Abstract:
Implants and methods for producing same are described, the implants featuring an adjustable porous shell, the inside being continuously interconnectingly adjustably porous and which can be sintered net shaped; these implants exhibit a high compression stability and show, when being combined with filler materials with or without active agents, different chemical, physical-mechanical, biomechanical or also pharmacological properties. The essential features of the manufacturing process are described in FIG. ( 1 ) and comprise expandable shaping elements, deformable elastic tools, the application of defined negative pressures, temperatures during defined application periods in combination with combined materials, which can be separated from each other physically, chemically or mechanically and removed.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    In surgery of the musculuskeletal system, there has always been a need to re-fill bone defects after fractures, the removal of tumors, a loss of bone substance after inflammations or in connection with bone cysts, with bone material or a substitute material similar to bone. For this purpose, partially also bovine substitute material was used [Tröster SD 1993: Die Hydroxylapatitkeramik Endobon®]. An alternative possibility for therapy for bone defects, in: Venbrocks R, Salis G of (publisher): Jahrbuch der Orthopädie, pp 231-246, Zülpich: Biermann] or material of coral reefs [Irwin R B, Bernhard M, Biddinger A (2001) Coralline hydroxyapatite as bone substitute in orthopaedic oncology. Am J Orthop 30:544-550], processed in laboratories (replaminiform processes) and inserted. Both materials have the drawback that they are biological and therewith directed structures, which can no longer be influenced and which can hardly be produced in a standardized manner. Both materials incorporate the anisotropy in structure and properties of a grown biological structure and are, in most cases, too stiff. A method for manufacturing such biological substitute materials is described in DE-A-3903695. Synthetic substitute materials can be manufactured from pure raw materials, however, lack a regular structure being similar to the bone; such a synthetic material is the foamed Ceros®; said materials lack a bony growing through, since the pores are mostly closed [Dingeldein E and H Wahlig (1992) Fluoreszenzmikroskopische Untersuchungen zur knöchernen Integration von Kalziumphosphatkeramiken. In: Merck Biomaterialien (publisher) Endobon® and DBCS®, Damstadt: Merck]. 
         [0002]    In the published documents DPA 2242867 and U.S. Pat. No. 3,899,556, a method comprising a pre-formed shaping framing is described, featuring a dense filling of balls, in which the shaping elements are poured with a solvent and shall be glued together in this way; however, with such a method, no regular, porous, interconnecting material can be produced in a standardized way; the conglutinations were too irregular and the solving process was not controllable enough. In EP 0553167 and EP 0204786, the problem was partially solved, in that deformable shaping elements were pressed on each other in contact by applying a pressure and were surrounded by a frame-forming mass in this state, which subsequently cured and was freed from the shaping elements chemically or thermally. The implants produced in this way showed beautiful and nearly regular interconnections in the half which faced the pressurization, however, in the other half, numerous closed pores were formed. Deformable and only partially elastic shaping elements dampen the applied force and the deforming effect is wears out by the dampening, such that no regular and continuous interconnection can be achieved. By pure chance, a method was now found which avoids said phenomena and achieves a completely regular deformation of all shaping elements associated with this process. Said method is rather simple and therefore very economic and completely reproducible. 
       DESCRIPTION OF THE INVENTION 
       [0003]    The use of a negative pressure applied on the shaping elements surprisingly led to a perfect result. Herein, the shaping elements being filled loosely into a tool are either charged with a defined negative pressure in a vacuum-sealed system before the filling and subsequently the frame-forming mass is suctioned and cured by applying the defined negative pressure at a defined temperature over a defined period of time, or are charged with the defined negative pressure together with the frame material after the filling and simultaneously cooled-down, e.g. by a metal setting plate. 
         [0004]    This nearly even simpler arrangement led to further standardized results and comprises the following steps: the loose fill of shaping elements was moulded in with the structure-forming framing mass and the closed container, which was not vacuum-sealed, was exposed to a defined negative pressure at a defined temperature and over a defined period of time in a sealed container charged with a negative pressure, and simultaneously cooled-down through the setting plate. The simple handling of this process made the result highly reproducible. 
