WO2007121457A1

WO2007121457A1 - Composition of biodegradable glass-ceramic

Info

Publication number: WO2007121457A1
Application number: PCT/US2007/066843
Authority: WO
Inventors: David Farrar; Mary Vickers; Serena Best; William Bonfield; Mark Akhshi; John Rose
Original assignee: Smith & Nephew, Inc.
Priority date: 2006-04-18
Filing date: 2007-04-18
Publication date: 2007-10-25
Also published as: GB0607605D0

Abstract

A homogeneous nano-scale glass-ceramic comprising a combeite phase and comprising oxides of Si, P, Ca, Na and Mg; a cast or moulded glass-ceramic which has a homogeneous nanoscale microstructure and comprises a combeite phase; a glass comprising oxides of Si, P, Ca, Na and Mg preferably in form and amount corresponding to the glass-ceramic; blends thereof; composites thereof with matrix or filler; processes for the preparation thereof; shaped artefacts thereof; methods for their manufacture and the use thereof as an implantable biodegradable device such as a medium to high strength trauma fixation device suitable for implantation into the human or animal body and the use of the parent glass in the preparation thereof.

Description

COMPOSITION OF BIODEGRADABLE GLASS-CERAMIC

This invention relates to biodegradable glass-ceramics having a nano-crystalline microstructure, particularly to biodegradable glass-ceramics having favorable mechanical properties and improved ease of manufacturing shaped artefacts; the corresponding glass; composites comprising the glass-ceramic or glass; processes for the preparation thereof; the parent glass precursor thereof; and to artefacts made therefrom and methods for their manufacture; and the use thereof.

Bone fixation devices (plates, screws, pins etc) are presently made of metal, however metal devices have several well known disadvantages.

To overcome these deficiencies glass and glass-ceramic implants have been designed as non-metallic bone fixation devices.

Bioglass ™ is a well known bioactive glass used as an orthopaedic material. It is claimed to have very high bioactivity, forming a layer of apatite on its surface within hours after being immersed into simulated body fluid (SBF). This glass composition has very poor mechanical properties after being cast. It is therefore largely used in low load bearing applications and as filler in composites. It also has a problem of aging since it reacts with moisture in air, hence requires packaging in a dry environment.

The major problem with most glass-ceramic implants is their poor mechanical properties which limit their use to low load bearing applications or require them to be incorporated into composites. Apatite-Wollastonite glass-ceramic (AWGC or Cerabone AW ™) has been used to produce orthopaedic implants such as intervertebral spacers and has been shown to possess better mechanical properties than most other glass-ceramics and the known Bioglass ™, has good bioactivity although not as good as Bioglass ™ but has poor biodegradability. It also cannot be cast into the final shape but needs to be powdered, pressed, sintered and machined into shape, which is inconvenient, and the composition has been adapted to compensate for weaknesses introduced by this processing method.

There is therefore a need for improved biodegradable glass - ceramics having acceptable bioactivity, biodegradation and strength and capable of being readily shaped without deterioration in properties.

Surprisingly we have now produced a glass - ceramic with improved handling and shaping properties compared to the currently available alternatives. Moreover the glass-ceramic has comparable or improved mechanical properties compared to the currently available alternatives. The glass-ceramic is suitable for use in the field of orthopaedics, such as bone-screws and bone fixation devices and can be produced through a casting or moulding process which enables near net shaping and is ideal for producing such artefacts.

The glass-ceramic has improved stability and mechanical properties compared with Bioglass ™, and comparable bioactivity. In one form it is able to form apatite on its surface in less than two days after immersion in SBF (simulated body fluid) which can be very advantageous in maxillofacial and orthopaedic surgery. Moreover it has improved bioactivity and shaping properties compared with AWGC and improved mechanical properties compared with other glass-ceramics, allowing it to be useful for medium load bearing applications.

Thus in accordance with the broadest aspect of the present invention there is provided a glass-ceramic having a nanoscale microstructure comprising a combeite phase and comprising oxides Of Si, P, Ca, Na and Mg.

Reference herein to combeite is to any crystalline phase falling under the classification thereof, and generally known as the lovozerite family. The combeite phase may be combeite high

(impure, contains impurities such as Fe and the like) or combeite low

(pure) and is preferably combeite high or a combination thereof. The lovozeritθ family has a silicate structure with the general composition M1 /W2₂/W3₃M4₃[Si₆Oi₈] where Mλ , M2, M3, MA are different metals and Si₆Oi₈ represents a chair-form ring silicate group. Combeite may have the formula Na_{5 2}TCa₃(Si₆Oi₈) (combeite high) or Na_{4 2}Ca_{2 8}(Si₆Oi₈) or Na₄(Ca, Al, Fe)₃(Si₆Oi₈) (combeite low) or Na₅Ca₃(Fe, Mn)_{0 6}(Si₆Oi₈) or Na₂Ca₂(Si₃O₉) or Na₄Ca₄(Si₆Oi₈) or Na_{4 4}Ca₃₈(Si₆Oi₈) or Na₆Ca₃(Si₆Oi₈). Combeite usually has a rhombohedral crystal system.

Preferably the glass-ceramic comprises a combination of crystalline phases including combeite and sodium-calcium- magnesium-phosphate. Sodium-calcium-magnesium-phosphate may have the formula Nai₈Cai₃Mg₅(PO₄)i₈. It usually has a rhombohedral crystal system.

Preferably the glass-ceramic comprises Mg present in an amount of from 2 to 15 wt%, preferably greater than 5 to less than 10 wt%. We have surprisingly found that low levels of Mg appear to be beneficial in a glass-ceramic, contrary to teachings in the art which advocate either no Mg or high levels thereof. Preferably the glass-ceramic comprises combeite in an amount of greater than 50wt%, preferably from 50 to 85 wt%, more preferably 50 to 75 wt%, most preferably 60 to 70 wt%. Preferably the glass-ceramic comprises sodium-calcium-magnesium-phosphate in an amount of from 10 to 53 wt%, more preferably 15 to 30 wt%, most preferably 20 to 25 wt%.

