MODIFIED CERAMICS WITH IMPROVED BIOACTIVITY AND THEIR USE FOR BONE SUBSTITUTE

Abstract

The present invention concerns ceramics having a modified surface with improved bioactivity, their process of preparation and their use for orthopedics, dentistry or reconstructive surgery, in particular for use as a bone filler.

Claims

1. A calcium phosphate ceramic having a modified surface, where said ceramic comprises: hydroxyapatite (HA), or tricalcium phosphate (TCP), or a mixture thereof in the form of biphasic calcium phosphate (BCP) characterized in that said ceramic comprises a nanoporous surface comprising deposited nanocrystals of apatite.

2. The ceramic according to claim 1 further comprising fluoroapatite (FHA) and/or chloro-apatite (CLHA).

3. The ceramic according to claim 1 wherein said phosphate is present in anyone of the following forms: Monocalcium phosphate monohydrate (MCPM) (Ca(H.sub.2PO.sub.4).sub.2.H.sub.2O), Monocalcium phosphate anhydrous (MCPA) (Ca(H.sub.2PO.sub.4).sub.2), Dicalcium phosphate anhydrous (DCPA) (CaHPO.sub.4), Dicalcium phosphate dihydrate (DCPD) (CaHPO.sub.4.2H.sub.2O), Octacalcium phosphate (OCP) (Ca.sub.8H.sub.2(PO.sub.4).sub.6.5H.sub.2O), -Tricalcium phosphate (-TCP) (-Ca.sub.3(PO.sub.4).sub.2), -Tricalcium phosphate (-TCP) (-Ca.sub.3(PO.sub.4).sub.2), Amorphous calcium phosphate (ACP) (Ca.sub.3(PO.sub.4).sub.2), Hydroxyapatite (HA) (Ca.sub.10(PO.sub.4).sub.6(OH).sub.2), Tetracalcium phosphate (TTCP) (Ca.sub.4(PO.sub.4).sub.2O), as well as the deficient or ion-substituted calcium orthophosphates. According to an embodiment, the modified surface of the ceramic of the invention further comprises one or more additional bioactive components chosen from bioactive ionic species and active ingredients.

4. The ceramic according to claim 1 where its modified surface further comprises one or more additional bioactive components chosen from bioactive ionic species and active ingredients.

5. A bone substitute material comprising the modified ceramic according to claim 1.

6. A metal implant coated with a modified ceramic according to claim 1.

7. The modified ceramic according to claim 1 for use for orthopedics, dentistry or reconstructive surgery.

8. A process for modifying a macroporous calcium phosphate ceramic comprising: hydroxyapatite (HA), or tricalcium phosphate (TCP), or a mixture thereof in the form of biphasic calcium phosphate (BCP), Said process comprising: reacting said ceramic with supercritical CO.sub.2 in the presence of an aqueous solution.

9. The process according to claim 8 wherein the aqueous solution comprises one or more organic solvents.

10. The process according to claim 8, wherein the quantity of the solution is such that the weight solution/ceramic ratio (L/S ratio) is comprised between 0.5 and 50.

11. The process according to claim 8, wherein the reaction is carried out at a pressure comprised between 2 and 10000 bar and a temperature comprised between 20 and 400 C.

12. The process according to claim 8, wherein the reaction is carried out at a pressure comprised between 60 and 150 bar and a temperature comprised between 30 and 50 C.

13. The process according to claim 8 wherein the reaction mixture is maintained at an acid pH.

14. A ceramic obtainable by the process according to claim 8.

Description

FIGURES

[0098] FIGS. 1 and 2 illustrate the influence of the quantity of the aqueous solution in the course of the process of preparation of the modified ceramics of the invention on the surface morphology. In FIG. 1, various LIS values are tested where the aqueous solution is water. In FIG. 2, US is 20 and both water and SBF solution are tested as aqueous solutions.

[0099] FIG. 3 illustrates the FTIR spectra of an unmodified ceramic and of a modified ceramic with comparison to bone mineral.

[0100] The following examples are given as a non-limiting illustration of the various objects of the invention.

EXAMPLE 1

Teatment of HA/TCP Ceramics Confined in Wet Cotton During 30 h at 50 C. and 100 Bar

[0101] Ceramic cubes with dimension 3 mm*3 mm*3 mm (1.45 g) consist in 65% hydroxyapatite (HA) and 35% tricalcium phosphate (TCP). Their total porosity is between 60 and 85% and the pore size is between 150 and 400 m. The cubes are evenly distributed between two hydrophilic cottons.

