WO2000018443A1 - Melt-mouldable composites - Google Patents

Abstract

Biodegradable, biocompatible, melt-mouldable composite suitable for use in the repair of tissue defects, said composite comprising a first bioresorbable, biocompatible polymeric component, which first polymeric component has a weight average molecular weight of greater than 3000 and becomes reversibly mouldable on heating.

Description

MELT-MOULDABLE COMPOSITES

The invention relates to a biodegradable, biocompatible material suitable for use in the repair of hard tissue defects resulting from, for example, tumour therapy, trauma and skeletal abnormalities. It can also be used in maxillofacial applications (ENT/cranial reconstruction) and for cosmetic reconstruction purposes. It finds application in the healthcare industry and more particularly the orthopaedic and endoscopic fields.

Reference herein to a material being "biodegradable" or bioresorbable means that it breaks down over a finite period of time due to the chemical/biological action of the body. Preferably, complete resorption occurs within about 5 years, more preferably within about 3 years. This breakdown is at a rate allowing the repair device to maintain sufficient integrity while the soft tissue or bone heals: surgical repair devices formed of materials which are resorbed too quickly may fail when compressive, tensile or flexural loads are placed on them when the bone has fully healed. Advantages of using biodegradable/bioresorbable materials over materials which do not biodegrade, e.g. metals, are that they encourage tissue repair and further surgery is not required to remove them.

Reference herein to a material being "biocompatible" means that it gives rise to essentially no adverse response when implanted into a patient and it does not cause physiologically induced damage.

The technique of bone grafting has a number of well identified problems associated with it, like those of source and supply, the risk of infection and the presence of inhomogeneities in the samples taken. Not to be forgotten are also the moral and religious reservations, which some societies have regarding these methods.

In the past, a wide range of synthetic alternatives for the repair/replacement of natural bone has been considered. Among these are products derived from coral, ceramic blocks, setting ceramics, gels, pastes and putties.

Substances which have previously been used as bone graft substitutes are polymers and copolymers of lactic acid and glycolic acids, poly(ethyleneoxide)/poly(ethylene terephthalate) copolymers, poly(methylmethacrylate), and α-alkyl-cyanoacrylates. Pre-formed ceramic materials have also been investigated for use in bone repair. Methyl methacrylate (MMA) has been used in applications such as bonding artificial hip joints to the femur. Ideally, bone replacement and repair materials should be biocompatible, formable in situ to a desired size and shape, and biodegradable while promoting or allowing natural bone ingrowth for ultimate repair of the injury. Pre-formed materials lack the flexibility required to accommodate odd-shaped and sized bone injuries and must be bonded to natural bone by a cement. Also, MMA cement, while formable to some extent, is composed of toxic methacrylate monomer, and is not biodegradable.

In conclusion, a large number of problems is associated with synthetic materials in the treatment of tissue defects. These can be summarised as follows:

- environmental issues (e.g. for coralline sources) - poor handling characteristics (e.g. they are not mouldable/conformable, are too brittle or friable) - poor mechanical performance (e.g. have low compressive/tensile/flexural strength)

- poor integration with bone (e.g. little or no adhesion)

- little degradability (i.e. they do not resorb or resorb too slowly) - high extractable levels (i.e. the levels of undesirable leechable components)

- setting behaviour which is not reproducible

- the material is incompatible with hardware (i.e. objects screwed in are not retained in the material).

Further to the last mentioned problem, the present invention is particularly concerned with providing a material which can be used with the hardware employed in a wide range of surgical procedures, like screws, plates, nails etc.

The present invention provides an improved material which solves the above-mentioned problems.

According to a first aspect of the invention, a composite is provided comprising a first bioresorbable, biocompatible polymeric component, which first polymeric component comprises a polyester with a weight average molecular weight of greater than 3000 that becomes reversibly mouldable on heating.

Below the weight average molecular weight limit of above 3000, the required mechanical properties like flexural and compressive modulus cannot be attained. As will be discussed, however, a weight average molecular weight significantly above this limit is preferred. Advantageously, the polyester is a polyhydroxy acid. These materials have the advantage that they can easily be metabolised by the body and that they tend to produce non-toxic breakdown products.