More preferably the glass-ceramic comprises the following crystal phases in combination : Sodium-calcium-silicate (combeite high), Sodium-calcium-magnesium-phosphate and Calcium-sodium- phosphate. Calcium-sodium-phosphate has the formula NaCaPO₄. It has an orthorhombic crystal system and is also known as Buchwaldite. Preferably the glass-ceramic comprises calcium- sodium-phosphate in an amount of from 3 to 25 wt%, more preferably 5 to 20 wt%, most preferably 10 to 15 wt%. Additional phases may be present in minor or major amount, for example apatite, wollastonite and the like.

It will be appreciated that the glass-ceramic may be obtained from many precursor mineral formulations and all such glass- ceramics are encompassed within the scope of the present invention. We have found that the glass-ceramic comprises the following oxides in wt% as shown:

SiO₂ from 40 to 53 wt%;

P₂O₅ from O to 15 wt%

CaO from 10 to 32 wt%

Na₂O from 5 to 32 wt%

MgO from 2 to 12 wt%

or may be conveniently obtained therefrom or from their equivalents, such as carbonates.

Preferably the glass-ceramic comprises the following oxides in wt% as shown:

SiO₂ from 43 to 48 wt%;

P₂O₅ from 6 to 13 wt%

CaO from 15 to 30 wt%

Na₂O from 10 to 30 wt%

MgO from 2 to 8 wt%

or may be obtained therefrom or from their equivalents, such as carbonates.

More preferably the glass-ceramic is obtained from a combination of SiO₂ and P₂O₅ together with CaCO₃, Na₂CO₃ and Mg₂CO₃ in appropriate amount according to the above. Most preferably the glass-ceramic has the following composition in wt% of its corresponding parent glass:

Reference herein to a glass-ceramic is to a material comprising amorphous glassy areas together with crystallites dispersed therethrough. It will be appreciated that when crystals grow from the substantially homogeneous material of a glass melt, the remaining glassy areas are depleted in composition as regards the materials comprising the crystal. Thus in a glass-ceramic the glassy areas may not have the same composition as the overall glass-ceramic. It is therefore necessary to measure the overall chemical composition of the material rather than the composition at localized areas thereof.

Prior art glass-ceramics comprise a uniform homogeneous microstructure of amorphous and crystalline phases with crystal sizes of the order of 10 micron or less. In a particular advantage the nanoscale microstructure glass-ceramic of the invention comprises a homogeneous composite of amorphous and crystalline phases with crystal sizes of the order of 1 to 250 nm, more preferably 1 to 150 nm, more preferably 1 to 100 nm, more preferably 3 to 70 nm, most preferably 5 to 50 nm. The crystallites or regions of crystallinity are conveniently observed by means of X-ray and may be measured by means of FESEM. Crystal size may be selected higher or lower in the range by varying the preparation conditions for the glass- ceramic. In a particular advantage the homogeneity of the small nanoscale crystallite size of the glass-ceramics of the invention confers superior properties of strength on the glass-ceramic. The homogeneity is such that the glass-ceramic exhibits beneficial mechanical properties. In a further advantage the glass-ceramic is conducive to a casting or moulding process to produce products (artefacts) with ease or to produce more complex shapes. We have found that the glass-ceramic of the invention exhibits highly desirable bulk nucleation on casting forming a bulk fine grained structure which leads to optimal mechanical properties. This is in contrast to prior glass-ceramics such as AWGC which display surface nucleation on casting, forming radial grain boundaries which reduce porosity and are prone to fracture. As a result AWGC is formed by powdering, pressing and sintering and machining but this limits the ease of shaping and the complexity of artefacts which may be produced therefrom.

The glass-ceramic of the invention is characterised by properties of high strength. Preferably the glass-ceramic of the invention has a biaxial flexural strength in excess of 80 MPa. We are not aware of any teachings suggesting the use of a combeite containing glass-ceramic as a bulk material. US 5,914,356 and US 5,681 ,872 disclose combeite as conferring added strength as a filler in a glass-ceramic reinforced resin matrix composite, but fail to suggest that such material might be useful as a bulk or castable material. In one embodiment of the invention the glass-ceramic is used without any additional reinforcing components to confer enhanced mechanical properties, such as strength or the like.

In a particular advantage the glass-ceramic is characterised by an increase in strength after onset of degradation, which is particularly surprising. This is attributed to the formation of surface layers during degradation which modify the surface mechanical properties and thereby the bulk properties of the glass-ceramic.

Accordingly in a further aspect of the invention there is provided a cast or moulded glass-ceramic which has a nanoscale microstructure and comprises a combeite phase, preferably characterised by the formation of a silica gel layer having superposed thereon a surface layer of honeycomb structured porous silica rich layer adapted to support growth of apatite crystals, whereby the glass-ceramic displays an increase in biaxial flexural strength at the onset of degradation. We have denoted this as a novel "self-strengthening" mechanism. More preferably the cast or moulded glass-ceramic is a glass-ceramic as hereinbefore defined.

According to this aspect of the invention we have found that the microstructure and crystal phases present in the glass-ceramic determine the release of ions at the surface, and thereby determine the surface layers formed. The glass-ceramics of the invention provide a novel balance between solubility of ions and reprecipitation on the surface. In a further advantage we have found that the cast or moulded glass-ceramics of the invention have unmodified surface properties on casting or moulding compared with sintered and machined equivalents which undergo surface modification on machining, and this preserves the surface behaviour of the glass- ceramics of the invention during degradation.

The glass-ceramic is suitably prepared from a parent glass having corresponding oxide composition. We have found that the parent glass is associated with beneficial properties and has applications in low to medium strength applications. Accordingly in a further aspect of the invention there is provided a glass comprising oxides of Si, P, Ca, Na and Mg, preferably comprising the following oxides in wt% as shown:

SiO₂ from 40 to 53 wt%;

P₂O₅ from O to 15 wt%

CaO from 10 to 32 wt%

Na₂O from 5 to 32 wt%

MgO from 2 to 12 wt%. More preferably the glass is provided in corresponding form and amount to the glass-ceramic as hereinbefore defined. We have found that the parent glass forms a surface silica gel layer on degradation, as hereinbefore defined, leading to an increase in strength on degradation.