[0102] The assembly is then placed in a container with 9.96 g water and then placed under vacuum so as to favor the penetration of water inside the porous ceramic network. The LIS ratio is 6.88. The vacuum is then cut and the whole (cotton+ceramics) slightly wrung to remove excess water. The assembly is then placed in the chamber of a supercritical CO.sub.2 dryer. The chamber temperature is raised to a temperature of 5 C. and then the chamber is filled in full with liquid CO.sub.2. The temperature of the chamber is gradually increased to 50 C. and the pressure adjusted to 100 bar.

[0103] After 30 hours of treatment, the pressure is reduced to atmospheric pressure and the assembly is removed from the enclosure. Ceramic cubes were then dried in the cotton in an oven at 50 C. for 48 h.

[0104] The morphology of the surface of the material is assessed by scanning electron microscopy and compared to the initial surface of the same material before treatment. The surface of the treated material has a large amount of entangled nanocrystals, characteristics of poorly crystallized apatite crystals. Tangling induces the formation of a nanoscale porosity.

EXAMPLE 2

Treatment of HA/TCP Ceramics Confined in Wet Cotton During 7 Days at 50 C. and 100 Bar

[0105] Ceramics and protocol used are identical to those described in Example 1. However, the processing time is 7 days. The morphology of the surface of the material is assessed by scanning electron microscopy (FIG. 1b) and compared to the initial surface of the material (FIG. 1a). The surface of the treated material has a large amount of entangled nanocrystals characteristics of poorly crystallized apatite crystals. The difference of crystal morphology compared to those observed in Example 1 is due to the fact that, during treatment, over time, the apatitic nanocrystals mature and their crystallinity is improved. Indeed, poorly crystallized apatite are very reactive phases that evolve over time, in the presence of water. This maturation of apatitic phases has the effect of improving the crystallinity and decreasing their reactivity.

EXAMPLE 3

Treatment of HA/TCP Ceramics Confined in Container with Small Amount of Water (US=2) During 30 h at 50 C. and 100 Bar

[0106] Ceramic cubes with dimension 3 mm*3 mm*3 mm (0.66 g) consist in 65% hydroxyapatite (HA) and 35% tricalcium phosphate (TCP). Their total porosity is between 60 and 85% and the pore size is between 150 and 400 m. Cubes are placed in a container with just enough water to cover all the cubes (1.33 g) so that L/S=2.02. The whole is dipped into liquid nitrogen to freeze the water. Once the cubes in the ice, the container is placed in the chamber of a supercritical CO.sub.2 dryer.

[0107] The chamber temperature is raised to a temperature of 5 C. and then filled in full with liquid CO.sub.2. The temperature of the chamber is gradually increased to 50 C. and the pressure adjusted to 100 bars.

[0108] After 30 hours of treatment, the pressure is reduced very gradually to atmospheric pressure and the assembly is removed from the enclosure. Ceramic cubes were then dried in an oven at 50 C. for 48 h.

[0109] The morphology of the surface of the material is assessed by scanning electron microscopy and compared to the initial surface of the material. The surface of the treated materials has a large amount of entangled nanocrystals characteristics of poorly crystallized apatite crystals. The arrangement of some crystals creates on the surface of the material porous spheres of a size not exceeding 3 m.

EXAMPLE 4

Treatment of TCP Ceramics Confined in Container with Small Amount of Water (US=2) During 30 h at 50 C. and 100 Bar

[0110] Ceramic cubes with dimension 3 mm*3 mm*3 mm (0.86 g) consist in 100% tricalcium phosphate (TCP). Their total porosity is between 60 and 85% and the pore size is between 150 and 400 m. The protocol used is identical to those described in example 3, with 1.76 g of water (L/S=2.05).

[0111] The morphology of the surface of the material is assessed by scanning electron microscopy (FIG. 1c) and compared to the initial surface of the material (FIG. 1a).

[0112] The surface of the treated materials has a large amount of entangled nanocrystals characteristics of poorly crystallized apatite crystals.

EXAMPLE 5

Treatment of HA/TCP Ceramics Confined in Container with Large Amount of Water (US=20) During 30 h at 50 C. and 100 Bar

[0113] Ceramic cubes with dimension 3 mm3 mm*3 mm (0.72 g) consist in 65% hydroxyapatite (HA) and 35% tricalcium phosphate (TCP). Their total porosity is between 60 and 85% and the pore size is between 150 and 400 m.

[0114] The cubes are placed into a container with 14.44 g of water (L/S=20.05). The treatment performed is identical to that described in Example 3.

