WO2005027991A1 - Dispositifs orthopediques - Google Patents

Dispositifs orthopediques Download PDF

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Publication number
WO2005027991A1
WO2005027991A1 PCT/GB2004/004000 GB2004004000W WO2005027991A1 WO 2005027991 A1 WO2005027991 A1 WO 2005027991A1 GB 2004004000 W GB2004004000 W GB 2004004000W WO 2005027991 A1 WO2005027991 A1 WO 2005027991A1
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group
alkyl
groups
hydrogen
polymer
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PCT/GB2004/004000
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English (en)
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Mariam Habib
Roger Audley Brooks
William Bonfield
Andrew Lennard Lewis
Peter William Stratford
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Cambridge University Technical Services Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials

Definitions

  • the present invention relates to orthopaedic devices for use by implantation in contact with bone.
  • the devices have surfaces formed of materials with improved osteointegrative properties.
  • biomaterials that are necessarily required to come into contact with hard or soft tissues, in order to lessen the body's response to these foreign materials.
  • One approach is to attempt to mimic the chemistry or structure of these tissues.
  • biomimetic or bio-inspired strategy that has been employed to great advantage in orthopaedic areas using hydroxyapatite-based technologies (such as HAPEX) [1 ,2].
  • PC phosphorylcholine
  • PC materials mimic the outer surface of the cell lipid membrane and have been shown to be effective in improving the biocompatibility of a number of medical devices including soft contact lenses [4] and WO-A-9207885, coronary guidewires [5] WO-A-9301221 and stents [6] and WO98-30615, extracorporeal circuits [7], tympanostomy tubes [8] and vascular grafts [9] to mention but a few. It is believed that the biocompatibility of PC surfaces depends at least in part upon the hydrophilicity of the zwitterionic group.
  • Protein adhesion is the basic first step in a variety of biological processes that would ultimately identify foreign surfaces, resulting in such events as thrombus formation, inflammation and fibrous encapsulation or bacterial adhesion and infection.
  • PC materials have been shown to significantly reduce protein adsorption as their hydrated surfaces are able to interact with proteins without inducing conformational changes in their three dimensional structures, unlike many other hydrogel-type materials [10].
  • PC- based surfaces are therefore associated with less cellular adhesion, a reduced inflammatory response and lessened fibrous capsule formation [11].
  • it has been shown that the presence of a bio- inert surface does not necessarily aid in the healing process and hence speed the integration of the implant and tissue.
  • An additional approach to obtaining bioactivity is to take the fundamentally bio-inert PC platform and to modify the materials with chemical groups that may be used to serve a particular function or to bring about a specific biological response.
  • the modified PC surface may be able to reduce non-specific interactions with biomolecules, whilst the modifying group may induce a degree of selectivity.
  • Many biomolecules and cells are known to interact with charged groups and to this end, PC-based materials containing a range of cationic charges have been prepared and characterised [16].
  • an orthopaedic implant has a surface carrying a coating comprising at least one phospholipid carrying a charge, in this case, a negative charge. The coatings are shown to induce calcium phosphate precipitation.
  • Phospholipids are believed to play a role in the mineralisation process, probably by virtue of their link with calcium levels within cells. For instance, phospholipids have been detected in calcified nodules, which forms the basis for a mineralisation matrix, by Silvestrini, G. et al in Bone (New York) (1996), 18 (6), 559 to 565.
  • charged groups have been identified as having an effect on apatite deposition. Negative charges (carboxyl groups and sulphonate groups) can induce apatite deposition, although these apparently need to be precomplexed with calcium ions for this effect to occur.
  • a new orthopaedic implant device has a surface which in use will contact bone which is formed of osteointegration- improving material, the device being characterised in that the said material comprises a polymer having pendant highly hydrophilic groups and having an overall charge at physiological pH.
  • the highly hydrophilic groups expressed at the surface of the material provide biocompatible properties.
