CARTILAGE REPAIR IMPLANT

The present invention relates to an implant for use in effecting a repair to damaged cartilage tissue and to use of the material in effecting repair of damaged cartilage or other soft tissue.

Cartilage is a type of connective tissue found on the ends of bones which protects and cushions them and absorbs the forces transmitted throughout the body. Cartilage permits the smooth movement of joints and is an elastic tissue without a direct blood supply. There are three main types of cartilage: hyaline, elastic and fibro cartilage. The most frequent and significant cartilage injury is damage to the crescent-shaped cartilage in the knee (meniscus) which occurs between the femur and the tibia.

Ultimately, treatment of orthopaedic presentations involving damaged cartilage require replacement using artificial joints. However, there is a need for temporary repair of the cartilage in order to delay and possibly even avoid the need for joint replacement, such as total knee replacement. This is particularly important in patients over the age of 40 where cartilage does not regenerate or repair naturally.

The structure of cartilage tissue is well known and is discussed widely in text books on human physiology and is therefore not discussed in detail here. Water constitutes between 65 and 80% of the entire wet weight of cartilage and this is about 15% more concentrated at the surface than in the deeper zones. Collagen makes up about 15 to 22% of the wet weight and contains 90 to 95% type 2 collagen fibres. Proteoglycans constitute about 4 to 10% of the total wet weight and are a mix of large aggregating (50 to 85%) and large non-aggregating (10 to 40%) proteoglycans.

Much of the work done previously concerning the repair of cartilage tissue is centred not only on filling defects in cartilage but also in encouraging cartilage formation and subsequent implant resorption. A number of different attachment modes for surgical repair implants have been described. For example, US-6629997 describes surgical implants that are designed to replace meniscal tissue and possibly cartilage in a mammalian joint. This

document describes a hydrogel which incorporates a mesh component that reinforces the smooth and lubricious surface and provides reinforced means for anchoring the implant to the tissue which surrounds the joint.

US-6632246 describes a preformed, pre-sized and pre-shaped cartilage replacement plug made from a biocompatible material. The plug is intended to replace a portion of damaged or diseased cartilage which has been resected. Ridges are formed in the periphery of the plugs to facilitate a mechanical interlocking with the surrounding natural cartilage, with bone and/or one another.

An alternative long-term treatment involves either self harvesting and use of denuded chondrogenic cells which are proliferated ex vivo as mono layer cultures and seeded in a pre-shaped well. When the cells redifferentiate they begin to excrete cartilage-specific extracellular matrix. An alternative to such a self-harvesting procedure involves the use of cadaveric cartilage specimens. Both these options present the problem of potential for infection or transmission of disease.

EP-A- 1270025 discloses an implant which can be attached to bone, which comprises a composite scaffold with a porous ceramic phase and a porous polymer phase. Both the ceramic phase and the polymer phase have a number of pores contained therein. The porous ceramic phase encourages bone attachment into the pores. The polymer phase is attached to the ceramic phase at an interphase reaction because the polymer phase infuses at least partially into the pores in the ceramic region.

When a hydrogel material is intended for use to repair a cartilage defect, a significant problem involves the need for adequate fixation of the hydrogel defect repair material to the patient's surrounding cartilage tissue or bone tissue or both. One problem that any candidate material must address is the need to be bonded and remain bonded to surrounding tissue even following hydration. If this is not achieved then the defect cannot be adequately repaired. Some of the prior art addresses this problem as described above by using a mesh component which provides reinforced means for anchoring the device to

tissue. However, this approach suffers the disadvantage that the repair material may potentially become detached during initial placement.

WO-03/065932 describes a non-resorbable implant for repairing or replacing damaged cartilage in a mammalian joint which provides a soft and bendable bearing surface which is bonded to a flexible anchoring grid.

The present invention provides a cartilage repair implant which comprises a layer of a resilient substitute cartilage material and an anchor layer comprising an acrylate based polymer (especially a methacrylate based polymer) which is loaded with a calcium salt.