More advantageously still, the polyhydroxy acid is selected from the group comprising polycaprolactone, polyhydroxybutyrate, lactide- glycolide copolymers, lactide-trimethylene carbonate copolymers and copolymers of glycolide and trimethylene carbonate ABA block- copolymer.

Most advantageously, the polyester is polycaprolactone. This material has the advantage of possessing a low melting point so that a surgeon can mould it by hand in the operating theatre.

Preferably, the weight average molecular weight of the polyester is in the range 3000 - 500,000.

More preferably, the weight average molecular weight of the polyester is in the range 10,000 to 220,000.

More preferably still, the weight average molecular weight of the polyester is in the range 10,000 to less than 200,000

Most preferably, the weight average molecular weight of the polyester is in the range 80,000 to 190,000.

Altering the weight average molecular weight of the polyester affects the viscosity and mechanical properties of the composite. Within the preferred ranges defined above, these properties and particularly mechanical properties like flexural and compressive modulus are highly beneficial for the present field of application.

According to a preferred variant of this aspect of the invention, the composite also comprises a filler material. Reference herein to a "filler" is a reference to a material whose presence causes the biocompatibility of the composite to be enhanced, mechanical and handling characteristics to be improved and the degradation behaviour to be modified, thus allowing the properties of the composite to be tailored to the specific requirements. In particular, a filler is a material which, when added to the composite, increases the tensile and compressive modulus thereof. The filler may be an organic or inorganic material, and is preferably a ceramic. Advantageously, the filler comprises a particulate which may be in the form of granules, rods, beads, spheres, plates, cubes, blocks or fibres to allow homogeous dispersion throughout the composite. The size range of such partculates is selected to achieve the desired physical properties of the bulk material and is preferably in the range 0.3 - 50μm.

Preferred ceramic fillers are aragonite, hydroxyapatite, tricalcium phosphate, calcium sulphate, calcite, BIOGLASS™ or mixtures thereof.

More preferably, the ceramic filler is aragonite, tricalcium phosphate, calcium sulphate or calcite or mixtures thereof. These ceramic fillers have the advantage that they biodegrade relatively rapidly in vivo.

The percentage weight of ceramic filler is selected to increase the compressive and flexural modulus of the composite. The upper limit is dictated by the degree of stiffness that can be tolerated in any given situation. Advantageously, the composite comprises up to 70%wt of ceramic filler (this is approximately 40% v/v, though the precise value depends upon the filler involved). More advantageously, the composite comprises up to 50%wt of filler.

According to a more preferred variant of this aspect of the invention, the composite also comprises a second bioresorbable, biocompatible polymeric component. The presence of a second such polymeric component allows the degradation and viscous flow characteristics of the composite to be further modified, allowing these to be tailored to the precise application.

Advantageously, the second bioresorbable biocompatible polymeric component comprises at least one hydroxy acid. These materials have the advantage that they can easily be metabolised by the body and that they tend to produce non-toxic breakdown products.

Advantageously, the at least one hydroxy acid is selected from PGA, i.e. poly(glycolic acid), PLA, i.e. poly(lactic acid), PLA/PGA copolymers, PGA/trimethylene carbonate (TMC) copolymers, PLA/TMC copolymers and polyhydroxybutyrate.

It is preferred that the first and, if present, the second bioresorbable, biocompatible polymeric component has a melting point in the range from 40 - 80°C. This temperature range has the advantage that surgeons may easily perform the steps of melting the composite according to the invention during a surgical procedure as well as applying the thus melted composite to human tissue during said procedure. Both polycaprolactone and poly-4-hydroxybutyrate (melting point 60°C) have melting temperatures within this range. In a further aspect of the invention, a process for the manufacture of the above-defined composite is presented, said process comprising the steps of dissolving said polyester in a solvent, adding a filler to said solution, mixing thoroughly, evaporating said solvent, then drying said mixture to form said composite.

Advantageously, the drying step is carried out under vacuum, more advantageously still in a vacuum oven.

