WO2011068451A2

WO2011068451A2 - Ceramic component for bone regeneration

Info

Publication number: WO2011068451A2
Application number: PCT/SE2010/000279
Authority: WO
Inventors: Erik Adolfsson; Lars-Åke JOHANSSON
Original assignee: Erik Adolfsson; Johansson Lars-Aake
Priority date: 2009-12-01
Filing date: 2010-11-29
Publication date: 2011-06-09
Also published as: WO2011068451A3

Abstract

The present invention relates to a unique ceramic bone regeneration system, where the shape of the part or parts assembled to a bone regeneration device, which facilitates blood clot formation and controlled bone regeneration. The ceramic bone regeneration device can have internal cavities or form a cavity in connection with the adjacent bone in order to allow and stabilize a blood clot formation. From this blood clot the formation of new bone is promoted and this can be used as either a pre-treatment, for example for dental implantation in order to enhance bone volume, or as a strategy for reshaping the bone structure.

Description

CERAMIC COMPONENT FOR BONE REGENERATION

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a unique ceramic bone regeneration system of a certain shape. When the ceramic bone regeneration device is used, the shape of the device contributes to the formation of a cavity which can be either within the device itself or when the device is attached to a bone surface. In this cavity the formation of a blood clot, with a shape that is controlled by the device, and subsequent guided bone regeneration will increase the bone volume and for example facilitate installation of dental implants when an insufficient bone volume is present. The ceramic component can be used either in an augmentation procedure before dental implantation in order to enhance bone volume or in order to increase bone volume for other reasons.

Description of the Related Art

Tooth loss affects many people. Between 6% and 10% of the populations of North America, Japan and Europe have no teeth in either their upper or lower jaw. More than 240 million people in these parts of the world are missing one or more teeth. Some five million (2%) have dental implants, while 50 million have traditional bridges or removable dentures. The majority of more than 180 million people receive no treatment at all and they simply live with one or more gaps in their mouth.

According to the World Health Organization, 29% of the population in the U.S., 50% in Australia and 20% in Japan above the age of 65 have no natural teeth. In Europe, the percentage of people over 65 years old who are missing all their teeth, varies considerably. Sweden (13%) and Switzerland (12%) have a lower percentage of those who are missing teeth, while Germany (25%) is in the middle of the range, and the UK (57%) and the

Netherlands (65%). The demand for functional teeth at all stages of life has also grown in recent years. One option for tooth replacement is a traditional bridge. A traditional bridge requires the dentist to grind down adjacent teeth so that there is a support to which the bridge can be fastened. However, supporting teeth can decay and/or loosen over time requiring the need for new bridges. When all the teeth in either the upper and lower jaw are gone, dentures represent another treatment option. But because traditional dentures do not help stimulate and maintain the jaw bone, the bone continues to resorb over time, leading to loose and ill-fitting dentures that often cause irritation to the gums and slurred speech. As a result, a common outcome is deterioration in the quality of life due to embarrassment and discomfort.

The field of dental implants is evolving rapidly. New technologies and improvements in biocompatible materials have enabled the development of systems that ensure faster healing, more reliable results and an esthetic outcome. Implants can now be used to replace missing teeth in all situations from a single tooth to the entire set of teeth in both jaws. The vast majority of dental implants can be simply defined as a titanium screw that is placed within the jaw bone allowing a crown, bridge or denture to be attached to it.

Often, the underlying bone volume is insufficient and has to be augmented to make an implant installation possible. This can be achieved by using a patient's own bone (autogenous graft), bone from the animal kingdom (xenograft), or synthetic (alloplast) material or combinations of these grafts. There are several reasons why bone substitutes will continue to replace autogenous bone grafts. Many want to avoid autogenous graft due to increased surgical time and costs, graft resorption and donor site morbidity such as pain, risk of hematoma formation, hernia formation and infection. When synthetic bone substitutes are used, they often consist of particles with a size of a few hundred microns. The amount of such bone substitute material clinically used (~lg) will then consist of several hundred individual particles, which cannot form a mechanically stable structure on their own. Such particulated materials therefore require some type of surrounding boundaries or barrier membrane in order to maintain the shape of the volume filled with particles. There would otherwise be a large risk that the particulated materials used would move around making it difficult to preserve the initial shape of the augmented bone volume. To create boundaries for the particles and secure the mechanical stability, a stiff titanium mesh or a Gortex membrane can be used. The disadvantage with this technique where a Gortex membrane or a titanium mesh are used is that these have to be removed after healing. The removal of the titanium mesh can be hazardous due to growths of soft tissue into the mesh. Ceramic scaffolds have also been used but the growth of bone into these scaffolds and the amount of integration of scaffolds to bone and implants are uncertain and can increase the risk for infection, and disintegration of the implant which finally can jeopardize the prognosis of the implant treatment.