The glass-ceramic or glass of the invention may be provided with no other glass-ceramics or glasses present, or as a blend of a number of different combeite-containing glass-ceramics or glasses of the invention having different properties such as crystallite size, percentage of combeite or other crystal phases, percentage of oxides and the like. Alternatively or additionally the glass-ceramic of the invention may be present as a blend with other known glass- ceramics such as AWGC and the like.

In a further aspect of the invention there is provided a biodegradable composite comprising a glass-ceramic or glass as hereinbefore defined present as matrix or as filler together with a filler or matrix component.

In one embodiment a composite of the invention comprises the glass-ceramic or glass as hereinbefore defined as matrix component, together with one or more filler components.

The glass-ceramic or glass as matrix component may be present in any desired amount, for example in an amount of from 1 wt% to 99 wt% of the composite, preferably 5 wt % to 90 wt %.

In an alternative embodiment a composite of the invention comprises the glass-ceramic or glass as hereinbefore defined as filler together with one or more matrix components and optionally additional filler components. The glass-ceramic or glass as filler component may be present in any desired amount, for example in an amount of from 1 wt% to 70 wt% of the composite, preferably 5 wt % to 50 wt %.

A matrix or filler component is preferably a biomaterial and may be selected from a ceramic, such as a calcium salt; calcium sulfate, hydroxyapatitθ, a calcium phosphate; bioactive glass, a vitreous based glass (such as may be used for cranio-maxillofacial applications); calcium carbonate, a calcium based mineral; various calcium phosphates, and calcium-rich minerals, including tricalcium phosphate and orthophosphate; apatite/ wollastonite glass ceramic, a calcium silicate often used in bone spacer applications; resorbable polymers such as polysaccharides, polyesters, polyaromatics (all of which can be blended or made as co-polymers to control the desired properties of the product); synthetic, ceramic, allograft or autograft bone graft substitute, and composites thereof. Bioactive glass is a material whose major components are CaO, SiO₂ and P₂O₅ and whose minor components may be Na₂O, MgO, AI₂O₃, B₂O₃ and CaF₂.

Suitable polysaccharides may include celluloses, starches, chitin, chitosan, alginates, hyaluronates and the like.

Suitable polyesters may include polyglycolates, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), copolymers of lactic and glycolic acids, copolymers of lactic and glycolic acid with poly(ethylene glycol), poly(e-caprolactone), poly(3-hydroxybutyrate), poly(p-dioxanone), polypropylene fumarate), poly(trimethylene carbonate) and the like and combinations thereof.

Suitable polyaromatics may include poly ether ketones (PEK), poly ether ether ketones (PEEK), poly ether sulphones (PES), poly ether ether sulphones (PEES) and the like and combinations thereof.

An inorganic filler or matrix component may be selected from osteoconductive materials and/or other ceramics. A ceramic may be selected from hydroxyapatite, calcium sulphate, alumina, silica, calcium carbonate, calcium phosphate, calcium tartarate, bioactive glass, Si-substituted hydroxyapatite, C-substituted hydroxyapatite, or combinations thereof, and is preferably a biological active such as hydroxyapatite. A biomaterial filler may include any synthetic or allograft or autograft bone graft substitute such as cortical - cancellous bone, demineralised bone matrix and the like.

The composite may also include a biological agent selected from a growth factor, an antibiotic, a strontium salt, a fluoride salt, a magnesium salt, a sodium salt, fibrin, a bone morphogenetic factor, a chemotherapeutic agent, a pain killer, a bisphosphonate, a bone growth agent, an angiogenic factor, and combinations thereof. A growth factor may be selected from the group consisting of platelet derived growth factor (PDGF), transforming growth factor b (TGF-b), insulin-related growth factor-l (IGF-I), insulin-related growth factor-ll

(IGF-II), fibroblast growth factor (FGF), beta-2-microglobulin (BDGF

II), bone morphogenetic protein (BMP), and combinations thereof.

An antibiotic may be selected from the group consisting of tetracycline hydrochloride, vancomycin, cephalosporins, and aminoglycocides such as tobramycin, gentamicin, and combinations thereof.

A factor may also be selected from the group consisting of proteins of demineralized bone, demineralized bone matrix (DBM), bone protein (BP), bone morphogenetic protein (BMP), osteonectin, osteocalcin, osteogenin, and combinations thereof.

A biological agent may also be selected from the group consisting of cis-platinum, ifosfamide, methotrexate, doxorubicin hydrochloride, and combinations thereof.

A pain killer may be selected from the group consisting of lidocaine hydrochloride, bipivacaine hydrochloride, non-steroidal anti-inflammatory drugs such as ketorolac tromethamine, and combinations thereof.

A composite of the invention may be provided in the form of a cement, which is suitably provided in two part form for mixing prior to use, comprising a first part having the glass-ceramic or glass as filler and a matrix polymer precursor and a second part having a catalyst or activator to polymerise the polymer precursor and set the cement.

A composite of the invention may comprise additional reinforcing in the form of fibres or the like, suitably inorganic fibres such as glass or the like or organic fibres such as carbon or polymer.

A glass-ceramic, glass or composite of the invention is biodegradable and may be in powder or particle or monolith form for moulding or shaping or may be in the form of any implantable artefact, or a coating thereof, preferably any implantable orthopaedic artefact such as orthopaedic plate, screw, pin, rod, anchor, scaffold or joint member. Examples of such artefacts include suture anchors, soft tissue anchors, screws or pins such as bone or interference screws, tissue engineering products such as scaffolds, plates such as maxillofacial plates or fracture fixation plates, rods, fibres, bone graft substitutes or fillers, implants and the like.

The glass-ceramic, glass or composite may be in the form of a standard or custom shaped artefact or may be in the form of particles which may be located in situ to fill a desired space. Particles may take the form of a jack, a tablet, a strip, a block, a cube, a chip, a pellet, a pill, a lozenge, a sphere, a ring, gel, putty, paste, formable granules, or powder and combinations thereof. Preferably particles take the shape of a jack which is a 4, 5 or 6 arm star shape, and more preferably a particle is a JAX™ particle.