The solvent employed for this process is preferably dichloromethane or chloroform. These solvents are volatile and can thus be removed relatively easily.

According to alternative according to this aspect of the invention, the process for the manufacture of the above-defined composite may comprise the steps of melting said polyester, adding a filler to said melted polyester, mixing thoroughly and cooling the thus prepared composite. This alternative "non-solvent" process has the advantage that it is easier to perform on the large scale and that solvent residues do not require to be removed. In addition, the blends produced tend to be more homogenous than those produced by the solvent method.

According to a final aspect of the present invention, a method of treatment of a bone defect site in a mammalian patient in clinical need thereof is presented, said method comprising the step of administrating the above-defined composite to said defect site either as a preformed shape or after heating said composite to make a putty which is formed into the desired shape in situ. The degradable material of the invention is of use in the healthcare industry. It can be provided in various forms like a solid block, porous foam or fibre. It becomes mouldable/injectable/extrudable on heating, but solidifies again on cooling. In one embodiment, the material is provided for use as a putty (which is rendered mouldable by heating). In another embodiment, it is provided as pre-formed, implantable shapes (whose precise shape can, nevertheless, be altered slightly by application of heat, if necessary). The preformed shapes may be porous or non-porous. On application, the material fills bone-defects to facilitate site stabilisation, prevent bone bleeding and enhance osseous growth.

The material is compatible with hardware used in a wide variety of surgical procedures (e.g. screws, plates, nails, fixation anchors): a self-tapping screw, once screwed into the set material, becomes firmly embedded. Drilling/screwing/carving/machining can be effected without fragmentation and/or significant particulate debris being generated.

The present material also serves as a binder for particulates such as autograft/al log raft bone chips, which can be used to enhance biological activity.

The material can be provided with an appropriate delivery system, e.g. a sachet, tube, syringe, injection gun, canula or other applicator for ease of delivery. Appropriate applicators make this material suitable for use in minimally invasive techniques.

The delivery system can incorporate means of heating the material, e.g. induction or chemical heating. Alternatively, in the case of a sachet, for example, it can be immersed in hot water. It is also possible to heat and render mouldable the material using a microwave-oven. The heating method used depends, to some extent at least, on the nature of the biodegradable polymer.

According to one embodiment of the invention, it is advantageous to employ polymers which melt at low temperatures (say below 70°C) so that they can easily be rendered mouldable by a surgeon in a hospital operating theatre (using, say, a water-bath) and can be shaped by hand by the surgeon. On the other hand, there are certain situations in which polymers with higher melting temperatures need to be used (because they impart properties which polymers with lower melting temperatures do not have). In such circumstances, melting and shaping is achieved by means of appropriate devices.

In use, the composite according to the invention is heated to melt it. In the case that such is being carried out by a surgeon, the melting temperature will normally be low, say 60°C. This is achieved in an appropriate way, say by immersing a sachet in a hot water bath or heating in an oven or by induction heating means incorporated into a syringe or gun delivery system. Once formable, it can be shaped by hand or using instrumentation, cut, injected, extruded, moulded or drawn. On cooling, the material sets to form a hard solid that is no longer mouldable, but may be drilled, sawed or screwed into, without fragmentation or significant particle generation. If reshaping or repositioning is required, the material can be reheated either in situ or after removal to facilitate this. Once in position, the material degrades over time such that it is ultimately resorbed by the body. The rate of resorption is a function of the composition of the composite and can be tailored to a particular situation. In addition to the first and second polymers and filler defined above, the composite of the present invention may also advantageously comprise a number of other materials, which enable the properties of the filler to be tailored to a wide range of specifications:

The material can optionally be combined with bioactive agents such as growth factors, bone morphogenic proteins (BMP), antibiotics and other pharmaceutical agents to provide localised delivery by means of controlled release.