         [0005]    However, also this result could be further enhanced by chance due to an initially unimpressive change, in particular in view of the adjustable porosity of the surface: If one used a deformable silicone mould instead of a solid metallic tool, this resulted in the fact that the implant, dependent on the applied negative pressure, had a continuous porosity extending up to the surface, said porosity being adjustable through the amount of negative pressure on the one side and the E-module of the tool on the other side. Said method enables to achieve a continuous porosity even if the shaping elements were not expandable, e.g. not air-containing, but were e.g. sugar balls. 
         [0006]    As the shaping elements in this method, preferably expandable polystyrene balls (EPS) are used, e.g. Styrofoam® F414, which is foamed with pentane as an expanding agent. Upon applying a negative pressure, these balls expand very fast and increase in volume. In this way, the contact bridge between the balls becomes wider and therewith determines the diameter of the interconnecting passages up to the surface; upon using of a silicone tool, the balls squeeze into the silicone wall and, furthermore, the negative pressure draws the deformable wall over the ball surface into the implant. 
         [0007]    Foamed materials to be used as shaping materials are preferably employed, also those to which an expanding agent was added, which is activated at a specific temperature or under specific preconditions. An especially preferred material is Styrofoam® F414, having a preferred volumetric weight of the foamed polystyrene between 17 g/l and 70 g/l, preferably approx. 20 g/l to 35 g/l. The grain size distribution of the foamed material lies between 200 μm and 15 mm, often used are the sizes between 1000 μm and 3000 μm. In order to determine the expansion and the deformability of the individual shaping materials, experiments were performed to determine the parameters in a simple manner, said parameters being required for the standardization of the method. For this purpose, different shaping elements having different volumetric weights, e.g. differently foamed polystyrene balls having different diameters, were filled into a cylinder with movable, vacuum-sealed abutting pistons up to a defined height of 84.3 mm and exposed to a defined vacuum; from the change of the original height in dependency of the applied negative pressure, quantities were determined which represent an initial reduction of volume by removing of air between the shaping elements, followed by an expansion of volume which was adjustable to the former initial length by applying a force F, measured in N, and represented the expansion pressure of the air in the shaping elements. Depending on the time period, the force slowly decreased, which could be explained by the bursting of the air bubbles in the plastics. Based on this phenomenon, the defined time periods for the charging with negative pressure were determined. 
         [0008]    Pressures between 150 mbar and 800 mbar, preferably approx. 300 mbar to 500 mbar, over a time period of 15 minutes, applied on a phosphorate-agar agar mixture, at a temperature of the implant of 4 to 12° C., showed especially advantageous results in view of the outside porosity and the inner interconnections. 
         [0009]    As deformable moulds, in particular silicones having a shore hardness below 25 shore, preferably below 18-20 shore, used in casting or injection die casting methods are suited. However, all plastically or elastically deformable materials can be used, the E-module of which lies clearly below that of the shaping elements. Correspondingly, the tools can be cast, but also be manufactures in mass production with injection moulding methods. Examples for plastically deformable tools are tools made of Styrofoam® having different density, examples for elastically deformable tools are the aforementioned silicones, wherein also foamed silicones can be used. The expansion pressure of said materials in vacuum adds in its effect to that of the expandable shaping elements. 
         [0010]    As castable material for the framing material, a mixture of hydroxylapatite (HA) or triphosphorate (TCP) and an agar agar solution in a ratio of 10 g powder/7 ml to 25 ml solution, corresponding to a ratio of 1.4 to 0.4, is preferably used, ideal would be preparations in which the mixing ratio powder/solution corresponds to 0.45 to 0.48, e.g. 1600 g HA and 3500 ml solution. 
         [0011]    Depending on the composition, the shrinking factor can already be calculated on the basis of the preparation: same lies between 0.95 to 2.9, preferably between 1.75 and 2.15, for a HA-agar agar mixture capable of flowing, which is filled at a temperature of 60° C., at a ratio of 16 g/35 ml of a 1.7% agar agar solution at exactly 1.91. Upon these two preconditions, expandable shaping elements, a deformable silicone mould and an exact preparation with defined shrinking, very precise implants could be sintered net shaped, without the necessity of a post-processing. 