SUBSTITUTE SHFFT W " P ⁿ*) There are several examples of different solutions to enhance bone formation and to improve bone volume, either by modifications and improvements of already used materials such as granules and scaffolds or by inventions related to fabrication methods of materials such as scaffolds that can be used for bone regeneration. But none of these inventions use a ceramic part with the aim to facilitate the formation of a blood clot and to stabilize the shape of the blood clot from which bone formation can proceed. This is the natural way for bone healing and the ceramic bone regeneration device invented is designed to assist this natural way to generate bone. When the shape of the blood clot is stabilized, the control of the shape of the newly formed bone can thus also be improved since this will correspond to the combined volume of the cavity and the ceramic part.

An example of a prior invention is US Patent 20080319547 Al, "Porous Material for Use as Implant, Bone Replacement and in General as Material." This invention concerns a method to produce scaffolds of various shapes with a defined and interconnected porosity. This was obtained by using a mold filled with expandable particles, which was further infiltrated with a ceramic suspension. When the pressure in the mold was reduced, the particles began to expand and came in contact with each other. Control of the initial particle size and amount of particles and the change in pressure allowed the pore size and the interconnectivity of the pores to be controlled by the shaping process that was patented.

Another example of a prior invention where the aim was to enhance the bone formation is WO2008104762 A2, "Bone -replacement materials, methods and devices." This invention concerns particles or granules to which a blood coagulating substance is added. These particles are small and not individually designed to create a larger homogeneous blood clot volume as the invention described herein. The structure of the blood clot obtained by the invention WO2008104762 A2 would form a fine network, which consists of the volume in between the particles. As the bone formation proceeds through this blood clot, it is continuously interrupted by the presence of a large number of particles, which is not the case in the herein presented invention where the ceramic is a bone regeneration device.

US Patent 5976140, "Foil for bone growth promotion" describes an invention related to the filed of the invention herein, but describes the use of a titanium membrane, rather than the ceramic structure of the invention herein. It is also a spherical form, rather than the invention herein, which can vary in shape, according to necessity. US Patent 20010012607 Al, "Guided tissue regeneration plate for use in a process for growing jaw bone in anticipation of performing dental implants," describes a titanium plate, rather than a designed ceramic structure of the invention herein.

US Patent 20090004627 Al, "Dental Material And Composite Dental Material Formed By Using Hydroxy Apatite" is also in a related field to the invention herein. However, US Patent 20090004627 Al is aimed at dental bone regeneration, based on hydroxyapatite particles and a bioabsorbable film membrane, which is a flexible sheet used to cover a bone cavity filled with bone graft material. This is unlike the invention herein, in terms of structure and shape where the ceramic bone regeneration device have the structural strength to maintain the shape of the cavity in which a blood clot is formed instead of using a supporting bone graft material.

It is an object of the invention to provide an improved and simplified ceramic system as a pre- treatment for example for dental implants in order to enhance bone volume and/or reshape the bone structure. Other objects and advantages will be more fully apparent from the following disclosure.

SUMMARY OF THE INVENTION

The present invention relates to a unique system where a ceramic bone regeneration device is used for bone regeneration. The design of the ceramic bone regeneration device is such that it creates a cavity to facilitate blood clot formation and controlled bone regeneration. The bone regeneration device can be used either as a pre-treatment for example before dental implantation in order to enhance bone volume, or as a strategy for reshaping the bone structure or in order to increase bone volume for other reasons. It can also be loaded with substances to enhance bone regeneration or blood coagulation in order to enhance the speed of bone reformation.

What is unique regarding the invention herein is that the component for building up bone achieves an osteoconductive mold for blood clot formation from where undifferentiated mesenchymal (multipotent) cells are recruited and stimulated to differentiate into osteoblasts and bone production. What is also advantageous regarding the invention herein is that the component does not need to be removed prior to installation of an implant. Initial findings in patients have revealed promising results both in clinical, radiographic and histological aspects.

The bone regeneration device according to the invention comprises a three-dimensional frame structure formed from a biocompatible ceramic material where the frame structure have a defined shape with a dimension of at least 1 ,5 mm configured to create a macroscopic cavity. The dimension of the frame structure is measured as the diameter of the smallest circular tube in which the bone regeneration device will fit. The macroscopic cavity can be found within the frame structure that is created by the frame structure and will be completely or partially delimited by an inner or outer surface of the frame structure or by a combination of inner and outer surfaces. An inner surface of the frame structure may be the walls of the macroscopic cavity while an outer surface is a surface that defines the outer shape of the frame structure.

