Surgical procedures related to dental and bone tissue deficiencies vary from tooth, molar, or joint replacement, tooth or bone grafting and internal fixation, to maxillo- facial reconstructive surgery. From a biological perspective, the ideal material to reconstruct osseous tissues is autogenous bone, because of its compatibility, osteoinductivity, osteoconductivity, and lack of immunogenic response. Likewise, the ideal material to reconstruct dental tissues is autogenous dental tissue (enamel and the like).

However, the limitations of harvesting an adequate amount of autogenous osseous or dental material, and the disadvantages of a secondary operation to harvest the material, make this "ideal"material in practice far from ideal for most surgical procedures.

One alternative may be found in other bone-derived material. This group of materials concerns allogeneic and xenogeneic bone grafts. A problem is that these materials exhibit the possibility of disease transfer, such as HIV or Hepatitis B, a higher immunogenic response, less revascularisation of the graft and manifest unreliable degradation characteristics.

Another alternative concerns man-made, alloplastic implant materials or biomaterials, which are readily available in large quantities. The wide variety of biomaterials that are used in clinical applications can be divided into four major categories: metals, ceramics, polymers and composites, which all have their own characteristics. For load bearing bone replacement, currently mostly metallic materials are being used. The most interesting alloplastic biomaterials for bone replacement are bioactive or osteoconductive materials, which means that they can bond to bone tissue. Bioactive materials include calcium

phosphate ceramics, such as hydroxyapatite and Bioglasses or glass-ceramics, polymers, such as polyether esters, and composites of such polymers with calcium phosphate ceramics.

For restorative dental applications, metals and ceramics are mostly used for large restorations, while polymers and composites find application in smaller restorations.

The advantage of the use of composite materials as biomaterials is that the properties of two or more materials, mostly a ceramic and a polymeric material, may be combined.

That way, a material is obtained which has properties which cannot be achieved by the provision of a singular material. A problem encountered in composite synthesis is that only limited amounts of ceramic material can be incorporated into a polymeric material. Also, when the resulting composite material is thermally processed, e. g. sintered, the polymeric material may decompose, which leads to a loss of desired properties.

In US-A-5,631,016, a process for producing a composite material has been proposed, wherein use is made of dynamic compaction (also called shock compaction). According to this process, a mixture of a mineral powder and a metallic or non-metallic matrix is subjected to a shockwave, which may be generated by explosives. Essentially, it has been found that the process of this US patent leads to a material wherein the different components of the composite are not fully integrated. In other words, the mineral powder is not homogeneously distributed throughout the metallic or non- metallic matrix.

The present invention aims to provide a material which has a high stiffness and strength, particularly a high impact resistance. It is further aimed at that the above indicated problems of the prior art materials and their preparation are overcome.

Surprisingly, it has been found that the above goals are reached by first coupling a polymer to a ceramic material, before the combination of the two materials is

subjected to dynamic compaction. Thus, the invention relates to a process for preparing an organoceramic, wherein a polymer is coupled to a ceramic material to form a composite material, which composite material is subjected to shock compaction.

In a material obtainable by a process according to the invention, the different components used in its preparation are substantially integrated and firmly attached to each other. As the material is not merely a physical mixture of two or more phases, but rather a heterogeneous compound, it is referred to herein as an organoceramic.

In a process according to the invention, a material is obtained, which can hardly be prepared by conventional techniques, if at all. The material has excellent properties, such as a high stiffness and strength, and particularly a high impact resistance.

The present organoceramic is prepared by starting from at least two different materials. One of these is a polymeric material, the other is a ceramic material, preferably in the form of a powder.

The polymeric material preferably is a biocompatible and/or a biodegradable material. In the context of the present invention, the term biocompatible is intended to refer to materials which may be incorporated into a human or animal body substantially without unacceptable responses of the human or animal. The term biodegradable refers to materials which, after a certain period of time, are broken down in a biological environment. Preferably, the rate of breakdown is chosen similar or identical to the rate at which the body generates autogenous tissue to replace the implant of which the biodegradable material is manufactured.

