WO2001083367A2

WO2001083367A2 - A process for the preparation of carbonated biomedical materials

Info

Publication number: WO2001083367A2
Application number: PCT/GB2001/001900
Authority: WO
Inventors: Jawwad Arshad Darr; Ihtesham Ur Rehman
Original assignee: ABONETICS 2000 Ltd; Abonetics Ltd
Current assignee: ABONETICS 2000 Ltd; Abonetics Ltd
Priority date: 2000-04-28
Filing date: 2001-04-30
Publication date: 2001-11-08
Anticipated expiration: 2002-10-28
Also published as: WO2001083367A3; GB0010411D0; AU2001250547A1

Abstract

The present invention provides a process for the preparation of a carbonated calcium phosphate-containing biomedical material, which process comprises a carbonation step in which a calcium phosphate-containing material is contacted with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into said material.

Description

A PROCESS FOR THE PREPARATION OF CARBONATED BIOMEDICAL MATERIALS

The present invention relates to a process for forming carbonated biomedical materials, particularly carbonated apatite compositions for use in biomedical applications.

The apatite group of minerals are based on calcium phosphate, with stoichiometric hydroxyapatite having a molar ratio of Ca/P of 1.67. Hydroxyapatite has the chemical formula Ca₁₀ (P0₄) ₆ (OH) ₂ and has some similarities with the crystal structure to that of the mineral component of bone. It is also biocompatible. Synthetic hydroxyapatite has, consequently, found use as a bone replacement material in porous, granular, plasma sprayed and dense forms.

Human and animal bone mineral contain significant amounts of carbonate ions, typically from 3 to 7 wt%. The carbonate groups are thought to substitute in two sites, the hydroxyl and phosphate sites, termed A and B respectively. Bone mineral is believed to contain significant amount of B type apatite and/or carbonate.

There has been increasing interest recently in the development of biomedical materials, such as bioactive glasses and apatites, which more closely match the chemical composition of bone mineral resulting in faster bone bonding between implant and host. It is, accordingly, envisaged that carbonated apatites will have a different bioactivity than stoichiometric hydroxyapatite which is currently used in commercial applications, such as plasma-sprayed coatings on metallic implants and porous hydroxyapatite ceramic bone substitutes.

A number of prior art techniques are known for the preparation of carbonated hydroxyapatite/apatite compositions. For example, it is known to heat a stoichiometric hydroxyapatite ceramic composition in a gaseous C0₂ atmosphere. This process results in low levels of carbonate substitution, with poor control over the extent of carbonate substitution and the homogeneity of the substitution throughout the sample. The processing time are also very long. At high temperatures (around 1000^°C) , complete removal of all hydroxides may be achieved after several days.

A wet precipitation method using Na₂C0₃, NaHC0₃ or (NH₄)₂C0₃ as a source of carbonate ions is also known. This process results in the substitution of additional ions (Na⁺ or NH₄ ⁺) into the hydroxyapatite structure which can lead to poor thermal stability of the product upon calcining/sintering and the loss of large quantities of the carbonate ions upon heating.

Another known technique involves incorporation of carbonate ions by soaking a carbonate-free sample in a solution saturated with carbon-dioxide. This method involves soaking pure, stoichiometric, sintered hydroxyapatite ceramic powder in mineral water for a very long period of time.

Supercritical (sc) fluids are highly compressed gases that combine the properties of liquids and gases, enabling a wide range of unusual processes to be conducted. The supercritical state exists above a specific pressure and temperature for any substance. In particular, sc-C0₂ (and dense phase C02) has found extensive use as an environmentally acceptable solvent alternative to some conventional hydrocarbon solvents. The critical parameters of carbon dioxide (critical temperature, T_c = 31.1°C, critical pressure, P_c = 73.8 bar) are relatively low compared to other supercritical fluids.

We have now developed a novel process for the incorporation of carbonate ions in a biomedical material and, in particular, for the preparation of a carbonated apatite composition, which uses a supercritical (or dense phase) carbon dioxide and addresses at least some of the problems associated with the prior art.

Accordingly, the present invention provides, in a first aspect, a process for the preparation of a carbonated calcium phosphate-containing biomedical material, which process comprises a carbonation step in which a calcium phosphate-containing material is contacted with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into said material.