         [0012]    The definite design multiplied with the shrinking factor leads e.g. to an implant body in plastics or any other material being easily processable in a CAD/CAM process, which is re-cast with a castable silicone in an original mould up to the top edge. After curing of the silicone, the shaping body can be mechanically removed easily, the silicone mould is perforated several times at the bottom and is subsequently filled with polystyrene balls of a desired size, the closed with a silicone lid having venting holes and filled in a filling mould with e.g. the ceramic mass. Immediately after the filling, the tool is as a whole charged with a negative pressure in an exsiccator and cooled down to 4-12° C., e.g. through the setting plate. After curing of the ceramic mass, the tool can be de-assembled and the green body can be easily removed. In an acetone washing, the Styrofoam is dissolved from the ceramic Styrofoam® implant, the ceramic is dehydrated in steps of 70/80/90 and 100% acetone and subsequently stepwise dried in air by cooling (cool drying). The result is documented every hour by means of a precision scale; if no further loss of weight in the air begins to show and the curve of weight remains to be linearly unchanged, the implant is dried for 24 hours in the exsiccator by adding P 2 O 5  in a vacuum of 150-250 mbar absolute pressure and subsequently burnt at 1300° C. in the sintering furnace. This results in an open pore implant being absolutely true to size, having a clearly higher strength compared to mechanically post-processed bone substitute material cylinders or cubes (Draenert et al. 2001: Synthetische Knochenersatzstoffe auf HA und TCP-Basis Trauma Berufskrh 3:293-300 Heidelberg New York Berlin Tokyo: Springer), said strength being able to be further increased by outside structuring, e.g. rings, contractions, massive edges etc. 
     
    
     EXAMPLE (1) 
       [0013]    Styrofoam® balls having a diameter of 12 mm are immersed and introduced into a cup in a cylindrical container having a perforated bottom with boreholes of 10-11 mm in diameter and a fixable lid seated flush on the balls and having the same boreholes, said cup being filled with hot wax having a temperature of 90° C. and being taken from the heating furnace for this purpose. The container with the Styrofoam® balls in its outer diameter hereby fits flush into the cylindrical wax container which has a removable bottom. After curing of the wax at room temperature, the bottom of the wax container is removed and the Styrofoam® container is pressed out. The Styrofoam® container is also freed from its bottom and lid and the wax-Styrofoam® cylinder is pressed out and freed from the Styrofoam® in an acetone washing. After drying in air, the resulting continuous, interconnecting, porous wax framing is inserted into a filling container receiving same in a flush manner. The filling container has a filler neck with perforations at the bottom of the container and may also contain a screen which is required for suctioning smaller Styrofoam® balls, furthermore, it is provided with a lid having venting boreholes, e. g. having a diameter of 1.5 to 2.5 mm. Styrofoam® balls having a diameter of e.g. 600-1200 μm are suctioned into the wax framing, wherein a screen having a mesh size of 400 μm is arranged upstream. The cavity system of the wax framing is completely filled with the smaller Styrofoam® balls and is then closed with a lid. The container is now filled with a ceramic mass, wherein the mass is suctioned through the venting holes through the filler neck or is filled without pressure simply through the filler neck. If the ceramic mass protrudes through the venting holes of the lid, the mould is filled and is put into an exsiccator together with the tool and charged with a negative pressure of 500-600 mbar for 15 minutes and cooled-down during this time period by the metallic setting plate. The thus cured wax-ceramic-Styrofoam® block is subsequently freed from the Styrofoam® in the acetone washing, dried in air and sintered together with the wax in a furnace at 1300° C. This results in completely isolated, at the outside continuously porous and at the inside completely interconnected porous balls having a diameter of 6 mm. Due to the shrinking of the matrix material, completely separated balls are formed. 