Suitable polymeric materials to be used in the process according to the invention include polylactic acid, polyether esters, gelatin, starch, collagen, poly (meth) acryl- ates, such as polyalkylmethacrylate and derivatives thereof.

It is also possible to use mixtures of these polymers, or to use copolymers or graft polymers.

The ceramic material is preferably biocompatible and/or bioactive. This means that it should be suitable for biological applications and that it shows a favourable interaction with human or animal tissue with which it is brought in contact. Suitable ceramic materials to be used include calcium phosphates, such as octacalcium phosphate, apatites, such as hydroxyapatite and carbonate apatite, whitlockites, such as p-tricalcium phosphate and a-tricalcium phosphate, and combinations thereof, silica, and Bioglasses or glass-ceramics. Of course, it is also possible to use mixtures of ceramic materials.

The ceramic material is preferably used in the form of a powder. It is preferred that a ceramic material is used which has a specific surface area of at least 60 g/m2.

Preferably, the average particle size of the powder lies in the micron scale, preferably between 0.01 and 100 pm. The average particle size may be measured by using laser diffraction, e. g. using a particle size measuring device of Malvern Instruments. In order to obtain an organoceramic having a particularly high relative density, it is preferred that the average particle size of the powder is higher than 0. 5 pm. Advantageously, the particle size of the ceramic powder may be used to control the ratio between the polymeric and ceramic parts of the organoceramic to be formed. It has been found that the use of smaller ceramic particles tends to lead to an organoceramic comprising more polymeric material.

On the other hand, it has been found that the use of larger particles leads to a better shock compaction. The skilled person will, on the basis of the information provided and given a certain application of the organoceramic to be prepared, be able to select a suitable particle size.

The ratio of the amounts of polymeric and ceramic materials preferably is selected such that the organoceramic comprises between 60 and 99 wt. %, more preferably between 75

and 95 wt. % of the ceramic material, depending on the purpose of the desired organoceramic. Surprisingly, it has been found possible to incorporate relatively large amounts of ceramic material with respect to the amount of polymeric material used. Because of this, in accordance with the invention, it is possible to suitably control the properties of the desired organoceramic.

According to the process of the invention, in a first step, the polymeric material is coupled to the ceramic material. A possible method to achieve this, has been disclosed by Liu, De Wijn and Van Blitterswijk in J. Biomed.

Mater. Res., 40 (3), 1998, pp. 358-364 and 490-497. In accordance with this method use is made of a suitable coupling agent, e. g. a alkylenediisocyanate, an aromatic diisocyanate, an isocyanatoalkyl ester, such as isocyanatoethyl methacrylate, an isocyanatosilane, such as isocyanatopropyl triethoxysilane, or an organic silane. The coupling agent, possibly through certain functional groups in the coupling agent, is capable of reacting with hydroxyl groups which are present on the surface of a ceramic material. In addition, the coupling agent is capable of reacting with functional groups of the polymeric material.

Examples of functional groups which may be present in the polymeric material to react with the coupling agent include, inter alia, glycidyl, vinyl, and aminoalkyl groups.

The coupling agent may be reacted with the ceramic material by adding said agent to a dispersion of the ceramic material in a suitable solvent and letting the resulting mixture react at elevated or ambient temperature for a period ranging from several hours to several days. At the end of this period, the excess, unreacted coupling agent is removed by washing and the modified ceramic material is retrieved.

On the surface of the thus obtained modified ceramic material, various kinds of polymers may be immobilized (or may be coupled thereto). In order to accomplis this, the modified ceramic material is dispersed in a solution of the

polymeric material, or in a liquid curing system, e. g. methylmethacrylate combined with a hardener, such as a benzoylperoxide tertiary aromatic amine system. After a suitable reaction time at elevated or ambient temperature, the excess, unreacted polymeric material is removed by washing with a suitable solvent and the remaining material is retrieved.