In a second aspect, the present invention provides a process for the preparation of a carbonated calcium phosphate-containing biomedical material, which process comprises a carbonation step in which two or more reagents capable of reacting to form a calcium phosphate-containing material are contacted with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into said material. The two or more reagents may first be mixed together, followed by contacting the resulting mixture with supercritical or dense phase carbon dioxide. Alternatively, one reagent (or reagents) may be added to a mixture of supercritical or dense phase carbon dioxide and another reagent (or reagents). The reagents will typically comprise a calcium-containing material and a phosphorus-containing material. Reaction of the two reagents results in a calcium phosphate-containing material. Reaction will typically be formed in solution resulting in a calcium phosphate-containing precipitate.

By the term biomedical as used herein is meant a material which is substantially free of components which are not tolerated by the human or animal body, for example toxic elements (eg Hg and Cd) and compounds .

In the process according to the present invention, carbonate ions are incorporated into the material. The carbonate ions may be incorporated by, for example, a substitution mechanism.

The process according to the present invention relies on a hyperstoichio etric concentration of carbonate ions, via supercritical or dense phase carbon dioxide, to form highly carbonated calcium phosphate-containing materials, for example carbonated apatites.

The carbonated calcium phosphate-containing material may be crystalline, microcrystalline or amorphous. A preferred material is a carbonated apatite having a microstructure which is part or substantially fully amorphous.

The process according to the present invention enables carbonated calcium phosphate-containing materials, for example carbonated apatite, to be produced which are substantially free of any hydroxide ions. This effect is evidenced by the lack of a sharp peak between 3500 cm^"1 - 3600 cm^"1 in the FT-IR.

For a carbonated apatite material produced according the process of the present invention, FT-IR studies indicate the presence of labile carbonate by a broad band at ca. 866 cm^"1. Because the carbonate is more labile / reactive, bone regrowth may be faster compared with prior art materials. This results in superior biological properties.

Carbonate ions are generally believed to be located in A or B sites in apatites. However, for a carbonated apatite material produced according the process of the present invention, at least some of the carbonate ions are also believed to be located in poorly organised sites, which may result in the carbonate ions being more labile. The carbonate may also be in the form of hydrogen carbonate within the amorphous apatite.

The starting material/reagents and/or the carbonated biomedical material may be bioinert or bioactive, resorbable, slowly resorbable, non- resorbable, osteoinductive or osteoconductive . The starting material/reagents will typically contain one or more constituents or phases which react with the supercritical or dense phase carbon dioxide to form carbonate ions in the material. The biomedical material may be produced in the form of, for example, a powder, a monolith, a disk, a moulded or cast object or a coating.

In the first aspect, the starting materials/reagents, which may be biomedical in nature themselves, preferably comprise or consist of one or more of calcium phosphate, apatite, hydroxide, hydroxyapatite, a biocompatible glass and/or a biocompatible glass-ceramic. The starting material may also comprise a composite of a polymer and one or more of the above-recited components. The starting material may further comprise one or more elements selected from alkali metals, alkaline earth metals, lanthanide metal and/or silicon, including phosphates of one or more thereof.

In a preferred embodiment of the first aspect, the starting material is a biomedical material which comprises a calcium- and phosphorus-containing biomaterial, preferably apatite. During the carbonation step, carbonate groups typically substitute in A and/or B sites, predominantly the B sites. Some of the carbonate ions may be located in neither the A sites nor the B sites.

The carbonated material in both the first and second aspects typically has a Ca/P molar ratio in the range of from 1 to 2, preferably from 1.5 to 1.8. The process according to both the first and second aspects of the present invention may be carried out at a pressure and temperature sufficient to generate supercritical or dense phase carbon dioxide. The process may be carried out at a relatively low temperature typically from 15 to 50°C, more typically from 32 to 45°C. The pressure will typically fall in the range of from 70 to 300 Bar, more typically from 150 to 250 Bar.

For biomedical applications, the starting material/reagents and the carbonated material are advantageously substantially free of undesirable toxic ions, such as Hg and Cd for example.

The carbonated biomedical material may consist essentially of single phase carbonated apatite, together with unavoidable impurities. Alternatively, the final sintered/calcined carbonated biomedical material may comprise a carbonated apatite and one or more secondary phases, for example calcium phosphate, calcium oxide and/or calcium carbonate.

