DE3517456C2 - - Google Patents

Description

The invention relates to a bone replacement material. Farther The invention relates to a method for producing a Bone replacement material. In particular, the invention relates a bone substitute material that essentially consists of a Cross-linked plasma protein consists of matrix in which Matrix calcium phosphate particles are distributed homogeneously. Farther the bone substitute material can contain various additives, such as fibrinolysis inhibitors, growth factors, antibiotics, contain homologous bone material and the like.

A material of this kind is from the European patent publication 00 68 149 A 1 known. The known material can serve as filling material for pathological bone cavities, forms a dry preparation obtained by freeze-drying with foam or fleece structure, and exists at least in addition catalytically effective amounts of thrombin essentially 30 to 45 wt% fibrin, 4 to 15 wt% fibrinogen as well as from natural, finely divided bone material and / or synthetic, bone-forming substitute and at least an antibacterial agent. As a synthetic, bone-forming Substitute come inorganic salts of potassium, Magnesium and calcium, especially tricalcium phosphate in Consider. In addition, the fleece can stimulate callus formation Active ingredients such as platelet growth factors or Contain hormones.

The well-known dry preparation is by freeze drying a dilute, aqueous solution or suspension which is typically about 1 g of plasma protein Contains 10 ml of water. As is typical for lyophilisates it is an extraordinarily light, loose, with a variety foam or fleece structure interspersed with cavities, whose density is still well below 0.2 g / cm³. In contact Such a fleece collapses with body fluid and forms a soft, mushy mass without inherent rigidity.

The natural bone tissue represents an extremely differentiated Tissue, forms the firm, flexurally elastic Parts of the skeleton and serves as a place of origin and attachment for the skeletal muscles.

For example, in scientific literature the following mechanical strength values are given:

Studies by Dempster and Colemann, 1960

Flexural strength

Human. Shin, dry, parallel *) 258.3 ± 28.0 N / mm²

Human. Shin, moist, parallel *) 191.4 ± 11.9 N / mm²

Human. Shin, dry, across *) 43.3 ± 13.1 N / mm²

Human. Shin, moist, across *) 32.6 ± 6.6 N / mm²

Human. Lower jaw bone, dry, parallel *) 164.8 ± 47.8 N / mm²

Human. Lower jaw bone, dry, transverse *) 70.1 ± 23.9 N / mm²

*) parallel or transverse to the preferred direction of the Havers system

Studies by McElhaney et al, 1970

Fracture compressive strength

Human. Skull bones, radial 75.2 ± 35.9 N / mm²

Human. Skull bones, tangential 98.4 ± 36.6 N / mm²

Pressure elasticity module Human. Skull bone, radial2461 ± 1476 N / mm² Human. Skull bones, tangential5694 ± 3093 N / mm²

Through pathological processes, such as tumor damage, chronic Osteomyelitis, tuberculosis, bone necrosis, cyst formation and The like. Bone material can be destroyed or accident-related Factors and the like are smashed. Especially if it is it is a mechanically stressed bone the desire to fill in the resulting bone cavity and / or replacement of the destroyed bone area with a bone replacement material, that have sufficient mechanical properties to ensure the typical resilience within limits, and to promote new bone formation. Here, the bone substitute material be completely absorbable, and to the extent the new bone formation is broken down and into natural bone tissue being transformed. Such a bone replacement material is also intended be mechanically editable to make it accurate to the contour of a given pathological bone cavity or defective can be adjusted. After all, it should the bone substitute material due to its composition Vascularization, the sprouting of tissue cells and the Promote callus formation.

Starting from a bone replacement material of the above Art is the object of the present invention is under Maintaining beneficial properties like complete Absorbability, promotion of new bone formation and adapted, gradual conversion to natural bone tissue the mechanical properties, especially density, hardness and to increase bending strength considerably, and a to ensure good mechanical workability.

In particular, an object of the present invention is to provide such bone replacement material that due to its hardness, rigidity and flexural strength are mechanical can replace stressed bones.

Another object of the present invention is essentially consisting of plasma protein and calcium phosphate Particles to provide existing moldings, the mechanically is editable, for example cut, sawn, milled, can be drilled and / or filed to match the machined Molded a cavity or defect in a mechanical to fill in stressed bone, which is the new bone formation promotes and gradually transforms into natural bone tissue.

Another object of the present invention is a manufacturing process that can be carried out on a commercial scale to specify such a bone replacement material. By simple variation of the procedural measures should be possible essential properties of the bone substitute material, such as size, Dwell time, mechanical resilience and the like. To a large extent to adapt to the mainly occurring requirement profiles.

It is still another object of the present invention therein, a method for producing such a bone replacement material specify that by varying the procedural measures the production of certain, to a particular one Patients and their bone defect individually customized bone replacement pieces allowed that targeted with regard to one certain illness can be produced and shortly after production are implantable.