  • the hydrophilic groups may be poly(ethylene glycol) moieties, or polyhydroxylated compounds, the highly hydrophilic groups which are believed to confer most biocompatibility should be zwitterionic groups.
  • Zwitterionic groups may have an overall charge at physiological pH. It is possible therefore for the pendant highly hydrophilic groups to confer the overall charge required of the polymer in the new device. Preferably, however, the zwitterionic groups have no overall charge.
  • the overall charge is conferred by other groups on the polymer.
  • the zwitterionic group is an ammonium, phosphonium or sulphonium phosphate or phosphonate ester zwitterionic group.
  • the zwitterionic group has of the general formula II
  • the moieties A 3 and A 4 which are the same or different, are - O-, -S-, -NH- or a valence bond, preferably -O-, and W + is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which is preferably a C.,.
  • W + is a group of formula -W 1 -N + R 3 3 , -W 1 -P + R 3 , -W 1 -S + R 4 2 or -W 1 -Het + in which: W 1 is alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, which group W 1 optionally contains one or more fluorine substituents and/or one or more functional groups; and either the groups R 3 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably
  • groups R 5 are the same or different and each is hydrogen or C 1-4 alkyl, and m is from 1 to 4, in which preferably the groups R 5 are the same, preferably methyl.
  • Another class of phosphate or phosphonate ester based zwitterionic groups is a phosphobetaine group which may have the general formula IV
  • a 14 is a valence bond, -O-, -S- or -NH-, preferably -O-;
  • R 21 is a valence bond (together with A 14 ) or alkanediyl, -C(O)alkylene- or -C(O)NH alkylene preferably alkanediyl, and preferably containing from 1 to 6 carbon atoms in the alkanediyl chain;
  • W 2 is S, PR 22 or NR 22 ;
  • the or each group R 22 is hydrogen or alkyl of 1 to 4 carbon atoms or the two groups R 22 together with the heteroatom to which they are attached form a heterocyclic ring of 5 to 7 atoms;
  • R 23 is alkanediyl of 1 to 20, preferably 1 to 10, more preferably 1 to 6 carbon atoms;
  • a 15 is a bond, NH, S or O, preferably O; and
  • R 24 is a hydroxyl, C 2 alkyl, C
  • a 14 is a bond; R 21 is a C 2-6 alkanediyl; W 2 is NR 22 : each R 22 is C,. 4 alkyl; R 23 is C 2 _ 6 alkanediyl; A 15 is O; and R 24 is C ⁇ alkoxy.
  • a zwitterion having no overall charge may be a sulphobetaine group, of the general formula XI
  • R 25 are the same or different and each is hydrogen or C,. 4 alkyl and w is from
  • the groups R 25 are the same. It is also preferable that at least one of the groups R 25 is methyl, and more preferable that the groups R 25 are both methyl. Preferably w is 2 or 3, more preferably 3.
  • Another example of a zwitterionic group has a carboxylate group.
  • One such group is an amino acid moiety in which the alpha carbon atom (to which an amine group and the carboxylic acid group are attached) is joined through a linker group to the backbone of the polymer.
  • Such groups may be represented by the general formula XII
  • a 16 is a valence bond, -O-, -S- or -NH-, preferably -O-
  • R 26 is a valence bond (optionally together with A 16 ) or alkanediyl, - C(O)alkylene- or -C(O)NHalkylene, preferably alkanediyl and preferably containing from 1 to 6 carbon atoms
  • the groups R 27 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or two or three of the groups R 27 , together with the nitrogen to which they are attached, form a heterocyclic ring of from 5 to 7 atoms, or the three group R 27 together with the nitrogen atom to which they are attached form a fused ring heterocyclic structure0 containing from 5 to 7 atoms in each ring.
  • a zwitterion having a carboxylate group is a carboxy betaine -N ⁇ (R 28 ) 2 (CH 2 ) x COO ⁇ in which the R 28 groups are the same or different and each is hydrogen or C 1 . 4 alkyl and x is 2 to 6, preferably 2 or 3.5
  • the polymer has additional ionic groups.