The carbonated biomedical material will typically contain up to 20 wt% C0₃ ^2", preferably from 6 to 15 wt% C0₃ ^2". Following sintering, the C0₃ ^2" content will typically fall to from 0.5 to 11 wt% C0₃ ² 2-

In both the first and second aspects, the starting material/reagents is/are preferably unsintered prior to the carbonation step.

The carbonated biomedical material may be provided as a coating on the surface of a substrate, for example the surface of an implant or prosthesis.

In the second aspect, the two or more reagents may be provided in the form of a solution (aqueous or other liquid medium) , suspension, sol-gel mixture, wet mixture, slurry or suspension containing one or more calcium phosphate compounds or their precursors, such as, for example, calcium hydroxide, calcium nitrate, calcium methoxide, phosphoric acid, ammonium phosphate, water. The calcium phosphate-containing material may be formed by a precipitation process and the thus formed precipitate may comprises one or more phases.

In a preferred embodiment of the second aspect, a calcium-containing reagent is added to a mixture comprising supercritical or dense phase carbon dioxide and a phosphate-containing reagent. Alternatively, a phosphate-containing reagent may be added to a mixture comprising supercritical or dense phase carbon dioxide and a calcium-containing reagent.

The two or more reagents may advantageously comprise or consist of calcium hydroxide and phosphoric acid. The reagents may be mixed together to form a calcium phosphate-containing material in, for example, an aqueous precipitation process. It will be appreciated that the carbonation step may result in the formation of some additional calcium carbonate by virtue of the reaction between calcium hydroxide and carbon dioxide. This may be preferable for certain applications. The starting material and the mixture of the two or more reagents may consist or comprise of one or more of Dahllite, MCPM, DCPD, OCP, CDHA, HA, α-TCP, β- TCP, TTCP.

In both the first and second aspects, other components may be present in the staring material/reagents. For metals (eg Mg, Sr, Na, K, Ti) and/or halides (eg fluoride) may be present, which are to be incorporated and/or doped into the product in order to alter its physical, chemical or biological properties .

In both the first and second aspects, the staring material/reagents is/are advantageously purified or sterilised either before or after the carbonation step. This may be achieved by contacting the material (pre-treated material/reagents or carbonated biomedical material) with supercritical or dense phase carbon dioxide under conditions whereby undesirable components in the material are extracted therefrom. In particular, the supercritical or dense phase carbon dioxide may act as solvent for undesirable components, such as organic molecules.

The process according to the present invention will typically be performed in a high-pressure reaction vessel. The walls of the vessel may be coated with or made from a polymer in order to reduce any metal contamination.

The process according to the present invention may further comprise the step of calcining or sintering the carbonated biomedical material following the carbonation step.

Upon calcining or sintering, some phase separation may occur, resulting in the formation of one or more secondary phases, such as tricalcium phosphate (TCP) , calcium carbonate and/or calcium oxide. Accordingly, the sintered material may comprise one or more of A-substituted, B-substituted, AB-substituted carbonated apatites and carbonated hydroxyapatites, optionally together with one or more of tricalcium phosphate, calcium oxide and calcium carbonate .

Furthermore, the carbonated material may lose some of the carbonate during calcining/sintering.

Sintering or calcining is typically performed at a temperature of from 600 to 1500°C, more typically, 800 to 1000°C. Sintering or calcining is typically performed in a substantially dry atmosphere comprising or consisting of carbon dioxide. Alternatively, sintering or calcining may be carried out in a wet atmosphere comprising or consisting of carbon dioxide.

During sintering or calcining, amorphous material tends to crystallize. The final sintered/calcined material will therefore typically be crystalline or at least microcrystalline. The carbonate may be located on A and/or B sites. For apatite materials, the process according to the present invention results in the carbonate being located predominantly on the B sites . The surface area of the sintered/calcined material, for example carbonated apatite, typically has as surface area of 160 to 225 m²/g, more typically from 180 to 200 m²/g (as measured by the nitrogen absorption method) .

The present invention also provides a carbonated biomedical material whenever produced or obtainable by a process as herein described.

The present invention also provides a synthetic bone material or a hard or soft tissue material which comprises a carbonated biomedical material as herein described.

The present invention further provides a composition which comprises a carbonated biomedical material, a synthetic bone material or a hard or soft tissue material as herein described, together with a pharmaceutically acceptable diluent or carrier.