A porogen can also be added to the composites of the invention to impart porosity and facilitate enhanced ingrowth. Examples of porogens suitable for use in the present invention are alkali metal salts, suitably of sodium or potassium, alkaline earth metal salts, water soluble polymers (e.g. alginates or polyols), sugars and rapidly degradable polymers (like PGA). Preferred porogens are sugars, on account of their fast resorption characteristics. A highly preferred porogen comprises sugar beads like Non-Pareil Seeds™, which come in sizes ranging from 250 - 1400 μm and comprise about 86% sucrose and 14% corn starch. These beads are spherical, giving them good flow characteristics (beneficial for injectable materials).

A radio-opaque agent may also be added to the composite to enhance x-ray or fluorescence visibility or visibility by other imaging techniques. Examples of such agents suitable for use in the present invention are zirconium dioxide and barium sulphate.

A colorant may also be added to facilitate ease of identification to the naked eye. Finally, a thermotropic indicator can be added to give the person working with the composite an indication of how much working time remains before setting.

Reference is made to the figures:

Fig.1 illustrates the results of the compressive modulus tests performed in Example 12, below, on composites according to the invention comprising polycaprolactone and certain fillers.

Fig.2 illustrates the results of the flexural modulus tests performed in Example 12, below, on composites according to the invention comprising polycaprolactone and ceramic fillers.

Fig,3 illustrates the degradation results of Example 13, as measured by change in molecular weight over time for samples of PCL, PCL/P(LA/GA) and P(LA/GA).

The following examples demonstrate how composites according to the invention may be prepared. Test results are also presented, demonstrating the advantageous nature of composites according to the invention in the area of biocompatibility, mechanical properties, mouldability, degradability, compatibility with metal hardware and ability to be sterilised without losing the above-mentioned properties.

Examples

(Note: hereafter M_n refers to the number average molecular weight and M_w the weight average molecular weight). Example 1 - Preparation of Polycaprolactone / Aragonite Composite

100g of polycaprolactone (P767E, ex Union Carbide, M_n -80000, M_w -140000) was dissolved in dichloromethane (600ml) to form a viscous solution. 50g of Aragonite were added and the mixture shaken to yield a smooth paste. The solvent was removed by evaporation under reduced pressure and the residue dried in a vacuum oven (40°C, 1 mmHg) for 6 hours to yield a white, opaque solid.

Example 2 - Preparation of Polycaprolactone/Aragonite Composite Without Solvent

Example 2A

Samples were produced using a Prism twin screw extruder with a 25:1 L/D ratio and a 16mm bore twin bore diameter. The polymeric material was fed from a "Roto Tube" feeder unit or "Brabender" gravimetric feed unit and the ceramic material from a volumetric "AccuRate" feeder unit. The volumetric feed units were calibrated prior to use by constructing graphs of the weight of material fed at a variety of motor speed settings. The twin screws were configured with a general purpose mixing screw arrangement.

The materials fed were polycaprolactone (P767E, ex Union Carbide, M_n -80000, M_w -140000) and 40% v/v tri-basic calcium phosphate (ex Sigma-Aldrich).

Process conditions were as follows:

- pressure: 71 bar - Roto Tube feeder speed: 500rpm

- AccuRate feeder speed: 10

- Temperature: zone 1 : 115°C zone 2: 116°C zone 3: 124°C zone 4: 132°C die tip: 128°C

- Torque: 17.4 N/mm

- Screw speed: 226rpm

Example 2B

This was a two-stage process involving the production of a polymer blend by dry-blending then subsequent melt-compounding followed by dry-blending the granulated polymer blend with the ceramic material prior to processing through the twin extruder.

The materials fed were polycaprolactone (P767E, ex Union Carbide, M_n -80000, M_w -140000), calcium sulphate fibre (Franklin Fiber™ produced by US Gypsum) and poly(DL-lactide-co-glycolide) 75:25 (from Birmingham Polymers).

The blend was 99:1 PCL/PLAGA with 10% vol. calcium sulphate.