Accordingly, in one aspect, the invention provides a cartilage repair implant comprising (a) a layer of a resilient substitute cartilage material and (b) an anchor layer to which the layer of the resilient substitute cartilage material is bound to form a composite structure, in which the anchor layer comprises an acrylate based polymer and contains calcium ions which can be leached from the layer to facilitate growth of bone tissue into the anchor layer.

The implant of the invention has the advantage of enabling secure fixation to bone tissue which underlies the cartilage which is to be repaired. The fixation is achieved by growth of bone tissue into the anchor layer at least at the surface of the layer where it contacts bone. The fixation can take place without the formation of fibrous tissue at the interface between the bone and the implant. The bone tissue growth can take place as a result effectively of progressive substitution of calcium salt filler particles in the material of the anchor layer, especially at the surface of the layer, as the filler is leached out of the layer. The use of a filler which can act as a source of calcium ions has the advantage of stimulating bone growth, at least under favourable conditions. Bone can grow into the cement composition over an extended period, for example of six months or more, to a depth of several micrometres, for example to a depth of at least about 50 μm, or at least about 100 μm, preferably at least about 250 μm, more preferably at least about 1 mm, and possibly to greater depths, for example at least about 2 mm, or at least about 4 mm.

Preferably, the resilient substitute cartilage material layer is bound directly to the anchor layer so that there is no intermediate layer between them. The resilient substitute cartilage material layer can be bound indirectly to the anchor layer, with one or more intermediate layers between them. An intermediate layer might be a layer of an adhesive or other bonding material by which the hydrogel and anchor layers are bound together. Other intermediate layers might be included, such as for example reinforcing layers, for example of fibres which might also be used to anchor the implant to surrounding tissue by suturing.

A mesh of suture material which might be provided by reinforcing fibres can provide reinforcement of the implant, and optionally also a method of attachment to the surrounding cartilage tissue. The advantage of the implant material of the present invention is that the risk of suture detachment is minimal because the same suture material provides both reinforcement to the repair material and the means of attachment. It is particularly advantageous if at least part of the reinforcing fibres are encapsulated within the body of the hydrogel layer. This reduces further the risk of suture detachment. The anchor layer may include means for attachment to the bone.

Preferably, the resilient substitute cartilage material is a hydrogel. A hydrogel is a three dimensional macromolecular network which swells when exposed to a liquid (which will generally be water based in the context of the present invention), and comprises a cross- linked polymer. The polymer might well tend to dissolve in the liquid under certain conditions if it is not crosslinked. Ideally, the properties of the hydrogel used in the repair material approach those of cartilage material. Accordingly, the repair material must be hydrophilic, i.e. it must be able to attract and hold a quantity of water to function well. The hydrated material must also be flexible, pliable and gel-like.

Polymers which can be used to make suitable hydrogels are frequently polymers which, at least at low molecular weight, are soluble in water. They can be made to swell to form a gel, instead of dissolving, by crosslinking. Techniques for making biocompatible hydrogel materials are disclosed in US-3822238, US-4107121, US-4192827, US-4424305, US- 4427808 and US-4563490. Examples of useful materials include certain polyurethanes, certain polymers based on vinyl alcohol monomers, certain polyacrylonitriles and certain

methacrylate or other acrylate polymers. A suitable material might be poly(2-hydroxyethyl methacrylate) (or pHEMA), or copolymers which are based on 2-hydroxyethyl meth- acrylate. The use of this material in the manufacture of cartilage replacements is discussed in an article by H R Oxley et al, in Biomaterials (1993), vol 14, pages 1064 to 1072.

Mixtures of polymers can be used for the hydro gel component of the implant, for example a mixture which comprises polyvinyl alcohol) with a small quantity (for example about 1% by weight) of polyvinyl pyrrolidone).

Suitable hydrogel materials can be chemically treated to optimise the lubricating properties, for example by a sulphonation treatment of the exposed surface. Surface treatments can also be used to optimise characteristics such as strength, toughness, and resistance to tearing or abrasion or both. Sulphonation can be carried out by exposure to dilute sulphuric acid.