  • the ionic groups are pendant groups from the backbone of the polymer.
  • the polymer therefore has pendant highly hydrophilic groups and pendant ionic groups different to the highly 0 hydrophilic groups.
  • the polymer at the device surface is crosslinked.
  • the polymer may be covalently bound to other components of the material or to underlying components of the device, for instance where the material is a coating on the device.
  • Crosslinked5 materials are found to be particularly stable over extended periods, for instance over long term use of the orthopaedic device.
  • the polymer is obtainable by polymerisation of ethylenically unsaturated monomers including a monomer having a highly hydrophilic substituent group, a monomer having an ionic substituent group, a surface o adherent monomer and a crosslinkable monomer capable of crosslinking after said polymerisation.
  • A is -O- or NR 1 ;
  • a 1 is selected from a bond, (CH 2 )A 2 and (CH 2 ), SO 3 in which I is 1 to
  • a 2 is selected from a bond, -O-, O-CO-, CO-O, CO-NR 1 -, -NR 1 -CO, O-CO-NR 1 - and NR 1 -CO-O-;
  • R is hydrogen or C,. 4 alkyl;
  • R 1 is hydrogen, C
  • R 2 is hydrogen, C,. 4 alkyl or BX;
  • B is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents;
  • X is the zwitterionic group.
  • B is an alkanediyl group, preferably having 2 to 6 carbon atoms and most preferably being a straight chain alkanediyl group.
  • R 6 is hydrogen or C r C 4 alkyl
  • R 7 is hydrogen, C,. 4 -alkyl or B 1 Q
  • a 5 is -O- or -NR 8 -, wherein R 8 is hydrogen or a C r C 4 alkyl group or R 8 is a group -B 1 -Q
  • a 6 is selected from a bond, (CH 2 ) n A 7 and (CH 2 ) n SO 3 in which n is 1 to 12
  • a 7 is selected from a bond, O, OCO, COO, CONR 8 , NR 8 CO, OCONR 8 and NR 8 COO
  • B 1 is a valence bond, a straight or branched alkylene, oxaalkylene or oligo-oxaalkylene group
  • the ionic substituent may be anionic, in which case the ion is selected from carboxylate, sulphonate, phosphonate and phosphate groups.
  • Q is suitably hydrogen where B 1 is a bond and Y is as indicated, to provide a carboxylate group.
  • group B 1 is other than a bond and Q is an anionic group, for instance a carboxylate, sulphonate, phosphonate or phosphate group.
  • the ionic group Q is cationic.
  • the group is preferably selected from a group -NR ⁇ 9 3 in which each group R 9 is the same or different, and is hydrogen or alkyl of 1 to 6 carbon atoms two of which groups R 9 may together from a heterocyclic ring containing from 5 to 7 atoms, preferably hydrogen or methyl, a group N ⁇ Het, where Het is an unsaturated heterocyclic group such as pyridyl, substituted or unsubstituted by one or more alkyl groups of 1 to 4 carbon atoms, and a group -P ffi R 10 3 in which each group R 10 is the same or different and is R 9 or OR 9 , preferably in which R 9 is hydrogen or alkyl of 1 to 6 carbons atoms, two of which groups R 10 may together form a heterocyclic ring containing from 5 to 7 atoms, preferably methyl.
  • the polymer is, as preferred, a crosslinked material
  • R 11 is hydrogen or C r C 4 alkyl
  • a 8 is O or NR 13
  • a 9 is selected from a bond, (CH 2 ) P A 10 and (CH 2 ) p SO 3 in which p is 1 to
  • Q 1 is a crosslinkable group.
  • Q 1 contains a group selected from cinnamyl, epoxy, -CHOHCH 2 Hal (in which Hal is a halogen atom), methylol, reactive silyl (e.g.