The macroscopic cavity in the frame structure can be formed in a controlled way by the shaping process with the use of moulds or pressing tools as well as by machining. Since the macroscopic cavity is configured to collect blood, the volume of the macroscopic cavity penetrating the bone regeneration device is preferably designed to be as large as possible within the frame structure without reducing the strength of the bone regeneration device. An additional type of macroscopic cavity can be found at the outer surface of the frame structure when the bone regeneration device is inserted between a hard surface and a flexible membrane, where the hard surface was enclosed by the flexible membrane before the frame structure was inserted.

Although the cavity formed by the bone regeneration device may be found only on the outside of the bone regeneration device or on the inside of the bone regeneration device, the total cavity created by the bone regeneration device will usually include the cavity found internally in the bone regeneration device as well as the cavity formed at the outer surface of the bone regeneration device. By way of example, the frame structure may have a "doughnut-shape" with a generally solid or porous structure and a through-going macroscopic hole, wherein a large proportion of the cavity space will be formed in the through-going hole. Moreover, the frame structure may have an irregular outer surface with one or more cavities where additional voids may be formed between the irregular outer surface and a bone surface or a membrane surface. Another example where a macroscopic cavity can be found on the outside of the frame structure is for a cupola or a shell of a potion of a sphere, spheroid or ellipsoid. The macroscopic cavity can then be found in between the outer surface of the frame structure and an enclosing surface having the minimal surface area for the frame structure to be enclosed.

The bone regeneration device can also be shaped as a sphere, a spheroid, an ellipsoid, a toroid, a dome, a shell, a cage or a cylinder. The shape can further be as a portion of these shapes such as a half of an ellipsoid. When the volume corresponding to the cavity is subtracted from the frame structure, it may cause the geometrical shape of the frame structure to be somewhat distorted from shapes given. Independent of the shape of the frame structure, the internal macroscopic void is configured to have a fluid communication to the outer surface through one or more openings, pores or channels in said three-dimensional frame structure.

The bone regeneration device can further consist of an assembly of up to 100 parts of the same or different shape, preferably up to 25 parts are used. These parts can be joined with a metal or polymer thread, which also can be used to attach the assembled bone regeneration device to the bone tissue. With such assembled bone regeneration device an additional macroscopic cavity volume can be formed in between the individual parts. The maximum dimension of said three-dimensional frame structure representing a part is in the range of from 1.5 to 60 mm and preferably in the range of from 5 to 30 mm.

The composition of the material used in the bone regeneration device can consist of various calcium phosphates, apatite, hydroxyapatite, tricalcium phosphate, calcium carbonate, calcium sulphate, zirconia or a mixture of two or more of these compounds. In an assembled bone generation device, frame structures with different compositions and microstructures can be combined to improve the performance. The microstructure includes the size and distribution of particles and pores in the material and is determined by the powder, additives, process and sintering temperature used. The material can thus contain both micro and macro porosity, configured to control the dissolution rate of the material, machinability of the material as well as controlled release of substances introduced in the pores. These substances can comprise one or more additives, such as substances for promoting machinability, bone formation promoting agents, blood coagulation promoting agents or binders. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows an illustration of a ceramic bone regeneration device with a spherical shape Figure 2 shows an illustration of a ceramic bone regeneration device with a shape as a shell. There is a hole through the shell that can be used to fixate the bone regeneration device to the bone with a screw.

Figure 3 shows an example of a part that can be assembled with other parts to form space making device.

Figure 4 is an illustration, showing a ceramic space making devise, installed to increase the width of the bone structure. The bone regeneration device was attached to the bone with a screw.

Figure 5 is an illustration, showing a ceramic bone regeneration device used to increase the height of the bone structure, which is a common situation when the bone volume is insufficient for implant installation due to pneumatization of sinus cavity and resorption of alveolar ridge.

Figure 6 is an illustration, showing the result when a ceramic space making devise was installed to increase the width of the bone structure. When the blood clot was transformed to bone, the fixating screw was removed and an implant was installed through the remains of the bone regeneration device, which was reduced in size due to dissolution.

Figure 7 shows an example where the bone level was not sufficient for a stable installation of an implant. The bone level was increased by the use of a ceramic bone regeneration device. After healing, an implant was inserted through the bone regeneration device, the newly formed bone and the original bone.

Figure 8 showing an illustration of a ceramic bone regeneration device that was made from several assembled parts used to cover a cranial bone defect. The different parts were joined with a thread and secured at the edge of the bone defect. DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

THEREOF

The present invention relates to a unique ceramic bone regeneration system where the micro and macro structural shape of the bone regeneration device are designed to enhance bone regeneration.