The present invention still further provides a bone implant, filler, bone cement, tissue engineering scaffold, synthetic bone graft or drug-delivery device which comprises a carbonated biomedical material, a synthetic bone material or a hard or soft tissue material or a composition as herein described.

A particularly preferred application of a carbonated apatite material produced according to the present invention is as a reagent or component for a bone cement formulation. Because the carbonate in the apatite material may be labile, the carbonated apatite material may advantageously be used in a cement / injectable bone graft formulation, which, in use, sets to form carbonated hydroxyapatite.

The process according to the present invention may be used to produce a coating of carbonated apatite material on a porous substrate, for example a porous coral material.

The present invention also provides a carbonated biomedical material, a synthetic bone material or a hard or soft tissue material or a composition as herein described for use in a method of treatment of the human or animal body by surgery or therapy.

The present invention also provides a method of altering bioactivity, biocompatability and/or resorption behaviour of a biomedical material, which method comprises:

(i) contacting the biomedical material with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into the material; or

(ii) contacting two or more reagents capable of reacting to form a calcium phosphate-containing material with supercritical or dense phase carbon dioxide,

whereby carbonate ions are incorporated into said material.

The process and method according to the present invention may be used to alter the properties of a biomedical material. For example, the process may be used to alter: (a) mechanical properties, such as compressive and tensile strength; (b) physical properties, such as microstructure, porosity and density; and/or (c) biological properties such as bioactivity, resorption behaviour in simulated or real body fluids.

By the process according to the present invention, a dense, carbonated material (eg an apatite) may be obtained, typically containing between 0.5 and 20 wt% C0₃ ^2" . Furthermore, the carbonated material produced by the process may be substantially single phase (i.e. a phase purity ≥ 95%, preferably ≥ 98%, more preferably approximately 100%) or, alternatively, a mixture of two or more phases. Also, the carbonated material produced by the process is substantially free of undesirable ions, such as Hg and Cd for example, which are not allowed to be present beyond trace levels.

The carbonated biomedical materials prepared in accordance with the present invention may be used in any of the applications for which conventional apatite/hydroxyapatite is used. For example, the material may be used in the formation of plasma- sprayed coatings on metallic implants, the formation of porous ceramic bone substitutes, the preparation of composites with polymeric materials such as high density polyethylene, as granules or beads for packing or filling bone defects.

The resulting ceramic material may be provided in the form of, for example, blocks, cylinders and granules . The ceramic -material produced by the process according to the present invention may be used for part or the whole of as a synthetic bone material, including dental materials, for example for use in bone reconstruction and augmentation, implants, and compaction graft-type fillers and for making hydroxyapatite-polymer composites .

The use of supercritical or dense phase C0₂ is well known and is discussed in, for example, US 5 518 540 and US 5,650,562. In the present process and method, a pressure of approximately 2000 psi may be used at a temperature of typically 32°C to 50°C.

In the process according to the present invention, biomedical materials are exposed to high pressure (supercritical or dense phase) C0₂, optionally together with one or more additional solvents, which reacts with the inorganic phase resulting in incorporation of carbonate ions into the biomedical material. The physical and biological properties of the biomedical materials may be altered by the process.

The process according to the present invention allows the ratio of carbonate to calcium and/or phosphate ions to be varied, whereby materials may be tailored for strength, porosity and bioactivity. The carbonate ions may substitute for ions in the biomedical starting material, for example carbonate groups may typically substitute in the A and/or B sites. There may also be other more labile positions where carbonate groups can reside. The synthesis of the biomedical material may involve an initial preparation step such as that involving a Sol-Gel, co-precipitation or other reaction. The method also applies to bone cement formulations consisting of one or more calcium (or other metal) phosphate compounds and water, which will set to form the same compound or a completely different compound or biomedical material altogether. The wet bone cement formulation can also be mixed with one or more additional components prior to or during the carbonation step, which may result in a composite biomedical material with different or similar biological and/or physical properties. Such additional components may include, for example, one or more of ceramic particles, polymer particles, other reinforcing materials (eg steel, polymer or glass rods) and/or a drug. The wet bone cement formulation can also be mixed with a monomer (and optionally an initiator) or any other material which will begin to polymerise or react after mixing. The supercritical or dense phase C0₂ may be used to initiate polymerisation of the monomer for certain applications. Furthermore, the supercritical or dense phase C0₂ may also be used to remove non-polymerised monomer units. Other additives including hardening, setting or cross-linking agents may be added prior to, during or even after the carbonation step.