An alternative method to achieve the coupling of the polymeric material to the ceramic material involves co- precipitation and has been disclosed by Stupp and Ciegler in J. Biomed. Mater. Res., 26,1992, pp. 169-183. This alternative method is particularly applicable when a polymeric material is used which is soluble in water.

According to this method, the ceramic material is precipitated from a solution that also contains the water soluble polymeric material. The precipitation may suitable be performed by addition of an acidic and a basic material or of two salts. The addition of said materials initiates the formation of insoluble salts, which, while precipitating, lock the polymeric material in their crystal structure.

The composite material resulting after the coupling step is, in a second step, subjected to shock compaction. In certain case, however, it may be preferred to subject the composite material to a pre-compaction step, prior to the shock compaction. This pre-compaction may be carried out by centrifuging the material or by subjecting it to an ultrasonic treatment or by isostatic pressure techniques (Cold Isostatic Pressing, CIP). Preferably, the pre- compaction is carried out to such a degree that a material is obtained which has 80% or more of its theoretical density (TMD). The density may be determined by measuring mass and volume of a sample of the material. The theoretical maximal density is a weighted average of the fractions constituting the sample.

The shock compaction technique is described in, inter alia, US-A-5,631,016 and in WO-A-96/27566 and may be

performed by generating a shockwave in the material. A preferred manner of performing the shock compaction is set forth in WO-A-96/27566, which is therefore incorporated herein by reference. Suitable manners in which to generate a shock wave include detonation of an explosive and launching a projectile toward the material.

Preferably, the shock wave is generated by detonation of an explosive. In order to carry out this step, the composite material is preferably confined in a mold cavity, which is surrounded by an explosive material. Suitable explosives include nonideally detonating explosives having a low detonation velocity, typically below 6 km/s, and preferably between 2-4 km/s. It has been found that the use of this type of explosives avoids the occurrence of cracks in the compacted material due to rarefaction waves. Examples include, but are not limited to, ammonium nitrate based explosives, such as AMPA (which is a TNO melange), ANFO (which is a mixture of ammonium nitrate and diesel oil) and Triamite. The amount of explosives used in relation to the amount of material to be compacted is not critical and highly dependent on the scale on which the compaction is carried out. Based on his ordinary skill, the artisan will be able to select a suitable amount of explosive to make sure that a minimal thickness of a layer of explosives is obtained to ensure proper detonation. Generally, the ratio of explosives to material to be compacted may range from 40: 1 to 1: 1.

Possible manners of carrying out the shock compaction have been described by E. P. Carton et al., in"Shock-wave fabricated ceramic-metal composites", Symposium C: Ceramic, Glass and Composites, Euromat, 1997, and by the same author in his PhD thesis, TU Delft, 1998, which are both incorporated herein by reference.

A preferred manner for carrying out the shock compaction is the cylindrical configuration. According to this embodiment, a cylindrical metal container (for instance aluminum with an inner diameter of 30 mm, a wall thickness of

2.3 mm and a length of 120 mm) is filled with the powder specimen which has been precompacted as described above. The container may then be closed by metal plugs and placed at the center of a 50 mm longer polymer or cardboard tube with a diameter 2-4 times that of the metal container. Then, the tube is filled with a powder explosive and placed in a concrete bunker where the explosive compaction is performed.

Preferably, an electrically ignited detonator is placed on top of the configuration at the axis of symmetry. The detonator is used to initiate the detonation of the explosive. After, the compaction, the container is removed.

An alternative manner for carrying out the shock compaction is by manufacturing plates, analogous to the procedure described by Stuivinga et al., 9th CIMTEC, World Ceramics Congress & Forum on New Materials, 14-19 June, 1998, Florence Italy. In accordance with this manner, a layer of the material to be compacted may be brought into a metallic profile, which has the form of a flat plate. The profile may be surrounded by explosives and shock compaction can further be carried out as described above.

The product of the above described process has extremely favorable properties, which for a large extent may be controlled by the parameters discussed above. Preferably the organoceramic has a density of at least 90%, more preferably at least 95% of its theoretical maximal density.