In summary, the invention herein is a ceramic bone regeneration device, preferably with openings or channels or designed as a cylinder, a cage, a dome, a sphere, spheroid, ellipsoid, toroid or as a shell of a portion of these shapes, preferably used to form a cavity and to allow for blood to be collected and to coagulate, acting as a bone regeneration device for guided bone regeneration. The cavity can be present within the bone regeneration device, around the bone regeneration device as well as in between the bone regeneration device and the surrounding hard tissue, periosteum or sinus membrane. The ceramic device can be used to enhance the height and/or the width of the bone in order to make installation of dental implants possible or to modify the bone volume for esthetical or other reasons. It can consist of calcium or calcium phosphates such as apatite, hydroxyapatite, tricalcium phosphate, calcium carbonate, calcium sulfate, zirconia or a mixture of these compounds. The ceramic bone regeneration device can be formed by powder compaction, direct consolidation methods, injection moulding, machining or combinations of such methods. The material can be exposed to various heat treatment or sintering procedures to increase the material strength, to remove organic additives or for the raw materials to react and form the desired phase composition. The ceramic bone regeneration device may further contain organic biocompatible materials such as polyethylene, polylactic acid or

polyglycolytic acid in order for the bone regeneration device to obtain a sufficient strength without a sintering procedure. The ceramic bone regeneration device may further be shaped by a hydratisation process with calcium or calcium phosphate based compounds.

The geometrical shape of the ceramic bone regeneration device can be shaped as a sphere, a spheroid, an ellipsoid, a toroid, a dome, a shell, a cage, a cylinder. The shape can further be as a portion of these shapes such as a half of a sphere. When material is removed from these geometrical shapes in order to increase the volume of the macroscopic cavity formed, the shape of the three dimensional frame structures can be distorted. A hemisphere can be transformed to a shell and a sphere with an internal cavity formed by the removal of material

S'_..'BS^"HTUTE SHEET (RULE: 26) along three perpendicular axes through the sphere can result in a loss of a large part of the convex spherical surface, due to the material removed.

The dimension of the bone regeneration device can be in the range of 1.5 to 60 mm and preferably between 5 and 30 mm and can be standardized as well as individualized to a specific patient. The dimension is measured as the diameter of the smallest circular tube in which the bone regeneration device will fit. One or several parts can be assembled in order to form a bone regeneration device where the cavity for blood clot formation also can be found in between the different parts. Additional additives can be used to promote coagulation or bone formation. Additives can be introduced in the porosity, which can be designed with respect to size, volume and interconnectivity in order to control the release rate of the substances.

Referring now to the figures 1-8, the ceramic bone regeneration device of the invention (1) has an outer surface (2) at which a cavity can be formed in between a part of the device and the bone, the periostum, the sinus membrane or other parts of the device and an inner surface (3) that surrounds the cavity in the part or between the part and the bone. The cavities formed facilitate the formation of a stable blood clot, from which controlled bone regeneration will occur. The ceramic bone regeneration device can be used either as a pre-treatment in order to increase the bone volume before installation of various implants such as dental implants or as a strategy for reshaping the bone structure to increase bone volume for other reasons.

In figures 1-3, different shapes of the bone regeneration devices are illustrated. In figure 1 is a spherical device shown with internal cavities formed as channels through the device. The surface surrounding the cavities represents the inner surface (3) and the surface of the sphere represents the outer surface (2). Figure 2 shows a bone regeneration device shaped as a cupola or a shell of a half sphere. The concave surface is thus the inner surface of the part since it was formed by removal of material from the half sphere. In figure 3, the part has a design that can be used to form an assembled bone regeneration device. The part has an internal cavity (14) for blood clot formation as well as smaller channels through the part (13) that can be used to connect different parts with threads as well as for blood clot formation.

When these types of three dimensional frame structures are installed in a bone defect, a cavity is created and maintained by the ceramic bone regeneration device, blood from the wound

SUBSTITUTE SHEET (RULE 36) area can fill the cavity (6) and be reorganized to bone involving the natural biological principals for bone healing. A cavity is also formed when these devices are installed between the bone and a flexible membrane such as the sinus membrane or the periosteum covering the bone surfaces. These ceramic bone regeneration devices consisting of one or several parts of the same or different materials can then be used to lift the flexible membrane to create a desired shape formed by the present bone structure, the bone regeneration device and the cavity.