Particles are suitably of the order of 0.1 to 2 cm in greatest dimension, preferably 0.1 to 1 .25 cm, depending on the intended use, more preferably less than about 1 cm in diameter, most preferably in the range of 0.2 to 1 cm.

The composite of the invention may be shaped in any desired manner, for example by casting or moulding, extruding or the like. The composite of the invention is characterised by favorable strength. Preferably the composite of the invention has a tensile strength in excess of 50 MPa.

In a further aspect of the invention there is provided a process for preparing a glass-ceramic as hereinbefore defined comprising heat treating a precursor parent glass comprising precursor oxides of combeite and comprising Si, P, Ca, Na and Mg ions, preferably having precursor oxides of phases as hereinbefore defined or having the corresponding oxide composition to the glass-ceramic as hereinbefore defined. More preferably the process comprises obtaining and heating the parent glass as hereinbefore defined at a temperature T₁ above the glass transition temperature T₉ for a first period ti and at a temperature T₂ above the crystallisation temperature T_c for a second period X₂. Preferably T₁ is greater than 590⁵C and less than 770⁵C. Preferably T₂ is greater than 770⁵C and less than 1070⁵C. Preferably I₁ is greater than X₂, preferably I₁ and t₂ are in the range 15 to 360 min, more preferably 15 to 240 min. Selection of T₁ and T₂ can influence or optimise microstructure.

In a particular advantage the glass-ceramic of the invention is conducive to casting without deterioration of mechanical properties. Casting or compression-moulding may be conducted by rendering the solid glass-ceramic in melt phase, casting or moulding in a suitable mould or form, and allowing to cool. The homogeneous parent glass melt is characterised by a high % density, where 100% density implies zero porosity. Preferably the homogeneous parent glass melt is characterised by a % density in the range 90% to 99%. In a particular advantage the glass-ceramic undergoes bulk crystallisation during the casting or moulding process whereby the cast or moulded product is characterized by a high density, and more preferably by an increase in density over the cross section of the product. Preferably density is in the range 90 to 100%, more preferably 95 to 100%, more preferably 99 to 100%, most preferably of the order of 99.9 to 100%. This provides a significant advantage over currently available alternatives such as AWGC which is usually shaped from powder or particles which are pressed, sintered and machined into shape and therefore by definition are of lower density and cannot be made 100% dense.

The parent glass may be obtained by techniques as known in the art, comprising mixing the component oxides in their oxide or other form as desired, melting and casting to achieve a rapid quench and form a glass frit. The glass frit may be remelted for shaping or may be ground for use in powder, granule or particle form.

Preferably the melting is conducted with stirring or melting twice, i.e. is conducted with intermediate cooling and remelting, or other suitable technique whereby the parent glass is obtained with beneficial homogeneity.

In a further aspect of the invention, there is provided a process for preparing a composite as hereinbefore defined comprising combining the glass-ceramic or glass together with matrix or filler as hereinbefore defined. In a first embodiment a composite may be prepared by providing the glass-ceramic or glass in powder or like form and combining with filler such as inorganic as hereinbefore defined. In an alternative embodiment a composite may be prepared by providing the glass-ceramic or glass in powder or like form and combining with matrix such as polymer or inorganic as hereinbefore defined. Matrix polymer is suitably combined in solid, solution or melt form with glass-ceramic or glass in accordance with the invention, for example by blending, impregnation, infusion, injection or the like as known in the art, and hardened for example by moulding, compression moulding or drying.

In a further aspect of the invention there is provided an artefact comprising a glass-ceramic or glass, or composite or coating thereof as hereinbefore defined in the form of an orthopaedic plate, screw, pin, rod, anchor, scaffold or joint member, preferably a suture anchor, soft tissue anchor, bone or interference screw, bone filler, tissue engineering product such as a porous or non-porous scaffold, plate such as maxillofacial plates or fracture fixation plate, rod, fibres, bone graft substitute or filler, implant and the like. Preferably the artefact comprises bulk glass-ceramic or glass, or comprises a composite wherein the glass or glass-ceramic is present as matrix or as filler, or comprises the glass-ceramic, glass or composite as a coating about all or part of a bulk material. Preferably an artefact is cast or moulded.

In a further aspect of the invention there is provided a method for manufacturing an artefact as hereinbefore defined comprising shaping a glass or glass-ceramic or composition thereof as hereinbefore defined, optionally with heat treating to produce the glass-ceramic.

Preferably shaping comprises casting or moulding. Casting or moulding may be from powder or particle form glass, glass-ceramic or composite. Pure glass-ceramic cast or moulded products provide the advantage that good mechanical properties allow use of the pure product unsupported by composite.

Alternatively shaping comprises applying as a coating. A powder or particle coating may be applied in spray form, or may be heat treated in situ to form a fully dense coating. Conventional methods, for example comprise applying a powder coating as a spray and drying or baking, or as a powder and melting or sintering, or by methods as conducted with apatite. In a particular advantage a bioactive coating of pure glass-ceramic or composite may be applied to confer bioactive properties on non-bioactive artefacts.

Alternatively shaping comprises laying down glass, glass- ceramic or composite for example by inkjet printing comprising applying the glass-ceramic or glass powder of the invention in a suitable fluid carrier and laying down on a releasable support in manner to build up a multilayer 3D shape or design, with subsequent heat treatment or sintering. This is a method for preparing custom artefacts.

Alternatively shaping comprises manufacturing fibres of glass- ceramic or glass, for example by conventional extrusion and spinning techniques, exhibiting the same nanostructure as the cast materials.

A tissue engineered product may comprise a non-porous or porous scaffold as known in the art. A porous scaffold may be prepared by techniques as known in the art for example mixing the glass-ceramic, glass or composite thereof with porogen, casting, moulding or otherwise shaping and removing porogen for example by washing.