Alternative materials for the resilient substitute cartilage material should be biocompatible and suitably flexible. These might include silicone, polyurethanes, ethylene, copolymers of poly(ethylene terephthalate), for example ethylene oxide/ethylene terephthalate copolymer (PEO/PET) and ethylene terephthalate/dilinoleic acid copolymer, (PET/DLA) and copolymers of poly(butylene terephthalate) for example butylene terephthalate/ethylene terephthalate copolymer (PBT/PET) and butylene terephthalate/dilinoleic acid copolymer (PBT/DLA).

Preferably, the implant includes reinforcing fibres. Preferably, the reinforcing fibres extend from the edges of the implant for suture attachment to surrounding tissue. Preferably, the reinforcing fibres are at least partially contained within the resilient substitute cartilage material layer. The reinforcing fibres can be provided at the upper exposed surface of the resilient substitute cartilage material, or at the bottom face of the resilient substitute cartilage material, where the resilient substitute cartilage material is bound to the anchor layer. Preferably, the fibres are at least partially embedded in the resilient substitute cartilage material layer. The fibres might be at least partially embedded in the material of the anchor layer.

The reinforcing fibres should preferably be bound to the material of the resilient substitute cartilage material layer or of the anchor layer. Binding the fibre to the material of the resilient substitute cartilage material layer or of the anchor layer may be improved by surface treatment of the fibre with for example corona or plasma. In addition, a surface coating may be applied to the fibres to provide a chemical bond e.g. silane such as

3-trimethoxysilylpropyl methacrylate. The reinforcing fibres can be made from resorbable or non-resorbable materials. They can be monofilament or multifilament. Non-resorbable sutures, made from a variety of non biodegradable materials, are ultimately encapsulated or walled off by fibroblasts. Any biocompatible material which is not resorbed under physiological conditions can be used for the reinforcing fibres of the repair implant of the present invention. Preferred materials include polyamides (nylons) and polypropylenes, and mixtures thereof.

The anchor layer should be fastened to the resilient substitute cartilage material layer so that the two will not readily separate when the implant is in normal use after implantation. The layers can be fastened to one another mechanically or chemically. For example, the resilient substitute cartilage material layer can be fastened to the anchor layer by mechanical trapping of the resilient substitute cartilage material within suitable voids provided in the anchor layer. The resilient substitute cartilage material layer can be fastened to the anchor layer by means of adhesive. The resilient substitute cartilage material layer can be chemically bound directly to the anchor layer. The layers can be fastened to one another as a result of one of the layers being formed in situ in the surface of the other layer.

The anchor layer comprises a methacrylate or other acrylate based polymer. Such polymers are known for use in bone cement materials. Suitable materials can be formed by copolymerising a liquid material and a powder material. The liquid component of a bone cement material can include one or more monomers, and components for controlling the polymerisation reaction such as an activator and an initiator. The powder component can include polymer components, and components for controlling the polymerisation reaction such as initiators.

A particularly preferred bone cement composition for use in the anchor layer of the implant of the invention comprises (a) the product of a polymerisation reaction between a high molecular weight dimethacrylate monomer having a molecular weight of at least 250 and bearing at least one hydrophilic group, a monofunctional methacrylate monomer having a molecular weight of not more than 250 bearing at least one hydrophilic group, an methacrylate monomer, and a polymer having a molecular weight of at least 200,000, and (b) an inorganic filler which is present in an amount of at least about 40% by weight, based on the total weight of the cement composition. Such a cement composition, which can be used to form the anchor layer of the cartilage repair implant of the present invention, is disclosed in an international application which is being filed with the present application claiming priority from UK patent application no. 0514076.9. Subject matter relating to the composition of this material for the anchor layer, and also relating to liquid and powder formulations which can be reacted together to form the material, which is disclosed in the specification of that application, is incorporated in the specification of this application by this reference.