Further, the organoceramic preferably has mechanical properties, such as an elasticity modulus, closely resembling those of bone or dental tissue.

The organoceramic of the present invention may, depending on its chemical composition, suitably be used for the production of medical or dental implants. When the ceramic powder is hydroxyapatite and the polymer is collagen, it is possible to prepare an organoceramic, which chemically and stoichiometrically has the same composition as natural bone tissue. In case silica is used as the ceramic powder, the organoceramic may be useful in restorative dental

operations, or as crown or inlay material having a color similar to the color of natural teeth. Further, the organoceramic may be of use in electro-optical applications, where specific optical properties in combination with a high stiffness and strength, particularly a high impact resistance are desired.

The invention will now be elucidated by the following, non-restrictive examples.

Example 1 In a suitable reaction vessel, 50 g of finely powdered and thoroughly dried hydroxyapatite (surface area: 66 g/m2) is dispersed in 500 ml thoroughly dried dimethylformamide (DMF) by magnetical stirring. To the mixture 10 ml isocyanatoethylmethacrylate (ICEM), 0.5 ml stannous octoate and 0.2 g hydroquinone are added. The vessel is placed in a waterbath and heated to 50°C and stirred at this temperature during 24 hrs while maintaining an atmosphere of dry N2 over the reaction mixture. After this period the solvent is removed by filtering and excess reagents further removed by successive washings with DMF and chloroform. Finally, the powder is dried. Typically the obtained hydroxyapatite contains 6% of organic matter coupled thereto as measured by thermogravimetric analysis. It can be shown by e. g. FTIR spectroscopy that the isocyanate groups have reacted with the hydroxyl groups on the surface of the hydroxyapatite powder particles so that the powder obtained in this example is provided with pendant methacrylate groups.

With exactly the same procedure but using hexamethylenediisocyanate, a powder is obtained having pendant isocyanate groups.

Example 2 In a suitable reaction vessel 10 g of finely powdered and thoroughly dried hydroxyapatite (surface area: 66 g/m2) is dispersed in 100 ml dry toluene and 3.1 ml of

methacryloxypropyl-trimethoxysilane (TMPS) and 40 mg hydroquinone are added. The mixture is stirred and heated to the boiling point of toluene (110°C) maintaining an atmosphere of dry N2 over the reaction mixture. After 24 hrs the powder is filtered off, washed several times with toluene and acetone, and dried. Typically the powder will contain 1- 5 wt % of organic material as measured by TGA. Where it has been shown that the methoxygroups of the silane used in this example condense with surface hydroxyls of inorganic powders and thus bond the silane to the surface, it is clear that the obtained hydroxyapatite powder is coupled with silane having pendant methacrylate groups.

Example 3 50 grams of hydroxyapatite powder coupled with pendant methacrylate groups as obtained in example 2 is added to a 150 grams room temperature curing methylmethacrylate/ poly-methylmethacrylate (MMA/PMMA) resin. After curing the composite blocks are dissolved in acetone. The undissolved powder is separated by centrifuging and repeatedly washed by acetone to remove all unbound PMMA and finally dried.

Typically the powder contains 20-30 weight percent of organic matter as measured by TGA and, judging from FTIR spectra of the powder, identified as PMMA.

Example 4 50 grams of hydroxyapatite powder coupled to pendant isocyanate groups as obtained in example 1 is added to a 500 ml of a 10 % percent chloroform solution of a poly (ether- ester) called PolyActive (which consists of blocks of polyethyleneglycol (PEG) and blocks of polybutylene- terephtalate (PBT)).

The mixture is stirred during 137 hrs at room temperature after which time the powder is separated by centrifuging and decanting. By washing the powder repeatedly with chloroform the excess of unbound polymer is removed.

After drying a powder is obtained containing 7-10 percent by weight of organic powder as measured by TGA and which by FTIR spectroscopy is identified as mainly PolyActive.