Figure 4 shows an example where the device (1) was inserted in between the present bone (4) and a flexible membrane (5), to increase the width of the bone structure. The shape of the bone structure after healing will be close to the shape of the flexible membrane (5) given by the bone regeneration device. The cavity (6) formed within and at the surface of the bone regeneration device was filled with blood that formed a stable blood clot. To reduce the risk for the devise to move, it can be fixated to the bone structure with a screw (7). In figure 5, a device (1) was used to increase the height of the present bone structure (4). The inserted device has an internal cavity and creates an additional cavity at the surface of the part below the flexible membrane (5). The entire cavity can then be filed with blood and form a stable clot (6) that will be transformed to new bone. In figure 6, the width of the bone structure was increased as a pretreatment to facilitate implant installation. The border of the former bone level (10) was expanded to the present bone level (9), following the outer surface of the former cavity formed by the flexible membrane in figure 4. The installed part has also been partly dissolved (1), the fixation screw was removed and an implant (8) was installed through the bone and the remains of the device. In figure 7 has an implant (8) been installed through the bone and the bone regeneration device, previously installed in figure 5. Bone was found both within and around the installed device and the border of the previous bone level (10) was expanded to a new level (9), corresponding to the border of the cavity previously formed with the bone regeneration device. In figure 8 is an assembled structure of several parts (1) inserted in a bone defect (1 1). The different parts in the assembly are connected with a thread (12) that can also be used to attach the bone regeneration device to the surrounding bone structure (4). The cavity for blood to be collected (6) was found inside the parts, between the parts and between the parts and the bone.

The external shape of the periosteum, sinus membrane or the ceramic bone regeneration device will then correspond to the future shape of the bone structure, which can be well controlled in terms of both size and shape through the use of this invention. The ceramic bone regeneration device, which lift the membrane for guided bone regeneration can be used to enhance the bone volume as a pre-treatment before dental implants are installed or in order to increase or restore the bone volume for other reasons such as esthetical, trauma or diseases.

The ceramic bone regeneration device is preferably made of calcium or calcium phosphate based material, such as apatite, hydroxyapatite, tricalcium phosphate, calcium carbonate, calcium sulphate, or any combinations of these. The ceramic raw materials can be used to prepare granules with binders such as polyvinyl alcohol, polyethylene glycol, cellulose, waxes, latex or a mixture of these to facilitate shaping by compaction. These powder compacts often called green bodies can be produced by uniaxial pressing and/or cold isostatic pressing (CIP). The produced green compacts used with or without a presintering procedure can be used as blanks for machining of the desired shape. The use of colloidal methods is an alternative shaping method where the ceramic raw materials, liquid and dispersant are used to prepare a ceramic suspension. An advantage with the colloidal methods is an increased freedom to design the micro porosity in the material used for the bone regeneration device. By the use of gelforming agents such as agar, proteins, monomers for gel-casting like

methacrylamide (MAM), methylene bisacrylamide (MBAM) or starch makes it possible to transform the suspension from a fluid to a solid green body through a consolidation process. This allows the suspension to be used to cast bone regeneration devices with desired shapes by using a mold. Additional features like internal cavities or pore channels that can be difficult to create by the mold can instead be obtained by organic materials that are removed after consolidation of the cast bone regeneration device by melting, dissolution or

decomposition. It would further be possible to produce the designed bone regeneration devices by a combination of casting and machining processes as known in the art. The bone regeneration device are then sintered in order to increase the strength and to facilitate machining or to maintain the shape of the cavity for the blood clot formation while exposed to the surrounding mechanical forces; however some of the materials do not need to be sintered such as calcium sulfate containing materials or when addition of polymers like polylactic acid are used. The fabrication procedures further allow additional organic and/or inorganic additives such as starch particles, graphite, polymer beads, wax structures and latex emulsions which can be used to produce different designed cavities, channels or porosities with one or several pore size distributions in the bone regeneration device. These additional pores do not necessarily have interconnections with a certain size as normally preferred in scaffolds. The porosity and the microstructure in the frame structure of the bone regeneration device are used to control properties such as dissolution behavior which can be varied from a rather stable material to a material that can be dissolved within a certain time frame, strength, slow release of active substances and machinability. The surface texture is also modified by the addition of the microporosity which also influences the cell attachment to the surface. All these pores can further be used for incorporation of substances that can promote coagulation and blood clot formation in the cavity or enhance the bone formation such as calcium chloride or bone morphogenetic proteins (BMP). The release rate of these substances can be controlled by the pore morphology. The micro structure of the ceramic material is further designed in such a way that drilling can be performed through both bone and ceramic bone regeneration device material to facilitate implant installation with the same tools normally used when dental implants are installed. One of the benefits of such a material design is that no further surgery is required in order to remove any parts of the bone regeneration device. The shape of the ceramic bone regeneration device is designed to create a suitable cavity for blood clot formation and to stabilize the shape of the blood clot during bone formation. This can be done through either standardized shapes or individualized shapes. In certain situations where an individualized shape is desired, computer tomography data or other patient specific data can be used to determine a suitable shape of the ceramic bone regeneration device.