Suitable liquid formulations for use in preparing bone cement comprise 5 to 35% by weight of a long chained monomer including hydrophilic groups, 5 to 35% by weight of a long chained monomer including hydrophilic groups, 5 to 35% by weight of a short chained monomer bearing hydrophilic groups and 30 to 90% by weight of a methacrylate monomer (preferably methyl methacrylate).

Suitable powder formulations for use in preparing bone cement comprise an inorganic filler in an amount of from 20 to 85% by weight, one or more biocompatible polymers having a molecular weight of at least 200,000 in an amount of from 15 to 80% by weight and an initiator in an amount of 0.10 to 2.0 by weight of the powder composition.

Preferably, the inorganic filler has a median particle size measured using a Beckman

Coulter laser diffraction particle size analyser which is at least about 1 μm, more preferably at least about 3 μm. Preferably, the size of the inorganic filler particles is not more than about 20 μm, more preferably not more than about 15 μm.

Preferably, the high molecular weight monomer is a bifunctional methacrylate-based monomer. This monomer should contain hydrophilic groups.

Preferred long-chained monomers include urethane dimethacrylate (UDMA) ₃ bis-glycol dimethacrylate (bis-GMA), polyethylene glycol dimethacrylate (PEGDMA).

The high molecular weight monomer is a monomer capable of cross-linking. The lower molecular weight monomer is a monofunctional methacrylate monomer. This monomer should also contain hydrophilic groups. Preferred monofunctional methacrylate monomers include tetrahydrofurfuryl methacrylate (THFMA).

Preferably, the methacrylate-based monomer is methyl methacrylate. Examples of hydro- philic groups present on the high molecular weight and lower molecular weight monomers included oxygen-containing groups and nitrogen-containing groups. Specific groups include oxygen containing heterocyclic groups, hydroxyl groups and amine or amide groups.

Preferably, the powder component contains an initiator to initiate the polymerisation reaction on contact with the liquid component. Preferred initiators include organic peroxides such as benzoyl peroxide. The initiator is present in an amount of 0.10 to 2.0% by weight of the powder composition. More preferably it is present in an amount of 0.20 to 1.0% by weight.

Preferably, the liquid contains an inhibitor to inhibit polymerisation because methacrylate polymers can polymerise spontaneously under normal storage conditions. Suitable inhibitors include hydroquinone, the monomethyl hydroquinone and butylated hydroxy- toluene. The inhibitor is present in an amount of 0.001 to 1.00% by weight.

Preferably, the activator present in the liquid is a tertiary amine such as N,N-dimethyl-p- toluidine or N,N-dihydroxyethyl-p-toluidine the polymerization reaction is initiated when the initiator and activator come into contact with one another during the physical mixing of the powder and liquid.

Preferably, the peroxide is contained in the polymer and additionally can be added as free peroxide to adjust the setting reaction.

Preferably, the liquid (monomer) contains an activator such as N,N-dimethyl-p-toluidine. The composition of the activator should be adjusted relative to the content of the initiator in the powder. Preferably, The liquid (monomer) also contains an inhibitor and an additional amount of inhibitor may be added during the manufacturing process to stabilise the cement liquid.

The high molecular weight polymer in the powder may be a single polymer or a combination of polymers. It can help to modify the viscosity of the material of the anchor layer in the period before it hardens.

Suitable polymers for use in the anchor layer include polymers of one or more of methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate and styrene. A preferred copolymer is methyl aciylate-methylmethacrylate.

It is preferred that the molecular weight of the high molecular weight polymer component of the material of the anchor layer should be at least about 200,000, more preferably at least about 500,000, especially at least about 750,000. Preferably, the high molecular weight polymer represents 15 to 80% by weight of the powder composition.

Preferably, the calcium ions are provided by an inorganic filler. Preferably, the filler is present in the material of the anchor layer in an amount of at least about 13% by weight of the material, preferably at least about 50% by weight of the material.