Process conditions were as follows:

Stage 1 :

- pressure: 60 bar - Roto Tube feeder speed: 650rpm

- Temperature: zone 1 : 105°C zone 2: 116°C zone 3: 117°C zone 4: 116°C die tip: 98°C - Torque: 17.0 N/mm

- Screw speed: 201 rpm

Stage 2:

pressure: 55 bar

Brabender speed: 250rpm

Temperature: zone 1 : 110°C zone 2: 116°C zone 4: 126°C die tip: 125°C

Torque: 14.0 N/mm

Screw speed: 231 rpm

The materials produced in both Examples 2A and 2B were extremely homogenous blends with good melt-moulding characteristics.

Example 3 - Preparation of Polycaprolactone / 75% D.L-lactide. 25% glycolide Copolymer / Aragonite Composite

2.00g of polycaprolactone (P767E, ex Union Carbide, M_n -80000, M_w -140000) and 1.00g of 75% D.L-lactide, 25% glycolide copolymer (Resomer RG 755, ex Boehringer Ingelheim) were dissolved in 15ml of dichloromethane to form a viscous solution. 1.00g of Aragonite was added and the mixture shaken to yield a smooth paste. The solvent was removed by evaporation under reduced pressure and the residue dried in a vacuum oven (40°C,

1 mmHg) for 6 hours to yield a white, opaque solid.

Example 4 - Preparation of Polycaprolactone / 75% D.L-lactide. 25% glycolide Copolymer Blend

1.00g of polycaprolactone (P767E, ex Union Carbide, M_n -80000, M_w -140000) and 0.50g of 75% D.L-lactide, 25% glycolide copolymer (Resomer RG 755, ex Boehringer Ingelheim) were dissolved in 8ml of dichloromethane to form a viscous solution. The solvent was removed by evaporation under reduced pressure and the residue dried in a vacuum oven (40 °C, 1 mmHg) for 6 hours to yield a white, opaque solid.

Example 5 - Mouldability of Polycaprolactone / Aragonite Composite

5g of polycaprolactone / aragonite composite (33% w/w aragonite) was placed in a sealed polyethylene bag and immersed in water at 70°C for 5 minutes. The material was removed from the water and the bag discarded to yield an easily mouldable putty that remained workable for about 5 minutes until it hardened on cooling. A similar effect is observed on heating the composite in an oven at the same temperature.

Example 6 - Microwave Heating of Polycaprolactone / Aragonite Composite

5g of polycaprolactone / aragonite composite (33% w/w aragonite) was placed in a domestic microwave oven (650W) and heated at full power for 2 minutes. The material warmed to form a mouldable putty that remained workable for about 5 minutes until it hardened on cooling.

Example 7 - Injectability of Polycaprolactone / Aragonite Composite

~2g of polycaprolactone / aragonite composite (33% w/w aragonite,) was heated and moulded into a 2ml polyethylene syringe barrel and allowed to harden on cooling. The plunger was replaced and the filled syringe immersed in hot water (80°C) for 5 minutes. On removal from the water, the composite was easily injected from the syringe until it hardening on cooling.

Example 8 - Mouldability of Other Biocompatible. Biodegradable Polyesters

Materials used:-

1. Polyhydroxybutyrate (Goodfellow)

2. 75% D.L-lactide, 25% glycolide copolymer (Resomer

RG755, Boehringer Ingelheim), M_n 28,800, M_w 64,000.

3. 70% L-lactide, 30% trimethylene carbonate copolymer (Resomer LT 706. Boehringer Ingelheim), M_n 69,600, M_w 150,700.

4. Maxon B (67% glycolide, 33% trimethylene carbonate ABA block copolymer, Smith & Nephew), M_n 45,000, M_w 110,000

2g of each polymer (2g) was heated in a boiling tube using a Woods metal bath until molten. The tube was removed from the heat and stirred with a thermometer until the polymer hardened and became non-mouldable.

All of the above materials exhibit reversible melt-mouldable behaviour.

Example 9 - Sterilisation

Polycaprolactone (P767E, Union Carbide) was sterilised using gamma irradiation (25kGy) to determine the effect of sterilisation on the molecular weight of the polymer.