[0115] The morphology of the surface of the material is assessed by scanning electron microscopy and compared to the initial surface of the material (FIG. 1a). The surface of the treated materials brings up an important modification of the morphology of the ceramic skeleton with dissolution of TCP grains. Nevertheless, some nanocrystals precipitated on the surface of the ceramic. The coated surface corresponds to the surface which was at the bottom of the container, that is to say in a space where the diffusion of the dissolved species is more limited. The observations allow us to say that the treatment of the ceramic must be done in a confined aqueous environment with an amount of water that allows full wetting of the ceramic but prevents diffusion and dispersion of dissolved ionic species.

EXAMPLE 6

Treatment of TCP Ceramics Confined in Container with Large Amount of Water (US=20) During 30 h at 50 C. and 100 Bar

[0116] Ceramic cubes with dimension 3 mm*3 mm*3 mm (0.856 g) consist in 100% tricalcium phosphate (TCP). Their total porosity is between 60 and 85% and the pore size is between 150 and 400 m.

[0117] The cubes are placed into a container with 17.21 g of water (L/S=20.1). The treatment performed is identical to that described in Example 3.

[0118] The morphology of the surface of the material is assessed by scanning electron microscopy (FIG. 1d) and compared to the initial surface of the material (FIG. 1a).

[0119] The surface of the treated materials brings up an important modification of the morphology of the ceramic skeleton with dissolution of TCP grains.

[0120] The resulting material is friable. As indicated in Example 5, the observations allow us to say that the treatment of the ceramics has to be made in a confined aqueous environment with an amount of water which enables total wetting of the ceramic but prevents diffusion and dispersion of the dissolved ionic species.

EXAMPLE 7

Treatment of HA/TCP Ceramics Confined in Wet Cotton During 24 h at 20 C. and 60 Bar in Liquid CO.SUB.2

[0121] Cubes treated are the same than those used in example 1.

[0122] They are, as indicated in example 1, ceramic cubes with dimension 3 mm*3 mm*3 mm (0.9757 g), placed between two wet cotton wool discs then wringed. The amount of water was 9.66 g. The LIS ratio is 9.9 g.

[0123] Contrary to example 1, the temperature used to realize the treatment is 20 C. with a pressure of 60 bars. In these conditions, the whole is maintained for 24 hours in the CO.sub.2 in the liquid state.

[0124] After 24 hours of treatment, the pressure is reduced to atmospheric pressure and the assembly is removed from the enclosure. Ceramic cubes are then dried in the cotton in an oven at 50 C. for 48 h.

[0125] The morphology of the surface of the material is assessed by scanning electron microscopy and compared to the initial surface of the material. The surface of the treated material presents formation of apatite nanocrystals but a partial dissolution of the particles that constitute the ceramic is observed. As in Example 4, the ions released during treatment are broadcast then dispersed in the solution preventing the local supersaturation and the precipitation of the nanocrystals.

[0126] This example allows us to affirm that whatever the fluid, the amount should not allow significant diffusion of calcium and phosphate ions and prevent the establishment of a local supersaturation failing to prevent the precipitation of apatite nanocrystals.

EXAMPLE 8

Treatment of TCP Ceramics Confined in Wet Cotton During 24 h at 20 C. and 60 Bar in Liquid CO.SUB.2

[0127] The cubes are similar to those used in example 4 and treatment is similar to those used in example 7, with 1.64 g of ceramic and 9.96 g of water (L/S=6.07).

[0128] The morphology of the surface of the material is assessed by scanning electron microscopy and compared to the initial surface of the material (FIG. 1a).

[0129] The observations are identical to those made in Example 7. The surface of the treated material has nanocrystals of apatite but a partial dissolution of the particles constituting the ceramic is observed.

EXAMPLE 9

Treatment of Non-Calcined Hydroxyapatite Powders

[0130] The uncalcined hydroxyapatite powders (4.89 g of powder in cotton impregnated with 7.29 g of water, L/S=1.49) are treated according to the protocol described in example 1, but treatment times and temperatures are different (30 h, 50 C. and 100 bar). The Fourier transformation infrared spectroscopy spectra are shown in FIG. 3 and compared with the spectrum of untreated powder (FIG. 3).

[0131] In FIG. 3, the FTIR spectra highlight chemical modifications of the powder with substitution of a part of PO.sub.4.sup.3 groupments with C0.sub.3.sup.2 (type B CO.sub.3) and HPO.sub.4.sup.2 ions as well as OH.sup. ions by CO.sub.3.sup.2 (type A CO.sub.3).

[0132] The FTIR spectra of the treated powder showed that the moist environment promotes the conversion of hydroxyapatite in carbonated apatite. Furthermore, they allow to identify the substitution of a portion of the PO.sub.4 by HPO.sub.4 and CO.sub.3 ions and a portion of the OH ions by CO.sub.3.