Preferred fillers include calcium phosphates (such as tricalcium phosphate (especially β- TCP)), calcium sulphate, and bioglass compositions. It will generally be preferred that the calcium containing compound be chosen according to the rate at which it will tend to be leached from the anchor layer, so that the rate of adsorption is comparable with the rate at which bone tends to grow into the anchor layer.

Preferably, the filler is present in the powder formulation in an amount of at least about 20%, more preferably at least about 30%, especially at least about 50%, by weight of the powder formulation. Preferably, the filler is present in the powder formulation in an amount of not more than about 90%, more preferably not more than about 85%, especially not more than about 75% by weight of the powder formulation.

Preferably, the filler is present in the material of the anchor layer in an amount of at least about 13% by weight of the material, preferably at least about 50% by weight of the material. Preferably, the filler is present in the material of the anchor layer in an amount of not more than about 63% by weight of the material.

Preferably, the amount of the filler in the material of the anchor layer is at least about 10% by weight, based on the total weight of the material of the anchor layer, more preferably at least about 25%, especially at least about 40%, for example at least about 50% or at least about 51%. Preferably, the amount of the filler in the material of the anchor layer is not more than about 70% by weight, based on the total weight of the material of the anchor layer, more preferably not more than about 65%, especially not more than about 63%, for example not more than about 55%.

The implant of the invention can include a quantity of an uncured bone cement material on the surface of the anchor layer which faces towards the bone, for bonding the cartilage repair implant to the surface of a bone. The uncured bone cement material can cure in situ when positioned between the anchor layer and the bone and can provide fixation, at least initially after the implantation procedure, of the implant to the bone. Subsequent growth of bone into the anchor layer surface can further secure the implant to the bone surface.

The configuration of the repair implant will be selected according to the intended application. The thickness of the resilient substitute cartilage material layer will generally be at least about 1 mm, preferably at least about 2 mm. Its thickness will generally be not more than about 20 mm, preferably not more than about 10 mm, for example about 3 mm. The thickness of the anchor layer will generally be at least about 1 mm, preferably at least

about 5 mm. Its thickness will generally be not more than about 20 mm, preferably not more than about 10 mm, for example about 7 mm.

The size and shape of the repair implant, when viewed from above, will generally be selected according to the requirements of a particular patient. It might have a surface area of at least about 0.1 cm ² , or at least about 0.25 cm ² , for example at least about 0.7 cm ² . The surface area of the repair implant will generally be not more than about 100 cm ² , preferably not more than about 50 cm ² , especially not more than about 7.0 cm ² , for many applications.

The repair implant of the invention can comprise a plurality of segments which are shaped so that they can be fitted together in a tessellated array, in which each of the segments comprises (a) a layer of resilient substitute cartilage material and (b) an anchor layer to which the layer of the resilient substitute cartilage material is bound to form a composite structure. An implant which includes a plurality of segments has the advantage that it can be used in the repair of cartilage defects whose sizes might vary, by selection and appropriate arrangement of a plurality of the segments. The segments should be capable of being fitted together in a tessellated array, in which the resilient substitute cartilage material presents an approximately continuous surface which does not include any significant gaps or spaces between adjacent segments. Preferably, each of a plurality of the segments has the same shape when viewed from above. A tessellated array can be formed then from segments in which the common shape of the segments is that of a regular polygon, in which the number of sides of the polygon is at least three, for example three, four, or six. A tessellated array can also be formed from a plurality of segments which have complimentary primary and secondary shapes. For example, a tessellated array might be formed from a plurality of primary segments which are shaped as regular octagons, with complimentary secondary segments which are shaped as squares, in which the length of the sides of the octagons is the same as the length of the sides of the squares.

Preferably, each of a plurality of the segments (which might be primary segments or secondary segments or each of them, when the implant comprises primary and secondary segments) is sized so that it fits wholly within a circle when viewed from above which has

a diameter of not more than about 10 cm, more preferably not more than about 7 cm, especially not more than about 5 cm, for example not more than about 3 cm. Preferably, each of a plurality of the segments (which might be primary segments or secondary segments or each of them, when the implant comprises primary and secondary segments) is sized so that a circle fits wholly within it when viewed from above, having a diameter of at least about 0.3 cm, more preferably at least about 0.5 cm, for example at least about 1.0 cm.

