6 n-BuLi (125ml, 200mmol) was added slowly to 4,4- dimethyl-2-oxazoline (19.82g, 200mmol) in 200ml of dry THF at -78 °C. The solution was stirred for 1 hour at -78 °C and methyl chloroformate (15.5ml, 200mmol) added dropwise.

After 30 minutes the solution was allowed to reach 25 °C.

The solution was washed with water and saturated aqueous NaCl and dried over anhydrous Na₂S0₄. Removal of solvent afforded the title compound in 75% yield. ^Η-NMR 4.10

(m, 2H) , 3.83 (s, 3H) , 1.47 (m, 6H) ; IR (neat) 2959,

2137, 1755, 1270cm^"1.

Example 5 Surface Reaction of PEEK™ with N-protected glycine and a C-protected glycine and [ (2-isocyano-2- methyl) -propyl-1-methylcarbonate.

Glycine methyl ester hydrochloride (1.26g, lOmmol) was added to a stirred solution of triethylamine (1.39ml, lOmmol) in methanol (30ml) at room temperature. A sample of PEEK™ film was immersed in the reactive solution followed by [ (2-isocyano-2-methyl) -propyl-1- methylcarbonate (1.57g, lOmmol) and tert-butoxycarbonyl glycine (1.75g, lOmmol). The solution was stirred at room temperature for 72 hours before the film was removed and washed with methanol, IM HCl and distilled water and was then dried at room temperature overnight .

Example 6 Surface Reaction of PEEK™ with L-glutamine, n- butylisocyanate and hydroxy terminated poly(dimethyl siloxane) .

A —solution- -of - Lr--giutamine (1.46g, lOmmol) and triethylamine (1.39ml, lOmmol) in freshly distilled THF (100ml) was cooled to -30° and stirred for 1 hour. A sample of PEEK™ film was added to the solution followed by n-butyl isocyanide (1.04ml, lOmmol) and hydroxy terminated poly (dimethyl siloxane) (5.5g, lOmmol). The mixture was stirred for 72 hours at room temperature. The film sample was then removed and washed with chloroform, methanol, distilled water and acetone and was then dried at room temperature overnight.

Example 7 Deprotection of surface modified PEEK™ from example 2.

A IM solution of hydrogen chloride in acetic acid was stirred in a 100ml reaction flask at room temperature. A sample of modified PEEK™ film from example 1 was added and the solution stirred for a further 6 hours. The film sample was removed and used directly in example 8.

Example 8 Reaction of surface modified PEEK™ from example 7 with KRSR The 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- atmσspherer of πxtrogeπ ±n- a scrlutxon of the peptide KRSR(160mg) in an aqueous buffer solution (40ml), pH 9. The functionalised PEEK™ was washed successively with the buffer solution and ether.

Example 9 Deprotection of the carboxyl group of surface modified PEEK™ from example 8.

A sample of PEEK™ film from example 8 was immersed in 30ml of a 10% sodium hydroxide solution and the solution refluxed for 6 hours. The sample was removed washed with

IM HCl followed by distilled water and the sample used immediately in example 10.

Example 10 Reaction of Surface modified PEEK from example 9 with RGDS.

The surface modified PEEK™ from Example 9 was stirred at 10°C for 1 hr under an atmosphere of nitrogen in an aqueous solution of the water soluble carbodiimide, 1- 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 RGDS(160mg) in phosphate-buffered saline solution (40ml) (Na₂HP0₄, 1.15g; KH₂P0₄, 0.2g; NaCl . 8g; KC1, 0.2g; MgCl₂, O.lg; CaCl₂. 0. lg in 1 Litre of distilled water). The functionalised PEEK™ was washed successively with phosphate buffer and distilled water.

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.

Claims

1. A method of preparing a polymeric material, the method including the steps of: (i) polycondensing at least one compound selected from each of groups (a) to (c) optionally in the presence of a compound selected from group (d) to prepare a polycondensation product, wherein at least one of the compounds selected from groups (a) to (d) is a polymer or a polymerisable monomer and wherein groups (a) to (d) include the following:

(b) a compound having an isonitrile functional group; (c) water or a compound having an acid and/or nucleophilic functional group; and (d) ammonia or hydrazine or a compound having a primary or secondary amine functional group or a hydrazine functional group; and

(ii) optionally derivatising the polycondensation product.