Independently of the situation the shape of the ceramic bone regeneration device should create a cavity within itself or in combination with the surrounding bone in which the blood clot can be formed. In addition to this, the bone regeneration device should also have the structural strength to maintain the shape of the blood clot. The shape of the ceramic bone regeneration device can be designed to form a cavity when attached to the surrounding tissue, within the part, at the surface of the part or between different parts assembled to a bone regeneration device or another shape that in conjunction with the hard tissue can form a cavity where blood is allowed to coagulate. The shape of the ceramic bone regeneration device can also be a shell, where a cavity between the shell and the bone tissue is formed. This cavity is in fluid communication with the outer surface of the bone regeneration device to allow for blood to fill the cavity.

Ceramic bone regeneration device with a spherical shape have successfully been used to increase bone volume in the lateral segments of the upper yaw where bone volume often is insufficient for implant installation due to atrophy. Ceramic bone regeneration device with a cupola shape have successfully been used to increase the width of the alveolar ridges to make implant installation possible or to improve esthetics before conventional tooth supported prosthetic treatment.

The ceramic frame structure of the bone regeneration device may consist of 1 or up to 100 parts or sub frame structures that can be assembled, preferably is 1 or up to 25 parts assembled into a coherent structure. The maximum dimension of the parts or sub frame structures can be in the range from 1.5 to 60 mm, preferably in the range from 5 to 30 mm. The overall design of the ceramic bone regeneration device allow for the blood to have access to the macroscopic void formed through openings, channels, voids or adjacent cavities. The dimension of these openings can be from 0.3 to 40 mm, preferably from 1 to 20 mm. The dimension is measured as the diameter of a circle that can be placed in the opening.

The combination of a suitable selection of materials and fabrication process parameters allow many important characteristics to be designed such as the dissolution rate of the bone regeneration device, the tissue response, the release rate of substances, and the blood clot formation as well as the machinability of the material during implant installation.

Examples

Example 1

For the fabrication of the ceramic bone regeneration device, a fine grained raw powder of hydroxyapatite was further processed with an addition of water and dispersant (poly acrylic acid) to prepare a ceramic suspension by ball milling. Starch particles were added to the suspension which was allowed to be stirred for one hour in order to obtain a homogeneous suspension before the suspension was poured into a mold with spherical cavities which had a diameter of 12 mm. The addition of starch made it possible to transform the suspension from a fluid state to a green body by an increase of the temperature of the mold to around 70°C for one hour. The cast spheres could then be removed from the mold, dried and presintered to burn out the organic additives and increase the strength of the material before channels with a diameter of 5 mm along three different and perpendicular directions were drilled through the centre of the sphere. The ceramic bone regeneration device was finally sintered for 2 hours to increase the strength of the part. The ceramic bone regeneration device consisted then of a hydroxyapatite sphere with a large internal volume for blood to coagulate and the

microstructure of the material contained a large volume fraction of a submicron sized porosity as well as pores of around 10-20 microns from the starch particles. Example 2

A fine grained raw material of hydroxyapatite was further processed with an addition of water and dispersant (poly acrylic acid) to prepare a ceramic suspension by ball milling with a high solids loading. The green bodies were produced by gel casting where an addition of an organic monomer based binder was made to the suspension. A small temperature change could then be used to transform the fluid suspension in the mold to a solid green body

(consolidation). After the consolidation, the green bodies were removed from the mold, dried and presintered. A model of a desired ceramic bone regeneration device was designed with a CAD program. The model was then used for preparation of the machining process where a CNC machine with a hard metal cutting tool was used to machine the designed ceramic bone regeneration device from the cast green bodies. The bone regeneration device produced consisted of a thin ceramic shell of hydroxyapatite that can be attached to the bone by small fixation screws. The internal volume within the shell can then be filled with blood that forms a clot. The parts were finally sintered at a temperature above 600°C for 2 hours, to ensure that all organic additives were burnt away and to improve the strength of the ceramic structure. The pore volume in the material consisted of a fine microporosity which was loaded with additional substances such as calcium chloride and bone morphogenic in order to promote the initial blood coagulation process as well as the following bone formation. Example 3