  • the crosslinkable monomer is an (trialkoxysilyl) alkyl(meth)acrylate, for instance 3-(trimethoxysilyl) propyl methacrylate.
  • R 14 is hydrogen or C,-C 4 alkyl
  • a 11 is -O- or -NR 15 - where R 15 is hydrogen or a 0,-0- 4 alkyl group or
  • R 15 is a group Q 2 ;
  • a 12 is selected from a bond, (CH 2 ) 2 A 13 and (CH 2 ) q SO 3 in which q is 1 to 12;
  • a 13 is selected from a bond O, OCO, COO, CONR 15 , NR 15 CO, OCONR 15 and NR 15 COO;
  • R 16 is hydrogen, C ⁇ alkyl or Q 2 .
  • Q 2 is (a) a straight or branched alkyl, alkoxyalkyl or (oligo-alkoxy)alkyl chain containing 6 or more, preferably 6 to 24, carbon atoms unsubstituted or substituted by one or more fluorine atoms and optionally containing one or more carbon-carbon double or triple bonds; or (b) a siloxane group -(CR 17 2 ) r (SiR 18 2 ) (OSiR 18 2 ) s R 18 in which each group R 17 is the same or different and is hydrogen or alkyl of 1 to 4 carbon atoms or aralkyl, for example benzyl or phenethyl, each group R 18 is alkyl of 1 to 4 carbon atoms, r is from 1 to 6 and s is from 0 to 49.
  • the surface adherent monomer is a compound in which Q 2 is an alkyl group of formula -(CR 19 2 ) t CR 19 3 wherein the groups -(CR 19 2 )- are the same or different, and in each group -(CR 19 2 )the groups R 19 are the same or different and each group R 19 is hydrogen, fluorine or C,.
  • ethyl or fluoroalkyl and t is from 5 to 23 if Q 2 contains no fluorine atoms or from 1 to 23, preferably 5 to 23, if Q 2 contains one or more fluorine atoms; an alkoxyalkyl having 1 to 12 carbon atoms in each alkyl moiety; unsubstituted or substituted by one or more fluorine atoms; or an (oligo-alkoxyl) alkyl group of formula -[(CR 20 2 ) n O] u (CR 20 2 ) V R 20 where the groups -(CR 20 2 )- are the same or different and in each group -(CR 20 2 )- the groups R 20 are the same or different and each group R 20 is hydrogen, fluorine or C,_ 4 alkyl or fluoroalkyl and u is from 2 to 6, preferably 3 to 4, and v is from 1 to 12.
  • the ethylenically unsaturated monomers may further comprise comonomers, for instance compounds
  • R 29 is selected from hydrogen, halogen, C ⁇ alkyl and groups COOR 33 in which R 33 is selected from hydrogen and C.,. 4 alkyl; R 30 is selected from hydrogen, halogen and C 1 . 4 alkyl; R 31 is selected from hydrogen, halogen, C, ⁇ alkyl and groups COOR 33 provided that R 29 and R 31 are not both COOR 33 ; and R 32 is a C ⁇ o alkyl, a C,. 20 alkoxycarbonyl, a mono-or di-(C,. 20 alkyl) amino carbonyl, a C 6 . 20 aryl (including alkaryl) a C 7-20 aralkyl, a C 6 .
  • acyloxy group any of which may have one or more substituents selected from halogen atoms, alkoxy, oligo-alkoxy, aryloxy, acyloxy, acylamino, amine (including mono and di-alkyl amino and trialkylammonium in which the alkyl groups may be substituted), carboxyl, sulphonyl, phosphoryl, phosphino, (including mono- and di- alkyl phosphine and tri-alkylphosphonium), zwitterionic, hydroxyl groups, vinyloxycarbonyl and other vinylic or allylic substituents, and reactive silyl or silyloxy groups, such as trialkoxysilyl groups; or R 32 and R 31 or R 32 and R 30 may together form -CONR 3 CO in which
  • R 34 is H or a C ⁇ n alkyl group. It is preferred for at least two of the groups R 29 , R 30 , R 31 and R 32 to be halogen or, more preferably, hydrogen atoms. Preferably R 29 and R 30 are both hydrogen atoms. It is particularly preferred that compound of general formula V be a styrene-based or acrylic based compound. In styrene based compounds R 32 represents an aryl group, especially a substituted aryl group in which the substituent is an amino alkyl group, a carboxylate or a sulphonate group.