2. A method according to claim 1, wherein the polycondensation product is pendent from the polymeric chain of the polymer.

3. A method according to claim 1 or claim 2 , wherein group (c) includes water or hydrogen selenide, or a compound having a carboxy, acid anhydride, sulphonic acid, azide, cyanate, cyanamide, thiosulphate, thiocyanate, secondary amine or carbonate moiety and/or functional group .

4. A method according to any preceding claim, wherein, when the process includes a compound selected from group (d) , said compound selected from group (a) includes a carbonyl group.

5. A method according to any of claims 1 to 3 , wherein a compound having a carbonyl group is selected from group (a) , together with compounds from groups (b) and (c) , but not including a compound from group (d) and wherein (c) represents a compound of type (M⁺)_n(B¹A)^n" with M represents an alkali metal or a hydrogen atom, n represents 1 or 2, B¹ represents the most nucleophilic part of B^ and A represents the rest of the moiety, wherein a product which includes the following moiety is formed

B^J

A-0-C*-C-NH-

6. A method according to any of claims 1 to 3, wherein a compound having a carbonyl group is selected from group

(a) , together with compounds from groups (b) and (c) but not including a compound from group (d) , wherein the compound from group (c) is an azide and a product which includes the following moiety is formed wherein the starred carbon atom (and the unspecified moieties extending therefrom) represent the residue of the carbonyl compounds used in the method

7. A method according to any of claims 1 to 3 , wherein a compound having a carbonyl group is selected from group

(a) , together with compounds from groups (b) and (c) but not including a compound from group (d) and the compound from group (c) is selected from a cyanate and the product is of formula

wherein B² represents -CO-NH- or -CS-NH, wherein the carbon atoms of the aforementioned moieties are bonded to the oxygen atom in structure III.

8. A method according to any of claims 1 to 3 , wherein a compound having a carbonyl group is selected from group

(a) together with compounds from groups (b) and (c) and a compound from group (d) which includes an -NH₂ moiety wherein the compounds selected from group (c) is of type

(M⁺)_n(B¹A)^π" wherein M represents an alkali metal or a hydrogen atom, n represents 1 or 2, B¹ represents the most nucleophilic part of B\ and A represents the rest of the moiety, wherein a product which includes the following moiety is formed in the polycondensation reaction: 6

A-N-C*-C-NH- IV

wherein the starred carbon atom (and the unspecified moieties extending therefrom) represent the residue of the carbonyl compound used in the method) .

9. A method according to any of claims 1 to 3 , wherein a compound having a carbonyl group is selected from group (a) together with compounds from groups (b) and (c) and a ""compound from -group (d)^~ which includes an""^~-NH₂ moiety, wherein the compound selected from group (c) is an azide, a cyanate or a thiocyanate and the product is of the formula *

wherein B² represents -N=N-N-, -CO-NH- or -CS-NH-, wherein the carbon atoms of the latter two mentioned moieties are bonded to the nitrogen atom in structure V and the starred carbon atom (and the unspecified moieties extending therefrom) represent the residue of the carbonyl compound used in the method.

10. A method according to any of claims 1 to 3, wherein a compound having a carbonyl group is selected from group (a) , together with compounds from groups (b) and (c) and a secondary amine compound from groups (d) , wherein the compound selected from group (c) is of type β

11. A method according to any of claims 1 to 3, wherein a compound having carbonyl group is selected from group (a) together with compound from groups (b) and (c) and a secondary amine compounds from group (d) , wherein the compound ^"selected frorrt group^s (^"C^") i^~s an ^~ azide ^" and the product is of the following

12. A method according to any of claims 1 to 3 , wherein a compound having a carbonyl group is selected from group (a) , together with compounds from groups (b) and (c) and a secondary amine from group (d) wherein the compound selected from group (c) is of the type R¹R²(B⁴)^"H⁺ wherein R¹ and R² independently represent optionally-substituted alkyl or aryl groups and B⁴ represents an electronegative atom, and the product is of the formula