[0133] The chemical composition of the powders obtained is similar to that of bone mineral. The chemical composition and crystallinity apatite crystals can be adjusted by the parameters used during the treatment until obtain the same composition of bone mineral more or less matured. Indeed, over time, the bone mineral consists of nanocrystals having a crystallinity increases and the amount of CO.sub.3 ions increases with a decrease in HPO.sub.4 ions.

EXAMPLE 10

Treatment of HA/TCP Ceramics Confined in Container with Small Amount of Aqueous Solution Containing Bioactive Ionic Species During 10 h at 50 C. and 100 Bar

[0134] Ceramic cubes with dimension 3 mm*3 mm*3 mm (0.82 g) consist in 65% hydroxyapatite (HA) and 35% tricalcium phosphate (TCP). Their total porosity is between 60 and 85% and the pore size is between 150 and 400 m. The treatment is similar to those used in example 3 but carried out during 10 h.

[0135] Moreover, in this example, the water is replaced with 2.23 g of a solution containing 25 mM Ca.sup.2+, 2 mM Mg.sup.2+, 2 mM Sr.sup.2+ and 10 mM HP0.sub.42. L/S=2.8.

[0136] During treatment, all the ionic species present in the ceramic environment contribute to the formation of apatite nanocrystals. The crystals thus formed are poorly crystallized apatite in which part of Ca ions are substituted by magnesium (Mg) and strontium (Sr) ions (known for their ability to stimulate osteoblast activity). The addition into solution of Ca.sup.2+ and HPO.sub.4.sup.2 ions reduces the treatment time and reduce the dissolution of the ceramic surface. In fact, the saturation in ionic species at the surface of the ceramic is reached quickly and is not related to the calcium and phosphate ions released during the treatment that is to say superficial by the ceramic.

EXAMPLE 11

Treatment of HA/TCP Ceramics Confined in Container with Large Amount of Aqueous Diluted SBF Solution (L/S=20) during 30 h at 50 C. and 100 Bar

[0137] Ceramics and protocol used are identical to those described in Example 5. However, the solution used during treatment consists in diluted SBF solution (SBF*0.9). The amount of solution used correspond to L/S=20. The treatment in supercritical CO.sub.2 atmosphere is realized during 30 h at 50 C. and 100 bar.

[0138] The morphology of the surface of the material is assessed by scanning electron microscopy (FIG. 2b) and compared to the surface of the same material treated in the same condition with water (FIG. 2a).

EXAMPLE 12

Treatment of HA/TCP Ceramics Confined in Container with Large Amount of Aqueous Diluted SBF Solution Containing Bioactive Ionic Species (L/S=20) During 30 h at 50 C. and 100 Bar

[0139] Ceramics and protocol used are identical to those described in Example 11. However, the solution used during treatment consists in diluted SBF solution (SBF*0.9) in which AgCl salt is introduced until saturation.

[0140] The amount of solution used correspond to L/S=20. The treatment in supercritical CO.sub.2 atmosphere is realized during 30 h at 50 C. and 100 bar.

[0141] The morphology of the surface of the material is assessed by scanning electron microscopy (FIG. 2c) and compared to the surface of the same material treated in the same condition with water (FIG. 2a).

EXAMPLE 13

Treatment of HA/TCP Ceramics Confined in Container with Large Amount of Aqueous Solution Containing Bioactive Ionic Species (L/S=20) During 30 h at 50 C. and 100 Bar

[0142] Ceramics and protocol used are identical to those described in Example 11. However, the solution used during treatment consists in AgCI saturated solution.

[0143] The amount of solution used correspond to L/S=20. The treatment in supercritical CO2 atmosphere is realized during 30 h at 50 C. and 100 bar.

[0144] The morphology of the surface of the material is assessed by scanning electron microscopy (FIG. 2d) and compared to the surface of the same material treated in the same condition with water (FIG. 2a).

[0145] FIG. 2 shows that when the amount of solution used is very important (ex: L/S=20), the use of SBF solution, even diluted, ie not having reached the metastable state (ex: SBF*0.9) reduces the damage of the ceramic. The use of bioactive ions (ex: Ag.sup.+) can be envisaged, introduced into the SBF solution or in water. Their use does not prevent the surface modifications of the ceramic and allows firstly the precipitation on the surface of the ceramic of Ag.sup.+ substituted apatitic nanocrystals and secondly, the precipitation of silver carbonate nanocrystals. The therapeutic activity of the ceramic will be due to the choice of the ions used and to their staged release related to the dissolution rate of active nanocrystals: fast for carbonate crystals and slower for apatitic crystals.