       EXAMPLE (2) 
       [0014]    Instead of individual porous balls, an interesting material may be produced, which corresponds to a negative print of the marrow combs, and a ball conglomerate having gaps between the porous balls for the regrowing of bone trabeculae and wide connecting bridges, which correspond to the contact points of the balls: The steps correspond to example 1, however, the wax-Styrofoam® framing is exposed to a defined negative pressure of e.g. 600 mbar during the curing in the excissator. The following expansion of the Styrofoam® balls results in wider bridges and thicker connecting arms between the balls. After curing of the wax-Styrofoam® framing, the Styrofoam® is removed. The following steps correspond to example 1, with suctioning of the smaller Styrofoam® balls, filling with ceramic mass, post-evacuating by cooling and subsequent dissolving of the shaping elements in acetone; contrary to example 1, the cool drying step follows: in steps of 2 hours each, in 70/80/90 and 3×100% acetone, it is cooled in air in steps in the freezer, at 4-12° C. increasingly in e.g. 4 steps of 3 hours each until room temperature is reached and subsequently dehydration in the exsiccator by using P 2 O 5  and a vacuum of about 150 mbar absolute pressure during 24 hours. Upon such a procedure, wide bridges between the porous balls remain and the wax framing may be burnt at e.g. 1300° C. together with the ceramic inlet; the wax may also be melt off in the heat furnace at 90° C.; a precondition is that the ceramic mass is already dried in air. The result is a perfect framing made of interrelated, in the inside perfectly interconnected porous balls with a continuous porous surface and an astonishing high compression strength. Same lies between 4-12 Mpa, depending on the size of the balls. 
       EXAMPLE (3) 
       [0015]    The production of a cube true in size, having an edge length of 15 mm and an open porosity over all surfaces: Upon a matrix mass of 16/35 HA/agar agar suspension of 1.7%, a shrinking factor of 1.91 is calculated and in a CAD/CAM process, a cube made of POM having an edge length of 28.65 mm is produced. Since the cube shall achieve a high strength of 4-6 Mpa, the edges are not rounded. The cube is put into a moulding tool and poured with self-curing silicone until its top edge. After 24 hours, the cube is removed mechanically and the silicone tool is inserted into a filling tool, the bottom of which consists inside of a perforated silicone bottom and is covered in a flush manner with a silicone lid having venting holes after having been filled with 1200 μm sized Styrofoam® balls. After the tool was closed with a screw cap having venting holes, it is filled with a ceramic mass; subsequently, the charging with negative pressure of 500 mbar for 15 minutes upon simultaneous cooling occurs in the excissator on a metallic and coolable setting plate. After that, the tool is de-assembled and the ceramic-Styrofoam® cube is carefully taken out mechanically and freed from the shaping elements in the acetone washing. For a crack-free drying, the cool dehydrating follows, as described in examples 1 and 2, and subsequently, the cube is sintered in the furnace at about 1300° C. The result is a cube true in size and having a very high compressive strength, with open porosity over all surfaces and a continuously interconnecting porosity of the inner structure and reinforced edges made of solid ceramics. 
         [0016]    In  FIG. 1 , a simple vacuum chamber in the form of an exsiccator ( 10 ) is described, comprising a venting valve ( 13 ) and a tap for attaching a pipe leading to the vacuum pump ( 12 ) and a metallic cooling plate ( 11 ) having a filling tool ( 1 ) arranged on the cooling plate and having a deformable tool received in a flush manner and consisting of three parts, a body ( 2 ), a lid ( 7 ) with perforations ( 4 ) and a bottom ( 8 ) with perforations ( 5 ) for filling e.g. a ceramic mass. 
         [0017]    In  FIGS. 2   a  and  2   b , ceramic implants according to claim  1  are shown ( 20 ), once in a plan view and in  FIG. 2   b  as a sectional view. The plan view on the ball shell shows the open porosity ( 22 ) and the rough shell ( 21 ). In the sectional view, the interconnecting pore structure ( 23 ) is shown. 
         [0018]    In  FIG. 3 , an implant according to claims  1  to  3  is shown as a bone dowel ( 30 ), e.g. for re-fixing a ligament in case of a cruciate ligament substitute across the outside of the dowel, which comprises horizontal ( 31 ) contractions, which can be arranged preferably also helical, and which has an outer shell interrupted by pores ( 32 ) across the complete surface. 
         [0019]    In  FIG. 4 , a light ceramic implant ( 40 ) is shown, sintered net shaped, having an open porosity across the complete surface ( 43 ), comprising crossing depressions or channels ( 41 ,  42 ), in which the eye muscles can be sewed, which is used as a part of an artificial eye. 
         [0020]      FIG. 5  shows a ball conglomerate ( 50 ) consisting of solid balls ( 51 ), which may however also consist of the elements of  FIG. 2  and features wide bridges ( 52 ) between the ball elements and regular ball intervals ( 53 ).