13. A method according to any of claims 1 to 3 , wherein a compound having a carbonyl group is selected from group (a) together with a compound from group (b) and compounds in groups (c) and (d) are provided by a single compound which is an amino acid and the product of the polycondensation reaction is of formula o o

II I II

-NH-C-*C-NH-CH-C- IX l

wherein the starred carbon atom (and the unspecified moieties extending therefrom) represent the residue of the carbonyl compound used in the method and wherein each R³ in the amino acid or in moiety IX is the same or different.

14. A method according to any preceding claim, wherein some of the functional groups described for the compounds in groups (a) to (b) are incorporated into polymer chains; or are pendent from polymer chains or polymerisable groups .

15. A method according to claim 14, wherein examples of polymers with carbonyl functional groups incorporated into the polymer chains include aliphatic or aromatic polyketones .

16. A method according to claim 15, wherein aromatic polyketones include moieties of formula I^A, II^A and/or III^A as described below, provided that said polymer includes at least one carbonyl group containing moiety of formula I^A or

II^A :

wherein the phenyl moieties in units I^A, II^A, and III^A are suitably independently optionally substituted and optionally cross-linked; 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

17. A method according to any preceding claims, wherein said polymer is selected from polyetheretherketone, polyetherketone, polyetherketoneketone, polyetherketoneetherketoneketone and polyetheretherketoneketone.

18. A method according to any preceding claims, wherein said polymer comprises polyetheretherketone.

19. A method according to any preceding claim, wherein the compound selected from group (a) is a polymer.

20. A method according to any preceding claim, wherein said compound having an isonitrile functional group is of formula R⁸-NC where R⁸ represents an optional substituent which does not include any functional group which may interfere with the polycondensation reaction.

21. A method according to any preceding claim, wherein a compound in group (c) having a carboxy functional group is of general formula R¹³COOH wherein R¹³ represents a functionality which aids the bio-compatibility of the polymer prepared in the method or includes functionality which can be derivatised to provide functionality which can aid the bio-compatibility of the polymer or includes functionality which can be associated with bio-compatible moieties which can aid bio-compatibility of the polymer.

22. A method according to any preceding claim, wherein a compound in group (d) is of general formula R¹⁵-NHR¹⁴ where R¹⁴ and R¹⁵ independently represent a hydrogen atom or an optionally-substituted alkyl, heteroaryl or cyclic group and R¹⁵ may additionally represent a group

where R¹⁶ and R¹⁷ independently represent a hydrogen atom or an optionally-substituted alkyl, heteroaryl or cyclic group .

23. A method according to claim 22, wherein said compound in group (d) is selected from primary and secondary amines and ammonia.

24. A device for use in medical applications, wherein said device comprise a polymeric material according to any preceding claim.

25. A device according to claim 24, wherein said device is an implant or a device which is arranged to be temporarily associated with a human or animal body.

26. A method of making a device for use in medical applications, 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 selected from one of groups (a) to (d) described in any of claims 1 to 24; and treating material in said shape with other compounds in groups (a) to (c) and optionally (d) thereby to cause formation of a polycondensation product.

27. The use of a polymeric material according to any of claims 1 to 24 in the manufacture of a device for use in medical treatment.

28. A polymeric material wherein said material comprises a polymer wherein a surface of said material comprises an optionally derivatised polycondensation product, prepared as described in any of claims 1 to 24 and wherein the bulk of said material comprise said polymer without an associated polycondensation product.

29. A functionalised polymeric material, wherein the bulk of said material comprises a polymer of a type which includes, in the polymer backbone, the following:

(A) phenyl moieties;

(B) carbonyl and/or sulphone moieties; and

(C) ether and/or thioether moieties;

wherein a surface of said material comprises a functionalised derivative of said polymer present in the

—bu-l-k— which - derivative —has a lower concentration of carbonyl moieties compared to the concentration of carbonyl moieties in the bulk.