EXAMPLE

1. Add 11.25 g of the liquid component to 2Og of the powder component. Mix the two components together for 45 minutes until an even paste is produced. Fill a 1 ml syringe with the cement.

2. Fill a suitable sized cylindrical mould cavity with the cement. Place the mould into a press, at room temperature until the cement has fully cured.

3. Push the cured cement into a polypropylene tube, which has internal dimensions approximately equal to the external dimensions of the cured cement cylinder.

4. The hydrogel may then be cured against the cured cement surface within the tube.

Alternatively the hydrogel may be chemically attached or physically attached to the cured cement cylinder.

A small amount of the uncured cement of this same composition may be placed on the bone surface prior to placing the implant against that surface, to give some immediate stability of the implant.

Molecular weight values which are referred to in this specification are weight average molecular weights.

Embodiments of the invention will now be described by way of example with reference to the accompanying drawings, in which:

Figure 1 is a schematic cross-section through a bone which has a cartilage repair implant according to the invention applied to it.

Figures 2 to 5 are plan views of cartilage repair implants according to the invention.

Figure 6 is a top view of one embodiment of a cartilage repair implant which includes reinforcing fibres .

Figure 7 is a top view of another embodiment of an implant with reinforcing fibres.

Figure 8 is a side view of an implant with reinforcing fibres.

Figure 9 is a top view of a section of a cartilage which has been repaired using an implant with reinforcing fibres. Figure 10 is a side view of the section of cartilage of Figure 9.

Referring to the drawings, Figure 1 shows a bone 2 (for example, the distal end of a femur) which has a bearing layer of natural cartilage tissue 4. A defect in the cartilage tissue has been repaired using a cartilage repair implant according to the invention. It comprises an anchor layer 6 of a cured acrylate polymer (as in the example above) and a layer 8 of a hydrogel which overlies the anchor layer.

The implant is fastened to the bone as a result of growth of bone tissue into the surface of the anchor layer. This follows gradual leaching of the calcium triphosphate from the anchor layer to create voids into which the bone tissue can grow.

The cartilage repair implants are provided tessellated segments which are arranged so that their edges abut to provide continuous bearing surfaces. Figure 2 shows segments 20 which have three sides. Figure 3 shows segments 22 which have four sides. Figure 4 shows segments 24 which have six sides. Figure 5 shows primary segments 26 which have eight sides and secondary segments 28 which have four sides.

Figure 6 shows a grid of reinforcing fibres 1 lying on top of a layer of hydrogel 2. The fibres are bound to the hydrogel (how) and extend beyond the edges of the hydrogel layer so as to provide points of attachment to surrounding cartilage.

Figure 7 shows another possible array of reinforcing fibres 1 on top of and bound to hydrogel layer 2.

The exact nature of the array is unimportant and any arrangement is permitted provided that suitable anchor points are present.

A side view of the repair material is shown in Figure 8 and illustrates an embodiment of the invention in which the reinforcing fibres 1 are present within the body of the hydrogel 2. This view also shows the base layer of the repair material which is formed of bone cement 3.

The hydrogel 2 and bone cement 3 effectively form a composite structure which has the appearance of a laminate with the hydrogel on top and the bone cement forming the base of the structure.

The base 4 of bone cement 3 is presented to a defect in the bone in use.

Figure 9 shows a section of cartilage which has been repaired with the repair material of the present invention.

Reinforcing fibres 2 are sutured into the area of undamaged cartilage 6 and the repair material 7 forms a unified structure with the cartilage 6.

Figure 10 shows a side view of the repaired defect 9 in which repair material 7 has completely filled the defect in the cartilage 6 and bone 8. In this view the reinforcing fibres penetrate into the undamaged region of cartilage 6 so as to provide a structurally strong repair.