Analysis of the polymer component shows virtually no change in the weight average molecular weight and a drop of -20% in the number average molecular weight. This indicates that cross-linking as a result of gamma-irradiation is unlikely to be a significant problem, i.e. the composites of the present invention will retain their mouldable characteristics after such a sterilisation process. Sterilisation by irradiation obviates the need to sterilise by chemical methods, e.g. with ethylene oxide, thus avoiding the need to remove chemical residues.

This suggests that such materials are suitable for sterilisation by gamma irradiation.

Example 10 - Biocompatibility

Polycaprolactone / aragonite composite (33% w/w aragonite) samples were sectioned and incubated in medium with SaOS-2 cells for 3 days. In an alkaline phosphatase assay, an activity level of 22.3nM pNP / min for the composite samples relative to a control value of 81.5nM pNP / min for tissue culture plastic (positive control) was determined. The good adherence and metabolic activity of the cells in contact indicate the biocompatible nature of the composite material.

Example 11 - Compatibility with Metal Hardware

Materials used:-

1. Polycaprolactone P767E (Union Carbide) (M_n 82800, M_v 140250)

2. Polycaprolactone P787 (Union Carbide) (M_n 117400, M_w 214700) 3. Polycaprolactone CAPA 656 (Solvay) (M_n -50000)

4. Polycaprolactone Diol 2000 (Sigma-Aldrich) (M_n -2000)

5. Polycaprolactone Diol 1250 (Sigma-Aldrich) (M_n -1250)

Test

All the above materials were heated in an oven at 120°C to melt and cooled to room temperature to form solid blocks. Attempts were made to screw a self-tapping stainless steel wood screw into each of the blocks.

Results

1 ,2,3 - All materials cooled to form hard, solid blocks.

The screw was tapped into the surface of the material, resulting in a slight indentation. Using a screwdriver, the screw was driven into the polymer where it became firmly embedded. The screw could be removed and reinserted into the same hole to provide firm fixation.

4,5 - The materials cooled to form soft, waxy solids (cf. candle wax). The screw could easily be pushed into the polymer by hand without the aid of a screwdriver. It did not become firmly embedded and was easily pulled out. Attempts to drive the screw into the polymer lead to fragmentation of the block and no fixation.

Example 12 Polycaprolactone (P767E ex Union Carbide, M_n -80000, M_w

-140000) / ceramic composites, as listed below, were assessed in compression and flexure. The same constituent batches were used for both of the mechanical tests:

I. PCL/20% v/v aragonite

I I . PCL/40% v/v aragonite

III. PCL/20% v/v calcium phosphate tribasic (hydroxyapatite)

IV. PCL/40% v/v calcium phosphate tribasic V. PCL/20% v/v calcite

VI. PCL/40% v/v calcite

VII. PCL/20% v/v calcium sulphate dihydrate

VIII. PCL/40% v/v calcium sulphate dihydrate

IX. PCL/20% v/v 45S5 BIOGLASS™ X. PCL/40% v/v 45S5 BIOGLASS™

XI. PCL Unfilled

Material Production

The PCL was dissolved in dichloromethane br rolling the two components together in a sealed vessel for 30 minutes, using an automated rolling machine. To ensure a homogenous mix, the ceramic filler was added to the dissolved PCL a small amount at a time. Mixing in the sealed vessel was continued for a further 30 minutes resulting in a slurry of the ceramic and PCL.

At this stage, the dichloromethane was evaporated off using a rotary evaporator, with the water bath set at a constant temperature of 45°C. The slurry was slowly rotated for 3 hours until all the solvent had evaporated. To ensure all the residual solvent had evaporated, the PCL/ceramic composite that remained was placed in a vacuum oven at 40°C for 7 hours.

The unfilled sample was prepared using the same method as above, but omitting the ceramic filler.

Preparation of compression test samples

The composites were placed in an oven at 90°C until they became mouldable and were then compressed by hand into stainless steel moulds. The moulds contained holes of the required dimensions for compression test pieces (cylindrical - 6mm diameter x 12mm length) as stipulated in ASTM F451-95. Once the moulds were filled, stainless steel plates were positioned on the top and bottom of the mould, with OPSITE™ release paper in between. A 50kN load was then applied across the mould via the plates for 10 seconds by the use of a mechanical press. Upon release of the applied load, the top stainless steel plate was removed to allow the test pieces to cool to room temperature over a period of 2 hours. The moulded samples were then removed from the mould by tapping out using a hammer and a flat ended metal pin.