  • R 32 is an alkoxycarbonyl, an alkyl amino carbonyl, or an aryloxy carbonyl group.
  • Monomers of the general formula V may be used to give the polymer the desired physical or mechanical properties.
  • Particular examples of diluent comonomers include alkyl(alk)acrylate preferably containing 1 to 4 carbon atoms in the alkyl group of the ester moiety, such as methyl (alk)acrylate; a dialkylamino alkyl(alk)acrylate, preferably containing 1 to 4 carbon atoms in each alkyl moiety of the amine and 1 to 4 carbon atoms in the alkylene chain, e.g.
  • 2-(dimethylamino)ethyl (alk)acrylate 2-(dimethylamino)ethyl (alk)acrylate; an alkyl (alk)acrylamide preferably containing I to 4 carbon atoms in the alkyl group of the amide moiety; a hydroxyalkyl (alk)acrylate preferably containing from 1 to 4 carbon atoms in the hydroxyalkyl moiety, e.g.
  • a 2-hydroxyethyl (alk)acrylate or a vinyl monomer such as an N-vinyl lactam, preferably containing from 5 to 7 atoms in the lactam ring, for instance vinyl pyrrolidone; styrene or a styrene derivative which for example is substituted on the phenyl ring by one or more alkyl groups containing from 1 to 6, preferably 1 to 4, carbon atoms, and/or by one or more halogen, such as fluorine atoms, e.g. (pentafluorophenyl)styrene.
  • a vinyl monomer such as an N-vinyl lactam, preferably containing from 5 to 7 atoms in the lactam ring, for instance vinyl pyrrolidone
  • styrene or a styrene derivative which for example is substituted on the phenyl ring by one or more alkyl groups containing from 1 to 6, preferably 1 to
  • Suitable diluent comonomers include polyhydroxyl, for example sugar, (alk)acrylates and (alk)acrylamides in which the alkyl group contains from 1 to 4 carbon atoms, e.g. sugar acrylates, methacrylates, ethacrylates, acrylamides, methacrylamides and ethacrylamides.
  • Suitable sugars include glucose and sorbitol.
  • Particularly suitable diluent comonomers include methacryloyl glucose or sorbitol methacrylate.
  • Further diluents which may be mentioned specifically include polymerisable alkenes, preferably of 2-4 carbon atoms, eg.
  • Diluent comonomers may be obtained by conventional known methods. Of the above diluent comonomers some are inert and act simply to modify the physical and mechanical properties of copolymers containing them. Others, and in particular the hydroxyalkyl(alk)acrylates and polyhydroxyl (alk)acrylates have a reactive role in addition to simply modifying physical and mechanical properties. Such comonomers contain functional groups, such as hydroxyl groups, which may react with a crosslinking group or may react with reactive groups in other molecules to attach them to the copolymer.
  • alkyl(alk)acrylates containing 6 or more carbon atoms in the alkyl group may be regarded as either diluent comonomers or as adherent comonomers capable of binding a polymer to a surface by physisorption.
  • the polymers described above when expressed at the surface of an orthopaedic implant, in particular, polymers having cationic and zwitterionic PC groups, have interesting properties when contacted with human osteoblasts (HOBS). Preliminary results suggest that the presence of charge in the polymer can induce the HOBS to undergo rapid mineralisation as demonstrated by significant calcium presence, alkaline phosphatase expression and lead to mineral-like nodules under scanning electron microscopy.