Hydroxyapatite and tricalcium phosphate powders were ball milled in order to obtain a homogenous ceramic suspension. Binder for granulation such as polyethylene glycol, polyvinyl alcohol or latex was added to the suspension as well as organic particles with sizes corresponding to the additional porosities desired. The homogenous suspension was freeze granulated and freeze dried. The granules was used to produce green compacts by uniaxial pressing at 25 MPa to a given shape followed by cold isostatic pressing (CIP) at 300 MPa and presintering at 700°C. The geometrical shape of the bone structure of a patient was received from computer tomography data and a model of the desired future shape was drawn with a CAD program. From the difference between the present and the desired future shape of the bone structure, a model of an individualized bone regeneration device was produced with a CAD tool. The model of the bone regeneration device was transferred to CAM program to prepare a suitable machining procedure of the component. The individually designed shape of the bone regeneration device was obtained by CNC machining with hard metal cutting tools before sintering at a temperature of 900°C for 2 hours.

Example 4

A bone regeneration device with a shell like structure was produced by a CNC machine. The bone regeneration device was used as a master model from which a silicon rubber mould was produced. A calcium sulphate powder was mixed with tricalcium phosphate and

hydroxyapatite before water was added. The prepared suspension of water and powder was injected into the cavity of the silicon rubber mold in order to prepare ceramic bone regeneration devices. When the hydratisation process transformed the suspension from a fluid state to a solid material, the cast bone regeneration devices were removed from the mould to dry.

Example 5

The posterior region of the edentulous maxilla often presents insufficient bone quantity and quality for prosthetic rehabilitation with endosseous implants. The inadequate bone volume is a result of ongoing maxillary sinus pneumatization and remodelling of the alveolar crest. The hollow, spherical and perforated ceramic bone regeneration device was evaluated in three patients where vertical bone height was insufficient for implant installation verified by radiographs. The approach to the posterior maxilla was made using a crestal incision along the posterior alveolar process. The alveolar crest and lateral aspect of the maxilla were subsequently exposed by raising a buccal mucoperiosteal flap and a bony window was established on the lateral aspect of the maxillary sinus. The sinus membrane was carefully elevated. After that the ceramic bone regeneration device was inserted under the sinus membrane. The bony window was either replaced or particulated bone was harvested by a bone scraper to cover the opening in the lateral sinus wall. Wound closure was made by absorbable sutures. After 6 months of healing a trephine was used to get a specimen of bone and ceramic bone regeneration device at the site where an implant was inserted. This specimen was histologically processed and examined. After 8 weeks a crown was fabricated. Radiographs were taken before surgery, during healing and at one year follow up. In all three patients there was bone formation inside and around the ceramic component. This was also verified histologically and by radiographs in all patients. No complications were noted during one year follow up after crown was inserted.

Example 6

Six mongrel dogs were used to investigate the bone regenerative capacity of a ceramic bone regeneration device with a design as a shell. The bone regeneration devices were attached to the lateral side of the mandible. Dogs were sacrificed after 120 days and blocks including shells and surrounding bone and mucosa are processed for histological investigation. All shells were properly covered with mucosa and there were no visible signs of inflammation.

While the invention has been described with reference to specific embodiments, it will be appreciated that numerous variations, modifications, and embodiments are possible, and accordingly, all such variations, modifications, and embodiments are to be regarded as being within the spirit and scope of the invention.

Example 7

Small granules of hydroxyapatite were mixed with polylactic acid in a screw extruder to obtain a homogenous mixture for low pressure injection moulding. From a model drawn with a CAD tool of a bone regeneration device with a shell like structure, an injection moulding tool was produced by a CNC machine. The prepared ceramic polymer mixture was heated and injected into the cavity of the mould. When the mould was cooled and the mixture was solidified, the ceramic bone regeneration device was removed.

Example 8

A mixture of hydroxyapatite, tricalcium phosphate, binder and polymer particles with a size of 40 microns was used to prepare granules for compaction. The mixture was cold

isostatically pressed to prepare green bodies for machining. From the green bodies, hexagonal parts with a cavity in the middle and fine channels through the part were machined with hard metal tools. The parts were sintered and assembled to a frame structure like a mosaic pattern. The individual parts were joined with a thread, which was drawn through the fine channels of the parts to build up a larger frame structure. The number of parts or the size of the structure can be customized for a specific bone defect or standardized to certain dimensions. The assembled structure can be connected to the bone structure surrounding the bone defect either with the tread or by fixation screws through the hole that is present in each part. The cavity formed for blood clot formation can then be found within the part, between the parts or in between the bone and the frame structure.