The biomedical material may also be in the form of a coating on another material such as a titanium implant. Another form of the biomedical material is as a glass which may or may not be bioactive or wollastonite or a similar biomedical material containing significant amounts of calcium (or other Group 1 or Group 2 or Lanthanide) phosphate and / or silicon (more of this element in bioactive glasses) .

The process according to the present invention has a number of advantages compared with the prior art processes for forming carbonated biomedical materials. In particular, the extent of carbonation can be precisely controlled by varying the supercritical fluid and reaction parameters. Furthermore, the carbonated material produced by the process may be substantially free of undesirable ions, such as Hg and Cd. It is also possible to produce materials that are substantially free of hydroxide and thus carbonated apatite can be produced.

By adjusting the conditions of the supercritical fluid carbonation treatment, the density and porosity of the biomedical material can be influenced.

A wide range of shapes and sizes can be carbonated from powders to moulded cement monoliths or even full-size coated implants.

Carbonation using the supercritical fluid treatment according to the present invention can give access to metastable carbonated materials, which are unattainable by conventional wet chemical synthetic routes, for example carbonated ion containing apatites and carbonated bioactive glasses.

The supercritical fluid treatment may also be used to adjust the final Ca/P ratio and, hence, affect the bioactivity and/or resorption behaviour of the implant in vivo. Additionally, carbonation can be used to affect the resorption behaviour of the biomedical materials in vivo or in vitro.

The porosity of the materials may also be affected by the technique, which means the carbonated materials can be used as drug delivery materials in the body.

The process is particularly advantageous in that it allows a controlled amount of carbonate ions to be introduced into, for example, apatite. A carbonated apatite may be prepared which has a carbonate content comparable to bone.

The process enables the production of carbonated calcium phosphate-containing biomedical materials from solution at a relatively low temperature, typically from 15°C to 50°C.

Amorphous carbonated apatite may be produced by the process according to the present invention, where the carbonate is located on one or both of the A and B sites. Some of the carbonate may also be located on more labile sites and may be in the form of carbonate or hydrogencarbonate ions.

For apatite, it has been found that carbonate substitution by the process of the present invention is predominantly on the B-site (the phosphate site) of the apatite. Accordingly, the majority (for example > 50%) of the carbonate is on the B site of the apatite, with the remaining carbonate being located on the A site and/or other less well defined positions or more labile sites. This is advantageous because the thus produced material more closely resembles natural bone (prior art methods have tended to result in substitution primarily on the A site) . The carbonated apatite thus produced will generally be at least partially amorphous or microcrystalline in character. On sintering or calcining, the material tends to crystallize, resulting in a crystalline or microcrystalline sintered/calcined material, for example carbonated apatite.

The materials according to the present invention closely resemble bone mineral or Dentine in their FT- Raman and FT-IR spectra.

The present invention will now be described further with reference to the accompanying drawing, which is provided by way of example.

Figure 1 is a schematic illustration of an apparatus suitable for performing the process and method according to the present invention. The apparatus comprises a C0₂ gas cylinder 5, which is fluidly connected via a pipe 6 to a compressor 10, which, in turn, is fluidly connected via a pipe 11 to a reaction cell 15. The reaction cell 15 is provided with stirring means 25 therein for stirring material 20 to be carbonated (e.g. a wet or bone cement formulation, solution, gel or suspension) . Conventional means (not shown) to heat or cool the chamber are also provided, for example a heating element and/or a refrigeration unit. Conventional means (not shown) are also provided for monitoring and adjusting the pressure and temperature in the reaction cell 15 so that the desired supercritical / dense phase C0₂ state can be achieved. The reaction cell 15 is fluidly connected via a pipe 16 to a tap/valve 30, which is fluidly connected via a pipe 31 to a back pressure regulator 35. A receptacle 40 is provided in fluid communication with the back pressure regulator 35 for collecting any water.