Compression Testing

Prior to mechanical testing, the length and diameter of each sample was measured using Mitutoyo electronic callipers and mass was measured using a Sartorious top-pan balance. Compression testing of the composites was carried out using a Zwick 1435 tensile test machine fitted with a 5kN load cell at a test speed of 1 mm/min. The ultimate compressive strength was determined using the NWG analysis software along with the slope of the load displacement curves from which the compressive modulus (E) was calculated using the following formula:

E (MPa) = slope(N/mm) x 1 pi x 0.25 x d²

- where: I = length (mm) d = diameter (mm)

Remoulding of test samples

PCL is melt-mouldable when heated above 60°C, it is possible to remould the compression test pieces into flexural test pieces. The remoulding process could possibly affect the mechanical behaviour of the samples due to degradation caused by the repeated heating.

One set of tested compression samples (20% and 40% v/v aragonite) was chosen along with unfilled PCL to be re-moulded and re-tested as above and the results compared to the initial results.

Flexural testing

The composites were heated in an oven to 90°C until mouldable and compressed by hand into steel flexural moulds. The moulds contained cavities of the required dimensions for flexural test pieces (4mm thick x 10mm width and 75mm in length). Once the moulds were filled, a load was applied using a mechanical press as described above in relation to "Preparation of Compression Test Samples". Following release of the applied load, the test pieces were allowed to cool to room temperature over a period of 2 hours before being removed from the mould by hand. Width and thickness of each sample were measured using Mitutoyo electronic callipers. Flexural strength testing of the composites was measured in a 4-point loading using a Zwick 1435 tensile test machine fitted with a 5kN load cell. All tests were conducted using a cross head speed of 1 mm/min, a loading span of 20mm and a support span of 60mm. Flexural strength was calculated using the following formula:

Flexural strength (MPa) = 3 x P x a

2 x b x d²

- where: P = failure load (N) a = horizontal distance between loading and support rollers (mm) b = breadth (mm) d = thickness (mm)

The slopes of the load displacement curves were determined using the following formula:

E (MPa) = 5/27 x slope OM/mm^ x l³ b x d³

- where: I = support length b and d are as previously defined.

The results of the above compression and flexural testing are illustrated in Figures 1 and 2 (note: there was no result for 40% v/v calcium phosphate tribasic filled polycaprolactone, as this material became crumbly and could not be remoulded). The compression results of the remoulded PCL/aragonite composites and unfilled PCL are shown below (mean values and standard deviation are shown). Four samples were tested for each material:

Conclusions

(a) The general trend reveals an increase in compressive modulus for samples containing ceramic filler over that for unfilled PCL. The greater increase was observed in the higher of the two loading levels (40% v/v) in all cases

(b) The data relating to the re-moulded samples reveal no significant changes in compressive modulus.

(c) The data show that PCL/ceramic composites have improved flexural modulus compared with unfilled PCL. The greater increase was observed in the higher of the two loading levels (40% v/v) in all cases (except 40% v/v calcium phosphate tribasic, for which no result was obtained). (d) There is no significant change in compressive modulus as a result of re-moulding.

Example 13

This example demonstrates the in vitro degradation behaviour at 37°C of PCL, P(LA/GA) and blends of PCL with P(LA/GA). In each case, polycaprolactone P767E (ex Union Carbide, M_n -80000, M_w -140000) was employed.

Sample details:

- 99% w/w PCL was blended with P(LA/GA) (75:25)

- 90%w/w PCL was blended with P(LA/GA) (75:25)

- 50% w/w PCL was blended with P(LA/GA) (75:25)

- PCL (100%) was used as control

- P(LA/GA) (100%) was used as control

All samples were prepared by solution blending in dichloromethane and evaporation under reduced pressure and vacuum drying. All samples were re-heated and moulded into compression piece moulds prior to submission. Degradation of the samples was carried out by the following method:

The samples of PCL, P(LA/GA) and PCL/P(LA/GA) blends were chopped into small pieces. About 0.6-0.9g of sample was weighed into a glass jar and 50ml of sterile PBS was added. Sufficient samples for eight time points was prepared. Samples were then placed in an oven at 37°C for the duration of the degradation. The pH of the degradation samples was monitored during the study, and the buffer replaced when necessary.