Other tasks, goals, advantages and special features of the present Invention emerge from the description below.

Starting from a bone replacement material of the above Art is the solution to this problem and the invention Goals therein, which are essentially cross-linked plasma protein and calcium phosphate particles compress to form a solid, mechanically machinable molded body to provide. After compaction and final Freeze drying is said to be the density of the finished bone substitute material be at least 0.6 g / cm³. Preferably, the Density of the finished bone substitute material at least 0.8 g / cm³ and particularly preferably at least 1.0 g / cm³.

To produce this bone replacement material, the starting components, namely plasma protein and calcium phosphate Particles and optional additives such as fibrinolysis inhibitor (s), Active ingredient (s), growth factor (s), natural, homogeneous bone material and the like in a predominantly aqueous solvent solved or suspended. After adding a crosslinking agent a crosslinking reaction is carried out. The one after networking gelatinous mass obtained is compacted, d. H., this gelatinous mass becomes smaller in volume Solvent removed; in particular, by using mechanical Pressure squeezed out of this mass of water. After this has been sufficiently compressed, for example the volume that from a concentrated batch (approx. 5 g plasma protein within about 20 ml of water) gelatinous obtained after crosslinking Mass reduced to at least half or still has been reduced to at least 1/3, it will finally obtained material frozen, freeze-dried, mechanically processed, sterilized and immediately implanted if necessary or stored.

Due to the compression provided according to the invention the finished bone substitute material has surprising properties on. The bone substitute material forms a firm, mechanical one machinable molded body with homogeneous structure and isotropic Properties. The dimensions are not limited; much more can be easily molded pieces with a length of 5 to 10 cm and more, and with a volume of 100 cm³ and make more. Its Shore D hardness is at least 40. The flexural strength of this bone replacement material is preferably at least 20 N / mm² and particularly preferably at least 25 N / mm². This is the flexural strength of the invention Bone replacement material of the order of magnitude in one Area like that of Dempster and Colemann for lower jaw bones is specified transversely to the preferred direction of the Havers system. The Compressive strength of the bone substitute material according to the invention is preferably at least 10 N / mm².

Despite these excellent mechanical properties this bone replacement material is a biologically active material represents the sprouting of natural tissue cells, Supports vessels and the like, which promotes callus formation and gradually and completely into natural bone tissue converts. This is a very important difference to other known, practically "biologically dead" bone replacement and prosthetic materials, for example from below Processed heat and / or pressure Masses of collagen and binder, such as a copolymer may consist of lactite and / or glycolite units (cf. DE-OS 28 43 963) or from under non-physiological conditions precipitated fibrin and crosslinked by means of formaldehyde can (see. US-PS 35 23 807).

According to the proposals that have become known so far, it was not possible to create a homogeneous, solid, mechanically resilient molded body of practically any dimensions in the sense of a protein plastic without the biological activity of the plasma protein largely or completely destroy. This is where the present invention provides novel prosthesis and bone replacement materials, on the one hand are firm, hard, machinable and resilient, and on the other hand are nevertheless biologically active, namely adapted of new bone formation gradually into natural bone tissue convert and finally be completely absorbed. The crosslinking and compression provided according to the invention is carried out in an aqueous environment under gentle conditions, so the structure and biological activity of the protein largely preserved. For the first time ever this way from protein solid, mechanically editable molded body produce.

The invention is explained in more detail below.

As stated, the bone substitute material according to the invention is made mainly from a matrix of cross-linked plasma protein, in which calcium phosphate particles are homogeneously distributed. Preferably fibrinogen, fibronectin, Albumin and / or globulin. Is particularly preferred used as plasma protein fibrinogen. Mixtures of several Plasma proteins are possible, for example mixtures from fibrinogen and albumin. Plasma proteins are preferred of human origin used to antigen reactions and the like. to exclude.

A well-suited fibrinogen preparation can, for example can be obtained according to the following regulation.

100 parts by volume of human plasma are concentrated with 10 parts by volume. Calcium phosphate solution (Ca₃ (PO₄) ₂) added. The mixture will centrifuged, and the sediment obtained thereby discarded. The supernatant is cooled to 15 ° C and in a proportion of 1/6 of its volume with saturated ammonium sulfate solution (Na₂SO₄) added. The resulting supernatant is discarded and the sediment formed was dissolved in 0.15 M NaCl solution. The the solution obtained is precipitated again with ammonium sulfate. The the sediment then obtained is dissolved in water and lyophilized.

In addition, the plasma proteins provided according to the invention provide commercially available preparations of human origin, the are available in the fine chemicals trade.