For the process according to the second aspect of the present invention, the two or more reagents may be provided inside the reaction cell 15. The carbon dioxide is supplied to the reaction cell 15 from gas cylinder 5, being compressed to the required pressure using compressor 10 (Pickel Pump type) . The reaction cell 15 is heated with an external jacket or oven to the desired final temperature and pressure and stirred using a magnetic flea or overhead stirring means 25. After the reaction is finished, the C0₂ can be vented and the products recovered. A filtration step may then be performed for wet products. This is followed by conventional calcining and/or sintering steps.

Alternatively, one or more reagent (s) may be first mixed with supercritical / dense phase C0₂ in the reaction cell 15. The other reagent (s) is/are then added to the mixture under pressure via a high- pressure liquid pump.

For the process according to the first aspect, C0₂ from gas cylinder 5 is slowly pumped (via Pickel pump 10) through the reaction cell 15, which contains the wet material 20 into which carbonate is to be incorporated. As before, the material 20 is stirred by stirring means 25 in order to take away any water or other product that is formed during the reaction. The C0₂ then passes through the back-pressure regulator 35 and is vented to air, while any water can can be collected in receptacle 40 and weighed if required. The process may also be carried out as a semi-batch process, whereby C0₂ is filled into the cell for a fixed time period and then replaced with fresh C0₂ intermittently.

Example

In this example the reagents have a Ca : P Ratio of 1.67.

A first mixture was formed comprising 3.54 g, 15 mmol of calcium nitrate hydrate, 10 ml water and 1 ml concentrated ammonia (specific gravity 1.18). A second mixture was formed comprising 1.20 g, 9 mmol of ammonium hydrogen phosphate, 10 ml water and 15 ml of concentrated ammonia solution to achieve a pH of approximately 12. The second mixture was then added to the first mixture, followed by stirring for 1 minute. The resulting mixture was placed in a reaction cell (as described above) , in to which liquid carbon dioxide was added at a pressure of 250 Bar at 20°C via a chilled compressor. The mixture and carbon dioxide were stirred for 1 hour. Thereafter, the carbon dioxide was released and the resulting reaction product filtered. The filtrate was washed with 10 ml water and the wet filter cake freeze dried for 24 hours. The resulting dried material contained approximately 3 wt% carbon (corresponding to approximately 15 wt% carbonate) . Following a sintering treatment in dry carbon dioxide for 2 hours at 900°C, the carbon content fell to approximately 2.3 wt% (corresponding to approximately 11.5 wt% carbonate) . FT-IR indicated an apatite material having characteristics very similar to the mineral phase of human bone, suggesting the presence of A and B type carbonate, with no sharp hydroxide band between 3500 and 3600 cm-1.

Raman spectroscopy indicated medium intensity peaks at 1074, 1049 and a strong band at 959 wavenumbers (and a very strong peak, which may be due to fluorescence, below 550 cm^"1) , again indicating a similarity with the mineral phase of human bone.

Claims

CLAIMS :

1. A process for the preparation of a carbonated calcium phosphate-containing biomedical material, which process comprises a carbonation step in which a calcium phosphate-containing material is contacted with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into said material .

2. A process for the preparation of a carbonated calcium phosphate-containing biomedical material, which process comprises a carbonation step in which two or more reagents capable of reacting to form a calcium phosphate-containing material are contacted with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into said material .

3. A process as claimed in claim 1, wherein the calcium phosphate-containing material and/or the carbonated calcium phosphate-containing biomedical material is/are bioinert or bioactive.

4. A process as claimed in claim 1 or claim 3, wherein the calcium phosphate-containing material and/or the carbonated calcium phosphate-containing biomedical material is/are resorbable or non- resorbable.

5. A process as claimed in claim 2, wherein one or more of the two or more reagents and/or the carbonated calcium phosphate-containing biomedical material is/are bioinert or bioactive.

6. A process as claimed in claim 2 or claim 5, wherein one or more of the two or more reagents and/or the carbonated calcium phosphate-containing biomedical material is/are resorbable or non-resorbable .

7. A process as claimed in any one of claims 1, 3 and 4, wherein the calcium phosphate-containing material comprises or consists of one or more of calcium phosphate, apatite, hydroxyapatite, containing-hydroxyapatite, a biocompatible glass and/or a biocompatible glass-ceramic.

8. A process as claimed in claim 7, wherein the calcium phosphate-containing material comprises a composite of a polymer with one or more of calcium phosphate, apatite, hydroxyapatite, containing- hydroxyapatite, a biocompatible glass and/or a biocompatible glass-ceramic.