Degradation was monitored by measuring change in molecular weight with time according to the following method:

At each timepoint, once the samples had been dried to constant weight, their molecular weights were determined. The samples were dissolved in chloroform at a concentration of 0.2-0.35 w/v. Filtration was carried out prior to analysis. The gel permeation chromatography analyses were carried out using a phenogel 10μm linear mixed bed column and the appropriate guard column with refractive index detection.

The results are illustrated in Fig.3.

The molecular weight analyses showed that all samples degraded over the 32 week degradation period. The 100% PCL had the lowest degradation rate, the 100% P(LA/GA) the highest, with mixtures having degradation rates falling between the two. This illustrates how the degradation characteristics of the composite may be tailored to the situation at hand.

The degradation characteristics of materials comprising a ceramic filler can be modified in a similar manner to that demonstrated in Example 13, by addition of a second bioresorbable, biocompatible polymeric component.

Claims

1. Composite comprising a first bioresorbable, biocompatible polymeric component, which first polymeric component comprises a polyester with a weight average molecular weight of greater than 3000 that becomes reversibly mouldable on heating.

2. Composite according to claim 1 , wherein the polyester is a polyhydroxy acid.

3. Composite according to claim 2, wherein the polyhydroxy acid is selected from the group comprising polycaprolactone, polyhydroxybutyrate, lactide-glycolide copolymers, lactide- trimethylene carbonate copolymers and copolymers of glycolide and trimethylene carbonate ABA block-copolymer.

4. Composite according to any one of the preceding claims, wherein the polyester is polycaprolactone.

5. Composite according to any one of the preceding claims, wherein the weight average molecular weight of the polyester is in the range 10,000 - 500,000.

6. Composite according to any one of the preceding claims, wherein the weight average molecular weight of the polyester is in the range 10,000 - 220,000.

7. Composite according to any one of the preceding claims comprising a filler material.

8. Composite according to claim 7, wherein the filler is a ceramic filler.

9. Composite according to claim 8, wherein the ceramic filler is aragonite, hydroxyapatite, tricalcium phosphate, calcium sulphate, calcite, BIOGLASS™ or mixtures thereof.

10. Composite according to any one of claims 8-9 comprising up to 70%wt of ceramic filler.

11. Composite according to any one of the preceding claims comprising a second bioresorbable, biocompatible polymeric component.

12. Composite according to claim 11 , wherein the second bioresorbable biocompatible polymeric component comprises at least one hydroxy acid.

13. Composite according to claim 12, wherein the at least one hydroxy acid is selected from PGA, i.e. poly(glycolic acid), PLA, i.e. poly(lactic acid), PLA/PGA copolymers, PGA/trimethylene carbonate (TMC) copolymers, PLA/TMC copolymers and polyhydroxybutyrate.

14. Composite according to any one of the preceding claims, wherein the first bioresorbable, biocompatible polymeric component and, if present, the second bioresorbable, biocompatible polymeric component have a melting point in the range from 40 - 80°C.

15. Process for the manufacture of the composite of any one of claims 1-14, comprising the steps of dissolving said polyester in a solvent, adding a filler to said solution, mixing thoroughly, evaporating said solvent, then drying said mixture to form said composite.

16. Process for the manufacture of the composite of any one of claims 1-14, comprising the steps of melting said polyester, adding a filler to said melted polyester, mixing thoroughly and cooling the thus prepared composite.

17. Method of treatment of a bone defect site in a mammalian patient in clinical need thereof is presented, said method comprising the step of administrating the composite according to any one of claims 1-14 to said defect site either as a preformed shape or after heating said composite to make a putty which is formed into the desired shape in situ.