  • the materials are suitable for application to the surfaces of a variety of materials useful for forming orthopaedic implant devices, such as metals for instance stainless steel and titanium, ceramics, plastics, etc. to form stable coatings.
  • the materials are biocompatible by virtue of the presence of the hydrophilic pendant groups.
  • the polymer appears to increase adhesion of osteoblasts to an implant device coated with the material, increase the rate of mineralisation on the surface of the device and increase the level of expression of alkaline phosphatase in osteoblasts growing on the surface of the device.
  • Implant devices which could make use of this invention include, but are not limited to:- hip implants, knee joints, finger joints, elbow replacements, bone screws and pins, other permanent fixation devices, spinal discs where some integration between disc and vertebral bone is desirable, bone defect filling materials, dental implants, cranio-maxillofacial devices, bone plates, bone and dental cements.
  • the polymer as defined above in the manufacture of an orthopaedic implant device, wherein the polymer is comprised in material at at least the bone-contacting surface of the device, for increasing the osteointegration of the device, increasing adhesion of osteoblasts to the device, increasing the rate of mineralisation on the surface of the device and/or increasing the level of expression of alkaline phosphatase in osteoblasts growing on the surface of the device.
  • a surgical method in which a device of the invention is implanted into an animal whereby the surface formed of the defined material is in contact with bone.
  • a process for manufacturing an orthopaedic implant device in which a device body is provided on at least a part of its bone-contacting surface with a coating of polymer as defined above.
  • the process involves coating by contacting the device body with a liquid coating composition comprising a solvent and a coating polymer followed by removal of the solvent to leave the coating polymer on the surface.
  • the solvent is removed by evaporation.
  • the coating polymer is cross-linkable and is crosslinked after coating to form the defined polymer.
  • Crosslinking may be by subjecting the polymer to conditions under which the crosslinkable groups form covalent bonds, for instance raised temperature, imposition of radiation, for instance UV radiation or contact with crosslinking agent.
  • the monomer 2-methacyloyloxyethyl phosphorylcholine (MPC) was synthesised and purified and described in US-A-5,741 ,923. Lauryl methacrylate (LMA), hydroxypropyl methacrylate (HPMA) and 3-
  • TMSMA trimethoxysilylpropyl methacrylate
  • CMA Choline methacrylate
  • Polymerisation was conducted using a monomer starved free radical polymerisation method and AIBN as initiator similar to that described by us previously [19]. All polymerisations were conducted under a nitrogen atmosphere at 83°C using isopropyl alcohol (iPA) to solubilise the monomer mixture and isopropyl acetate to dissolve the initiator.
  • iPA isopropyl alcohol
  • Example 2 Confirmation of surface charge.
  • Polymers described in example 1 can be applied to surfaces as a solution in alcohols such as ethanol. Coatings may be applied by conventional methods including dip, spin and spray-coating.
  • the presence of the charged groups can be visualised by staining with an appropriate dye that will interact with the charged groups.
  • the anionic dye amaranth is a suitable choice for visualisation of positively charged polymers (see Figure 1 ). Which shows the visualisation of surface charge by amaranth staining of polymers with varying cationic charge.
  • Table 1 Generic Structure of Cationically-charged Phospholipid Polymers and their Composition v, w, x, y and z molar represent parts of starting monomers.
  • Analysis Range Polymer yield 57 - 85% Silicon content (by EA) 0.39 - 0.51 wt% Residual monomer content (by HPLC): MPC 0.18-0.34% LMA 0.03-0.17% HPMA 0.025-0.03% TMSMA 0.012-0.055% CMA 0.02-0.14% Molecular weight (by GPC) 131 ,000 - 425,600
  • Example 3 Culture of human osteoblasts (Hobs) on polymer surfaces and analysis by staining. Tissue culture flasks (25ml) were coated with 1 wt% ethanolic solution of polymers containing 0, 5 & 20% CMA and cured at 72°C for 72 hours. Uncoated tissue culture flasks were used as controls. Human osteoblasts (Hobs) were seeded into flasks at a density of 1x10 4 /cm 2 and cultured in McCoy's medium containing 10% foetal calf serum, 1 % glutamine and 30 ⁇ g/ml vitamin C. Images of cells on polymer and control surfaces were captured using an optical microscope and 3-chip colour camera connected to a computer with frame grabber and image analysis software.