In a further aspect of the invention there is provided a glass- ceramic, glass or a composite or coating thereof as hereinbefore defined for use as a non-medical device or as an implantable biodegradable medical device such as a medium to high strength trauma fixation device suitable for implantation into the human or animal body, for example plates, screws, pins, rods, anchors, scaffolds or joint members, preferably suture anchors, soft tissue anchors, interference screws, bone filler, tissue engineering scaffolds, maxillofacial plates, fracture fixation plates and rods and the like. Use may be for cosmetic or non-cosmetic therapeutic purpose and include surgery, dental applications and the like.

In a further aspect of the invention there is provided a parent glass comprising oxides of Si, P, Ca, Na and Mg for use in preparing a glass-ceramic as hereinbefore defined.

The present invention is now illustrated in non-limiting manner by reference to the following examples and accompanying figures:

Figures 1 a-1 e show FESEM images of the glass-ceramics after polishing to VA μm finish;

Figures 2a and 2b show SEM images of the cross-section of glass (a) and glass-ceramic GC620 (b) after two weeks of immersion in tris-buffered saline;

Figures 2b (1 -4) show EDX analysis of the cross-section of glass-ceramic GC620 (Figure 2b above) at positions (1 ) to (4) after two weeks immersion in tris- buffered saline. The C and Pd peaks are from the sputtered coating;

Figures 3a and 3b show a schematic arrangement of the surface layers on the glass-ceramic samples (3b - right) which may explain their ability to maintain a higher biaxial flexural strength after degradation in tris-buffered saline, unlike the glass samples which do not have this extra silica layer (3a - left);

Figures 3c-3e show the structure of the silica rich layer (S) beneath the apatite layer after 2 weeks in tris-buffered saline; and

Figure 4 shows a graph of biaxial flexural strength of degraded cast glass and glass-ceramic samples.

In the Examples, glass-ceramic microstructure was examined using XRD or Field Emission SEM (FE SEM), identification of crystalline phases present in the glass-ceramic was perfomed using XRD and High Temperature XRD.

Example 1 - Synthesis of parent glass

All raw materials were used in 99% purity.

SiO₂ (fumed) - 32.77wt%

CaCO₃- 32.49 wt% P₂O₅ - 7.28 wt%

Na₂CO₃ - 18.68 wt%

MgCO₃ - 8.77 wt%

Adding raw materials in their carbonated form was to reduce the melting temperature of the first melt as much as possible, since the oxides have higher melting temperatures. The weighed out powders were mixed and transferred to a Platinum-5% Gold crucible and then into an electric furnace at 1600 ⁰C for two hours. The molten glass was then poured rapidly onto a stainless steel plate and covered with another thick plate of stainless steel to achieve a rapid quench. The cooled frit was returned to the crucible and placed into the furnace at 1600 ⁰C for a further 2 hours. The molten glass was cast into a stainless steel split- mould at 500⁰C and held in the furnace at 500⁰C for 1 hour before cooling to room temperature at 2°C/min. The cooled demoulded casts were then sliced into 1 mm thick discs which were used for preparing the glass-ceramic.

The composition of the parent glass in wt% was as follows:

XRF was used to verify the composition of the glass. XRD showed that the glass was amorphous.

Example 2 - In vitro bioactivitv of parent glass

The in vitro bioactivity of the glass was investigated by conducting Simulated Body Fluid (SBF) immersion for time periods 1 , 2, 4 and 7 days and used AWGC as control material. SBF is a protein free acellular fluid developed by Kokubo and his colleagues in 1990 (Kokubo et al. 1990b). SBF has ion concentrations similar to those of the inorganic constituents of human blood plasma (Table 3.2.1 ).

Table 3.2. 1: Ion concentration (mM) in SBF and in human blood plasma (Kokubo et al. 1990b).

The SBF solution was produced with the reagents listed in

Table 5.4.1 with a pH of 7.4 (similar to that of human plasma at 36.5 ⁰C, 7.2 - 7.4). A comparison of the ionic concentration and pH between the human blood plasma and of the prepared SBF is shown in Table 5.4.2. The chemicals were dissolved in deionised water at 36.5 ⁰C in the order that they are listed in Table 5.4.1 and in order to obtain the exact pH of 7.4 at 36.5 ⁰C only 80% of the HCI was added initially, the remainder was used to buffer the solution.

Table 5.4.1: The list of reagents used for preparing simulated body fluid (SBF). The quantities are for preparation of 1 litre of solution

(Kokubo et al. 1987).

The composition of AWGC given in wt% is as follows:

The specimens were suspended and immersed into 20 ml of SBF solution.

After 1 day in SBF the surface of the glass of the invention became smoother as a result of silica gel formation, and there were numerous apatite nuclei present on the surface. After 2 days the surfaces of the glass samples were completely covered with a thin layer of apatite crystals and with thick apatite by the 4^th day. Overall the parent glass produced is highly bioactive and capable of forming apatite after only 1 day of immersion in SBF.

Example 3 - Synthesis of glass-ceramics The heat treatment of the glass-ceramics was based on the thermal properties of the parent glass shown in the following table (temperatures are rounded up to the nearest whole number):

Table - critical thermal transition point determined by DSC analysis

The glass discs of Example 1 were heated at T₁ above the glass transition temperature T₉ for 3 hours and at T₂ above the crystallization temperature T_c for 30 minutes. The first step T₁ treatment was a nucleating treatment to cause small regions of crystalline order to form randomly throughout the glass structure. The second step T₂ treatment was to allow crystals to grow from the nuclei formed. In order to obtain a microstructure of fine crystals a short T₂ treatment step was used.

Four samples were prepared which varied in the T₁ temperature but had the same T₂ temperature as follows:

Samples were raised to T₁ in 5°C/min increments then held then raised to T₂ in 5°C/min increments then held then cooled at 10°C/min increments to room temperature. This heat treatment was aimed at changing the microstructure of the glass-ceramics produced and not the crystalline phases. The composition of the glass-ceramics did not change, compared to the parent glass.

The heat treatment generated the following crystal phases:

Figure 1 a - 1 e shows FESEM images of the parent glass and glass-ceramics after polishing to a ¹Λ micron finish. From the

Figures, the parent glass is clearly amorphous in nature, while white crystal phases can be observed in samples GC620, GC660, GC700 and GC740. Crystal size can be estimated visually in the range 50 to

100 nm. The images showed that crystal size increased with increased nucleation temperature. Further studies showed that glass-ceramics which experienced higher nucleation temperature started growing crystals during their first isotherm T₁ , while the glass-ceramics which experienced lower nucleation temperature isotherms did not undergo crystal growth until the second isotherm T₂ had started.