9. A process as claimed in any one of claims 1, 2, 3, 4, 7 and 8, wherein the calcium phosphate- containing material further comprises one or more elements selected from alkali metals, alkaline earth metals, lanthanide metal and/or silicon, including phosphates of one or more thereof.

10. A process as claimed in any one of claims 2, 5 and 6, wherein the two or more reagents comprise or consist of calcium hydroxide and phosphoric acid.

11. A process as claimed in any one of the preceding claims, wherein the calcium phosphate-containing material comprises or consists of apatite and wherein during the carbonation step carbonate groups preferably substitute in the B (phosphate) sites.

12. A process as claimed in any one of the preceding claims, wherein the carbonated calcium phosphate- containing biomedical material comprises apatite having a Ca/P molar ratio in the range of from 1 to 2, preferably 1.5 to 1.8.

13. A process as claimed in any one of the preceding claims, wherein the carbonated calcium phosphate- containing biomedical material is substantially free of toxic elements and compounds.

14. A process as claimed in any one of the preceding claims, wherein the carbonated calcium phosphate- containing biomedical material consists essentially of single phase carbonated apatite, together with unavoidable impurities.

15. A process as claimed in any one of the preceding claims, wherein the carbonated calcium phosphate- containing biomedical material contains up to 20 wt%

CO ²

16. A process as claimed in any one of the preceding claims, wherein the carbonated calcium phosphate- containing biomedical material is provided as a coating on the surface of a substrate.

17. A process as claimed in any one of claims 1, 3, 4, 7 to 9 and 11 to 16, wherein the calcium phosphate- containing material is un-sintered or partially sintered or prior to the carbonation step.

18. A process as claimed in any one of claims 1, 3, 4, 7 to 9 and 11 to 17, wherein the calcium phosphate- containing material is purified and/or sterilised either before or after the carbonation step by contacting the material with supercritical or dense phase carbon dioxide under conditions whereby undesirable components are extracted therefrom.

19. A process as claimed in any one of claims 2, 5, 6, 10 to 16, wherein one or both of the two or more reagents is/are purified and/or sterilised either before or after the carbonation step by contacting the reagent (s) with supercritical or dense phase carbon dioxide under conditions whereby undesirable components are extracted therefrom.

20. A process as claimed in any one of the preceding claims, further comprising the step of sintering or calcining the carbonated calcium phosphate-containing biomedical material following the carbonation step.

21. A carbonated calcium phosphate-containing biomedical material whenever produced by a process as claimed in any one of claims 1 to 20.

22. A synthetic bone material or a hard or soft tissue material which comprises a carbonated calcium phosphate-containing biomedical material as claimed in claim 21.

23. A composition which comprises a carbonated calcium phosphate-containing biomedical material as claimed in claim 21 or a synthetic bone material or a hard or soft tissue material as claimed in claim 22 together with a pharmaceutically acceptable diluent or carrier.

24. A bone implant, filler, cement, tissue engineering scaffold, synthetic bone graft or drug- delivery device which comprises a carbonated calcium phosphate-containing biomedical material as claimed in claim 21, a synthetic bone material or a hard or soft tissue material as claimed in claim 22 or a composition as claimed in claim 23.

25. A carbonated calcium phosphate-containing biomedical material as claimed in claim 21, a synthetic bone material or a hard or soft tissue material as claimed in claim 22 or a composition as claimed in claim 23 for use in a method of treatment of the human or animal body by surgery or therapy.

26. A method of altering bioactivity and/or biocompatability of a biomedical material, which method comprises contacting the material with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into the material.

27. A method of altering the resorption behaviour of a biomedical material, which method comprises contacting the material with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into the material.

28. A method of altering bioactivity and/or biocompatability of a biomedical material, which method comprise contacting two or more reagents capable of reacting to form a calcium phosphate- containing material with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into said material.

29. A method of altering the resorption behaviour of a biomedical material, which method comprise contacting two or more reagents capable of reacting to form a calcium phosphate-containing material with supercritical or dense phase carbon dioxide, whereby carbonate ions are incorporated into said material.

30. A method as claimed in any one of claims 26 to 30, wherein the biomedical material comprises or consists of apatite.