Example 5 In this example, PMMA-hydroxyapatite powder having a specific mass of 2.205 g/cm3 an average particle size smaller than 1 pm and which was prepared as described in Example 3 was shock compacted in a cylindrical configuration.

The powder was put in an aluminum tube having an inner diameter of 9. 5 mm and a thickness of 2.25 mm. The tube was closed at both ends with metal plugs. Filling was done in batches of about 5 mm height by mechanically tapping (50 times at 2 Hz) and uniaxially pressing at 310 MPa. In this manner, a starting density of 85% of the TMD was obtained.

The aluminum tube was placed in the middle of a larger PVC tube. The 16 mm space between these tubes was filled with an explosive, AMPA 2, a mixture of ammonium nitrate, TNT and aluminum, having a detonation velocity of 3.6 km/s. Above the tube, a 5 cm thick layer of the explosive was present. By detonation of the explosive with a detonator, the powder was densified to 94% of its TMD. Slices of about 4 mm thick of the obtained material were shown to be transparent to visible light.

Example 6 In this example, a PMMA-hydroxyapatite powder which was prepared as described in Example 3 was shock compacted in a cylindrical configuration.

The powder was precompacted by uniaxially pressing at 36 MPa to obtain a bar having a length of 19 mm. This bar was placed in an aluminum tube having an internal diameter of 30 mm. The top and bottom ends of the tube were filled up with alumina powder. Shock compaction was carried out using AMPA 2, which was placed around the tube in a layer of 20 mm thick. Also, a layer of 5 cm AMPA 2 was placed on top of the

tube. By detonation of the explosive with a detonator, the powder was densified to 100% of its TMD. Slices of about 4 mm thick of the obtained material were shown to be transparent to visible light.

Of the obtained organoceramic and of the starting materials PMMA and hydroxyapatite, the density was determined using the Archmides-method in water. Further, the longitudinal and transversal sound velocities in the materials were determined by sending sound waves originating from a tranducer through the material in either longitudinal or transversal direction. After propagation through the material, reflection of the sound waves took place, after which they propagated through the material for a second time.

The sound waves thus reflected were registered by the transducer and visualized by an oscilloscope. Using the time period between sending the sound waves and registration of the reflected sound waves, in combination with the thickness of the sample used, the sound velocities in the material were determined. From wherein C is the sound velocity, p is the density and M is the elasticity modulus, it follows that the Young's modulus (E) and the shear modulus (G) may be independently determined from the longitudinal (CL) and transversal (CT) sound velocities in the following manner.

Since, 4G PCL2 = K +- (2),<BR> <BR> <BR> <BR> <BR> <BR> PCT2 = G (3), and 9KG E = (4), 3K + G wherein K is the bulk modulus of elasticity, it can be concluded that G = PCT (5), and

4G<BR> <BR> <BR> K = PCL-3 (6), wherein E can be determined from formula (4).

Table I shows the density and Young's modulus (E) of the shock compacted material compared to those of the PMMA and hydroxyapatite starting materials. It is particularly interesting to note that the elasticity modulus of the prepared organoceramic is almost identical with the known elasticity modulus of cortical bone tissue.

Table I: density and Young's modulus of organoceramic, PMMA and hydroxyapatite Material density Young's modulus (E) (g/cm3) (GPa) PMMA 1. 187 5. 4 Hydroxyapatite 3.001 110.6 Shock compacted 2.010 19.5 organoceramic <BR> <BR> <BR> <BR> <BR> <BR> Example 7<BR> A powder of PBMA coupled to hydroxyapatite (prepared analogous to the procedure of Example 3, except that butyl- methacrylate was used instead of methylmethacrylate) was precompacted analogous to the procedure described in Example 5 to a density of 89% of its TMD. The powder was placed in a stainless steel tube having an internal diameter of 9.5 mm and a wall thickness of 2.25 mm. Around the tube, a 14 mm thick layer of AMPA 2 was placed, which was subsequently detonated using a detonator. The organoceramic thus obtained had a density of 100% of its TMD. A scanning electron- microscopy photograph of the obtained material is shown in Figure 1.