The density of samples was measured using a Micromeritics AccuPyc 1330 Pycnometer. The samples were placed into the 1 cm³ sample chamber (to fill a minimum of 2/3 rd by volume) and weighed. The sample chamber was then loaded into the AccuPyc for analysis. AccuPyc is a fast, fully automated density analyser that provides high-speed, high-precision volume and density measurements.

AccuPyc works by measuring the amount of displaced gas (helium). The pressure observed upon filling the sample chamber and then discharging it into a second empty chamber allow computation of the sample solid phase volume. Gas molecules rapidly fill the tiniest pores of the sample; only the truly solid phase of the sample displaces the gas. The density of glass and glass- ceramics obtained is shown in the following table:

This data shows a very high density of the glass - ceramic which can be explained by the compact crystal structure present in the nanoscale microstructure.

Example 4 - Mechanical Properties of cast glass-ceramics

The cast and polished samples of Example 3 were tested to determine their mechanical properties. Pressed, sintered and machined AWGC and cast Bioglass ™ cut into 1 mm thick discs were used as comparison.

This data shows that the flexural stress of the cast glass - ceramics of the invention are 50% greater than the parent glass and comparable to or greater than cast Bioglass ™. This is attributable to the microstructure of the cast samples. Sintered and pressed AWGC, although giving higher values, suffers from poor ease of shaping and limited complexity of artifacts, as hereinbefore referred.

Example 5 - In vitro Bioactivitv of Glass-ceramics The same procedure as used for parent glass samples of

Example 2 was followed here. After 1 day in SBF the surface of GC 620 and 660 samples became much rougher with large crevices appearing on the surface due to dissolution of ions from the glass- ceramic into the solution. After 2 days it appeared that these crevices were filled, EDX analysis showed higher ratio of Ca and P to Si, indicative of apatite formation. After 4 days GC 620 and 660 samples were completely covered with apatite crystals.

After 1 day in SBF the surface of GC700 and 740 samples showed dissolution and a rise in Ca and P indicated apatite formation. After 2 days the surface was completely covered in apatite.

In vitro bioactivity was also carried out using tris-buffered saline (TBS), which is a simple stable pH buffer solution, pure water buffered with tris-hydroxymethyl-aminomethane. The buffered saline solution was prepared by diluting tris(hydroxymethyl)aminomethane

(HOCH₂)₃CNH₂ (Sigma-Aldrich) (6.057 g per litre) with deionised water at 37 ⁰C to produce 50 mM TBS. The pH was brought to 7.4 at 35 ⁰C using 1 M HCI. All samples showed bioactivity by forming bone like apatite on their surface after one week immersion in TBS. The apatite layer allows chemical binding to bone as well as physical binding. Bioactivity was determined to be greater than AWGC.

Samples were able to form apatite on the surface in less than 2 days after immersion in SBF, which is particularly useful for maxillofacial and orthopaedic surgery.

Example 6 - Biodeqradation

Cast samples of Example 3 were subsequently immersed in TBS (tris-buffered saline) to initiate degradation. A decision was made not to use SBF since it contains many of the ions already present in the composition of the glass and glass-ceramics. TBS allowed observation of effects which would have not been possible to observe using SBF. Immersion periods of 1 , 2, 4, 8 and 12 weeks were selected to study the in vitro degradation of the parent glass and the produced glass-ceramics.

TBS does not contain any of the elements present in the glass or glass-ceramic which enabled simple interpretation of ion detection in solution after the study. The change in dry mass and density of samples pre and post immersion was recorded. Ion concentration in immersion solutions was measured at 2 week intervals for the 12 weeks for Na, P, Ca, Mg and Si. The samples showed good stability in air (they did not age and lose bioactive capability).

All samples degraded over the period of 12 weeks. The glass- ceramic samples showed greater mass loss than the parent glass.

Mass, density and ion concentration results show a higher degradation rate for GC700 and GC740 than other samples.

Release of ions was detected. Concentration of released Na and Mg ions was greater than concentration of released Ca and Si ions - this suggests that the presence of these ions is important to the biodegradation of the samples. The formation of a Diphasic apatite layer on the surface of the glass-ceramics GC700 and GC740 was also observed after 8 weeks, identified as beta-tri-calcium phosphate Ca₃(PO₄)₂. This is known for being resorbable, slowly and gradually dissolving in the body, whilst the hydroxyapatite which this new phase replaced, is known for its bioactive capability and being a stable phase.

Example 7 - Mechanical properties of cast glass-ceramic after onset of degradation

Samples of Example 6 were tested to determine their mechanical properties during degradation at 1 , 2, 4, 8 and 12 weeks.

The biaxial flexural strength of degraded dry samples was measured using an lnstron 5567. The results are shown in the following table as biaxural flexural strength (MPa).

Time/weeks 0 1 2 4 8 12 Sample glass 46 .0 58.1 30.5 29.4 42.2 36.8

GC620 73 .4 101 2 103.0 1 10. 3 1 14.1 1 10.1

GC660 73 .8 100 3 98.9 105. 8 123.3 107.8

GC700 77 .0 120 8 120.1 123. 0 1 1 1.3 83.5

GC740 77 .5 141 0 1 12.1 120. 9 98.1 86.5

The results are also shown in graph form in Figure 4 below.

The strength of the glass and glass-ceramic samples increased after one week of degradation. On average the glass and glass-ceramic samples experienced an increase of 150% in their biaxial flexural strength after one week, the cast samples exhibiting strength levels approaching those of pressed and sintered AWGC.

However the biaxial flexural strength of the glass sample dropped to below its original value after two weeks while the glass-ceramics maintained a biaxial flexural strength well above their original value for up to 8 weeks in the case of GC700 and GC740 and throughout the 12 weeks for GC620 and GC660.