Claims

1. A bone regeneration device, characterized in that said bone regeneration device

comprises a three-dimensional frame structure formed from a biocompatible ceramic material, said frame structure having a dimension of at least 1,5 mm with a macroscopic cavity within the frame structure and/or at an outer surface of the frame structure when inserted between a hard surface and a flexible membrane.

2. A bone regeneration device in accordance with claim 1 , wherein said bone

regeneration device has a shape selected among: a dome, a cage, a cylinder a sphere, a spheroid, an ellipsoid, a toroid or as a portion of these shapes and/or as a shell of these shapes.

3. A bone regeneration device in accordance with claim 1 or 2, wherein said cavity of said bone regeneration device is in fluid communication with the outer surface of said bone regeneration device.

4. A bone regeneration device in accordance with claim 3, wherein said inner cavity is in fluid communication with the outer surface of said bone regeneration device through one or more openings, voids, pores or channels in said three-dimensional frame structure.

5. A bone regeneration device in accordance with any one of the preceding claims, wherein said ceramic material comprises calcium phosphates, apatite, hydroxyapatite, tricalcium phosphate, calcium carbonate, calcium sulphate, zirconia or a mixture of two or more of these compounds.

6. A bone regeneration device in accordance with any one of the preceding claims, wherein said three-dimensional frame structure is a coherent assembly of up to 100 frame substructures, preferably of from 1 to 25 parts.

7. A bone regeneration device in accordance with claim 6, wherein at least two frame substructures have different compositions.

8. A bone regeneration device in accordance with claim 6, wherein at least two frame substructures have different shapes.

9. A bone regeneration device in accordance with any one of the preceding claims, wherein a maximum dimension of said three-dimensional frame structure is in the range of from 1.5 to 60 mm and preferably in the range of from 5 to 30 mm.

10. A bone regeneration device in accordance with any of the preceding claims wherein a maximum dimension of said internal macroscopic cavity of the three dimensional frame structure is in the range of from 0.3 to 40 mm, preferably of from 1 to 20 mm.

11. A bone regeneration device in accordance with any one of the preceding claims, wherein said three-dimensional frame structure is a porous structure.

12. A bone regeneration device in accordance with claim 11, wherein said porous three- dimensional frame structure has a micro porosity.

13. A bone regeneration device in accordance with claim 1 1, wherein said porous three- dimensional frame structure has a macro porosity.

14. A bone regeneration device in accordance with any one of the preceding claims, wherein said bone regeneration device comprises one or more additives, such as substances for promoting machinability, bone formation promoting agents, blood coagulation promoting agents or binders.

15. Method for producing a bone regeneration device in accordance with any one of the preceding claims, characterized in:

1 mixing a ceramic raw material with a binder;

2. forming the mixture into particles or granules,

3. forming a green body by compacting the particles or granules; and

4. forming a three-dimensional frame structure from the green body.

16. Method for producing a bone regeneration device in accordance with claim 15,

wherein the binder is selected from polyvinyl alcohol, polyethylene glycol, cellulose, waxes, latex or a mixture of two or more of these compounds.

17. Method for producing a bone regeneration device in accordance with any one of claims 1-13, characterized in:

1. mixing a ceramic raw material in an aqueous suspension with process additives for casting of the suspension

2. forming a three-dimensional body by consolidation of the mixture in a mould.

18. Method according to any one of claim 17, wherein said gelforming agent is selected from agar, proteins, monomers, starch and mixtures thereof.

19. Method for producing a bone regeneration device in accordance with any one of claims 1-13, characterized in:

1. mixing a ceramic raw material with a polymer or mixtures of polymers

2. forming a three-dimensional body by injection moulding of the mixture

20. Method according to claim 15 or 17, wherein the three-dimensional body is further shaped by machining

21. Method in accordance with any one of claims 1-13, wherein the three-dimensional body is formed by a hydratisation process.

22. Method in accordance with any one of claims 1-13, wherein the three-dimensional body is formed by a mouldable mixture of ceramic materials and a biocompatible polymer.

23. Method in accordance with any one of claims 14 - 22, wherein said ceramic material is a calcium phosphate based material, apatite, hydroxyapatite, tricalcium phosphate, calcium carbonate, calcium sulphate, zirconia or combinations thereof.

24. Method in accordance with any one of claim 14 - 22, wherein imaging technology, CAD/CAM processes, manual machining or combinations of these methods are used to shape said bone regeneration device.

25. Method for inducing bone formation at the surface of living bone tissue comprising inserting a bone regeneration device in accordance with any one of claims 1-13 between said bone tissue and an outer membrane, thereby enclosing said bone regeneration device between said bone tissue and said membrane.

26. Method according to claim 21 wherein said outer membrane is a periosteum or a sinus membrane.