  • Hobs human osteoblasts
  • ALP activity was measured by staining with Alizarin red and Fast Red TR respectively: a) Mineralisation: Dissolve Alizarin red in water, adjust pH to 4.2 with ammonium hydroxide. Stain cells for 1-5 min at room temperature. Rinse in acetone, followed by xylene-acetone (1 :1 ). Final wash in xylene. b) ALP Activity: Stock solution of 0.2mg/ml napthol AS-MX phosphate (dissolved in N,N dimethylformamide) diluted in 0.1 M Tris buffer at pH 9.2. Add 1 mg/ml Fast Red TR Salt to stock solution & sterile filter before immediate use. React with fixed cells for 2 min at room temperature. Hobs expressed distinct morphologies on PC and control surfaces
  • FIG. 3(c) shows an image of Hobs on CMA(O)(a), CMA5(b), CMA20(c) and control (d).
  • the scale bar is 100 ⁇ m and N in (c) signifies a mineral nodule.
  • the results show that PC surfaces are capable of inducing specific morphologies in Hobs. Cell adhesion and spreading increases with cationic charge. There is also the early deposition of mineral in granular modules which showed positive staining for calcium.
  • HAPEX topography influences osteoblast response. Tissue Eng. 2002; 8: 453-467.
  • Phosphorylcholine coating offers natural platelet preservation during cardiopulmonary bypass.
  • Berry JA Biedlingmaier JF, Whelan PJ. In-vitro resistance to bacterial0 biofilm formation on coated fluoroplastic tympanostomy tubes. Otolaryngol Head Neck Surg 2000; 123: 246-251.
  • Chen C Lumsden AB, Ofenloch J, Beverly N, Campbell EJ, Stratford PW, Yianni YP, Taylor AS, Hanson SR.
  • Phosphorylcholine coating of ePTFE grafts reduced neointimal hyperplasia in canine model. Ann Vase Surgery5 1997; 11 (1 ): 74-79.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne un dispositif sous forme d'implant orthopédique, tel qu'un implant de remplacement osseux, comportant des surfaces de contact osseux constituées de matériaux favorisant l'ostéo-intégration et renfermant des groupes hautement hydrophiles pendants et présentant une charge globale au pH physiologique. Les groupes hautement hydrophiles sont généralement des groupes zwittérioniques, tels que des groupes phosphorylcholine. La surface peut être formée par revêtement d'un substrat de dispositif avec un polymère renfermant des groupes zwittérioniques et des groupes ioniques, et par stabilisation de ce polymère sur la surface, notamment par réticulation. L'invention se rapporte en outre à des ostéoblastes humains permettant d'adhérer à des surfaces.
PCT/GB2004/004000 2003-09-19 2004-09-17 Dispositifs orthopediques WO2005027991A1 (fr)

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US5645883A (en) * 1993-01-28 1997-07-08 Biocompatibles Limited Zwitterionic materials
US6251964B1 (en) * 1996-11-20 2001-06-26 Biocompatibles Limited Biocompatible compositions
WO1999055742A1 (fr) * 1998-04-29 1999-11-04 Marchant Roger E Tensioactifs presentant un mimetisme par rapport au glycocalyx
US6447920B1 (en) * 1998-04-30 2002-09-10 Novartis Ag Organic articles
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WO2001049268A1 (fr) * 2000-01-05 2001-07-12 Imarx Therapeutics, Inc. Formulations pharmaceutiques pour l'administration de medicaments ayant une faible solubilite aqueuse
WO2001052915A1 (fr) * 2000-01-24 2001-07-26 Biocompatibles Limited Implants revetus
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