All glass-ceramics showed an increase in their strength ranging from 100 to 140 MPa over the 12 week degradation period. This was observed despite the glass-ceramic samples losing between 15 to 25% of their mass and 3 to 5% of their density over the 12 weeks. The glass-ceramic flexural stress is approximately 50% greater than the parent glass. It is known that silica forms a silica gel layer which smooths the surface and reduces defects which lead to crack initiation. In the case of glass-ceramics a novel "self-strengthening" mechanism observed during their degradation has been attributed to additional changes that took place at the surface of the glass-ceramics, the dissolution of ions from the glass- ceramics leaving behind a porous-silica rich layer, hereinbefore described.

Figure 2a and 2b shows SEM images of the cross-section of glass (a) and glass-ceramic GC620 (b) after two weeks of immersion in tris-buffered saline. The Figures reveal the novel silica rich layer which had formed only on the glass-ceramics. In Figure 2b showing the glass-ceramic samples three distinct structural layers formed after immersion in TBS for 2 weeks. The top layer was highly concentrated in calcium and phosphorus and about 5 micron thick. The layer below this was of lower density and rich in silica and approximately 15 micron thick. The third layer which was on top of the core glass-ceramic material contained a high concentration of silica and was about 30 micron thick. In Figure 2a, on the surface of the glass only two distinct layers were observed. The top layer was a calcium and phosphorus rich layer. Beneath this top layer (and above the core glass) was a 10 - 15 micron thick silica-rich layer. Figure 2b (1 -4) shows EDX analysis of the cross-section of glass- ceramic GC620 at positions (1 ) to (4) after two weeks immersion in tris-buffered saline. The C and Pd peaks are from the sputtered coating. Figures 3a and 3b show a schematic arrangement of the surface layers on the glass-ceramic samples which may explain their ability to maintain a higher biaxial flexural strength after degradation in tris-buffered saline, unlike the glass samples which do not have this extra silica layer. Figure 3a shows a sample (1 ) made of glass (2). A silica gel layer (3) is disposed on the glass (2). Apatite crystals (4) are disposed on the silica gel layer (3). Figure 3b shows a sample (1 ) made of glass-ceramic (5). A silica gel layer (3) is disposed on the glass-ceramic (5). A honeycomb structured porous silica rich layer (6) is disposed on the silica gel layer (3). Apatite crystals (4) are disposed on the honeycomb structured porous silica rich layer (6).

The formation of the silica-rich layer has previously been observed on Bioglass ™ arising from hydrolysis of the silica groups, soluble silica being lost to the solution, followed by condensation and repolymerisation thereof at the surface, In the case of the glass- ceramics the polymerization and condensation led to a finer, more organized microstructure on top of the typical silica-rich layer. This characteristic porous silica-rich "honeycomb" structure observed beneath the apatite layer on the glass-ceramics was attributed to hindering crack propagation through the material during mechanical testing. Figures 3 c to 3e show the structure of the silica rich layer (S) beneath the apatite layer after 2 weeks in tris-buffered saline.

All samples investigated degraded over the period of 12 weeks. As the glass-ceramics degraded they either left behind or formed a porous silica-rich layer which was "honeycomb" shaped. This led to glass-ceramics having improved biaxial flexural strength as they degraded. They did not experience drastic changes in their properties and showed stability for long enough to allow bone healing had they been implanted in vivo.

Claims

1. A glass-ceramic having a homogeneous nano-scale microstructure comprising a combeite phase and comprising oxides Of Si, P, Ca, Na and Mg.

2. A glass-ceramic as claimed in claim 1 comprising a combination of crystalline phases including combeite and sodium- calcium-magnesium-phosphate.

3. A glass-ceramic as claimed in claim 1 or 2 comprising Mg present in an amount of from 2 to 15 wt%.

4. A glass-ceramic as claimed in any of claims 1 to 3 comprising combeite in an amount of greater than 50wt%.

5. A glass-ceramic as claimed in any of claims 2 to 4 comprising sodium-calcium-magnesium-phosphate in an amount of from 10 to 53 wt%, more preferably 15 to 30 wt%, most preferably 20 to 25 wt%.

6. A glass-ceramic as claimed in any of claims 1 to 5 comprising the following crystal phases in combination : Sodium-calcium-silicate (combeite), Sodium-calcium-magnesium-phosphate and Calcium- sodium-phosphate.

7. A glass-ceramic as claimed in claim 6 comprising calcium- sodium-phosphate in an amount of from 3 to 25 wt%.

8. A glass-ceramic as claimed in any of claims 1 to 7 comprising the following oxides in wt% as shown:

SiO₂ from 40 to 53 wt%;

P₂O₅ from 0 to 15 wt%

CaO from 10 to 32 wt%

Na₂O from 5 to 32 wt% MgO from 2 to 12 wt%

or obtained therefrom or from their equivalents, such as carbonates.

9. A glass-ceramic as claimed in any of claims 1 to 7 comprising the following oxides in wt% as shown:

SiO₂ from 43 to 48 wt%;

P₂O₅ from 6 to 13 wt%

CaO from 15 to 30 wt%

Na₂O from 10 to 30 wt%

MgO from 2 to 8 wt%

or obtained therefrom or from their equivalents, such as carbonates..

10. A glass-ceramic as claimed in any of claims 1 to 7 having the following composition in wt% of its corresponding parent glass:

1 1 . A glass-ceramic as claimed in any of claims 1 to 10 which comprises a homogeneous composite of amorphous and crystalline phases with crystal sizes of the order of 1 to 250 nm.

12. A glass-ceramic as claimed in any of claims 1 to 10 which comprises a homogeneous composite of amorphous and crystalline phases with crystal sizes of the order of 1 to 150 nm.

13. A glass-ceramic as claimed in any of claims 1 to 10 which comprises a homogeneous composite of amorphous and crystalline phases with crystal sizes of the order of 1 to 100 nm.

14. A cast or moulded glass-ceramic which has a homogeneous nanoscale microstructure and comprises a combeite phase.

15. A cast or moulded glass- ceramic as claimed in claim 14 characterised by the formation of a silica gel layer having superposed thereon a surface layer of honeycomb structured porous silica rich layer adapted to support growth of apatite crystals.

16. A glass comprising oxides of Si, P, Ca, Na and Mg.

17. A glass as claimed in claim 16 comprising the following oxides in wt% as shown:

SiO₂ from 40 to 53 wt%;

P₂O₅ from O to 15 wt%

CaO from 10 to 32 wt%

Na₂O from 5 to 32 wt%

MgO from 2 to 12 wt%.

18. A blend comprising a glass or glass-ceramic as defined in any of claims 1 to 17.

19. A biodegradable composite comprising a glass-ceramic or glass or blend as hereinbefore defined in any of Claims 1 to 18 present as matrix or as filler together with a filler or matrix component.

20. A composite as claimed in claim 19 wherein glass-ceramic or glass or blend as matrix component is present in an amount of from

1 wt% to 99 wt% of the composite, preferably 5 wt % to 90 wt %.

21 . A composite as claimed in claim 19 wherein glass-ceramic or glass or blend as filler component is present in an amount of from 1 wt% to 70 wt% of the composite, preferably 5 wt % to 50 wt %.

22. A composite as claimed in any of claims 19 to 21 wherein matrix or filler component is a biomaterial and is selected from a ceramic, such as a calcium salt; calcium sulfate, hydroxylapatite, a calcium phosphate; bioactive glass, a vitreous based glass (such as may be used for cranio- maxillofacial applications); calcium carbonate, a calcium based mineral; various calcium phosphates, and calcium-rich minerals, including tricalcium phosphate and orthophosphate; apatite/ wollastonite glass ceramic, a calcium silicate often used in bone spacer applications; resorbable polymers such as polysaccharides, polyesters, polyaromatics; synthetic, ceramic, allograft or autograft bone graft substitute, and composites thereof.

23. A composite as claimed in any of claims 19 to 22 in the form of a cement, provided in two part form for mixing prior to use.

24. A composite as claimed in any of claims 19 to 23 comprising additional reinforcing in the form of fibres.

25. A glass-ceramic, glass, blend or composite as claimed in any of claims 1 to 24 in powder or particle or monolith form for moulding or shaping or in the form of any implantable artefact, or a coating thereof, preferably any implantable orthopaedic artefact such as an orthopaedic plate, screw, pin, rod, anchor, scaffold or joint member.

26. A glass-ceramic, glass, blend or composite as claimed in any of claims 1 to 25 in the form of suture anchors, soft tissue anchors, screws or pins such as bone or interference screws, tissue engineering products such as scaffolds, plates such as maxi No-facial plates or fracture fixation plates, rods, fibres, bone graft substitutes or fillers, implants and the like.

27. A glass-ceramic, glass, blend or composite as claimed in any of claims 1 to 26 in the form of a standard or custom shaped substitute or in the form of particles which may be located in situ to fill a desired space, such as a jack, a tablet, a strip, a block, a cube, a chip, a pellet, a pill, a lozenge, a sphere, a ring, gel, putty, paste, formable granules, or powder and combinations thereof.

28. A glass-ceramic, glass, blend or composite as claimed in any of claims 1 to 27 in the form of a jack which is a 4, 5 or 6 arm star shape, and more preferably a JAX™ particle.

29. A glass-ceramic, glass, blend or composite as claimed in any of claims 1 to 25 in the form of an artefact of 0.5 to 2cm in dimension or in the form of a particle of from less than about 10 millimeters in diameter.

30. A process for preparing a glass-ceramic as hereinbefore defined in any of Claims 1 to 15 or 25 to 29 comprising heat treating a precursor parent glass comprising precursor oxides of combeite and comprising Si, P, Ca, Na and Mg ions, preferably having precursor oxides of phases as hereinbefore defined or having the corresponding oxide composition to the glass-ceramic.

31 . A process as claimed in claim 30 comprising obtaining and heating the parent glass as hereinbefore defined at a temperature T₁ above the glass transition temperature T₉ for a first period I₁ and at a temperature T₂ above the crystallisation temperature T_c for a second period X₂-

32. Process as claimed in claim 31 wherein T₁ is greater than 590⁵C and less than 770⁵C and T₂ is greater than 770⁵C and less than 1070⁵C.

33. Process as claimed in claim 31 or 32 wherein I₁ is greater than X₂, preferably I₁ and t₂ are in the range 15 to 360 min, more preferably 15 to 240 min.

34. Process for preparing a composite as claimed in any of Claims 19 to 29 comprising providing glass-ceramic or glass as defined in any of Claims 1 to 18 or 25 to 29 and combining the glass- ceramic or glass together with matrix or filler as hereinbefore defined in claim 22.

35. An artefact comprising a glass-ceramic or glass, blend or composite or coating thereof as hereinbefore defined in any of claims 1 to 29 in the form of an orthopaedic plate, screw, pin, rod, anchor, scaffold or joint member, preferably a suture anchor, soft tissue anchor, bone or interference screw, bone filler, tissue engineering product such as a porous or non-porous scaffold, plate such as maxillofacial plates or fracture fixation plates, rod, fibre, bone graft substitute or filler or implant.

36. An artefact as claimed in claim 35 which is cast or moulded.

37. A method for manufacturing an artefact as claimed in claim 35 or 36 comprising shaping a glass or glass-ceramic, blend or composite thereof as hereinbefore defined in any of claims 1 to 29, optionally with heat treating to produce the glass-ceramic.

38. A method as claimed in claim 37 wherein shaping comprises casting or moulding.

39. The use of a glass-ceramic, blend or a composite thereof as hereinbefore defined in any of Claims 1 to 29 as an implantable biodegradable device such as a high strength trauma fixation device suitable for implantation into the human or animal body, for example plates, screws, pins, rods, anchors or scaffolds, more preferably suture anchors, soft tissue anchors, bone or interference screw, bone fillers, tissue engineering product such as a porous or non- porous scaffold, plates such as maxi No-facial plates or fracture fixation plates, rods, fibres, bone graft substitutes or fillers or implants.

40. A parent glass comprising oxides of Si, P, Ca, Na and Mg for use in preparing a glass-ceramic as hereinbefore defined in any of claims 1 to 29.