The bone substitute material according to the invention also contains Calcium phosphate particles. These contribute to the strength of the bone replacement material and promote bone growth. The Calcium phosphate particles can be made from any, in the physiological Milieu insoluble calcium phosphate, which supports natural bone growth. For example the tricalcium phosphate known for this purpose (Ca₃ (PO₄) ₂) be used. Hydroxyapatite is particularly preferred (3Ca (PO₄) ₂ · Ca (OH) ₂) used because of its restructuring runs particularly fast in natural bone tissue. in the Within the scope of the present invention, a hydroxyapatite (Calcium phosphate hydroxide) particularly proven and is preferably used. The calcium phosphate particles should be finely divided and preferably an average particle size of less than 200 μm, particularly preferably have less than 100 microns. The calcium phosphate Particles are homogeneous in the plasma protein matrix distributed.

The respective proportions of plasma protein and calcium phosphate Particles influence the mechanical properties of the finished product. Preferably, 1 part by weight of plasma protein 0.2 to 1.2 parts by weight of calcium phosphate particles are provided. At is less than 0.2 part by weight of calcium phosphate particles achievable strength of the finished product is insufficient. Also with more than 1.2 parts by weight of calcium phosphate particles the strength of the molded body quickly decreases. You get a crumbly, fragile material, which in some cases is used as a filling material can be useful for pathological bone cavities, however, the flexural strength of such a material is Too little to replace a mechanically stressed bone. A proportion of 0.4 to 0.8 parts by weight is preferred Calcium phosphate particles are provided on 1 part by weight of plasma protein. Particularly good results are achieved with a share of about 0.5 parts by weight of calcium phosphate particles per 1 part by weight Obtained plasma protein. Such material shows after cross-linking and sufficient compression particularly good mechanical Properties such as a bending strength of 30 N / mm² and more, as well as a compressive strength of approx. 12 N / mm², and will currently used with particular preference.

In order to achieve a homogeneous distribution, plasma protein and calcium phosphate particles in a solvent with each other mixed. Preferably in an aqueous or predominantly worked aqueous solvent. With this solvent it can be water, human serum or an aqueous one Act saline solution. The pH and salinity of the Saline are said to largely depend on the physiological conditions be adjusted; for example, physiological saline or Ringer's solution. In some cases it may be appropriate to add a predominantly aqueous solution use, in addition to water, water-soluble, organic Contains solvent, for example, to improve solubility for increase certain active pharmaceutical ingredients. To suitable organic solvents include monohydric alcohols such as such as ethanol or isopropanol, polyhydric alcohols such as glycerin or polyglycols, cyclic ethers such as dioxane and the like maximum proportion of organic solvent may later do not interfere with the intended lyophilization; mostly the proportion of organic solvent is 10 vol .-% of do not exceed the total amount of solvent.

Preferably at room temperature or only moderately elevated temperatures up to about 35 ° C worked to any Avoid denaturing the plasma protein. In some However, targeted denaturation of the plasma protein can also occur be useful, for example, if a special long retention time of the bone substitute material in the organism is aimed for becomes; this can be the case for an implant for an elderly patient with slow bone growth be appropriate. In such a case, for example Fibrinogen or one of the other plasma proteins in aqueous Solution to be heated to temperatures of 70 to 80 ° C. To Such a heat treatment is partially denatured Protein as a solid that pulverizes after drying and can be used in this form.

The amount of solvent or the protein concentration within of the liquid approach depend on various factors. First of all, after the crosslinking reaction, a gelatinous one Mass with sufficient inherent rigidity and cohesion be obtained so that the solvent from this mass can mechanically squeeze out without being excessive at the same time losing a lot of protein. That's why the liquid approach is supposed to contain at least 2 g protein in 100 ml solvent. A higher protein concentration is preferred because of the solvent largely in the subsequent compression step are pressed out of the cross-linked plasma protein matrix got to. On the other hand, too high a protein concentration can do that Affect the result of the crosslinking reaction. Aimed for becomes a homogeneous, completely networked product with three-dimensional cross-linked polymer strands. If it is too high Protein concentration can be a less desirable particulate Material. However, the results are still very good with a concentration of 30 g plasma protein in 100 ml Water has been obtained.

Since plasma proteins from human serum are preferably used, it may be advisable in individual cases to sterilize the aqueous plasma protein solution before further processing, for example in order to specifically inactivate viruses such as hepatitis viruses. Treatment with β-propiolactone, followed by UV radiation, can be provided for this purpose. Alternatively, sterilization can be carried out using high-energy γ or X-rays.

Crosslinking of the plasma protein can be carried out using conventional crosslinking agents respectively. Suitable crosslinking agents include divalent, with the existing amino groups peptide bonds resulting substances such as glutaraldehyde, phenol-2,4- disulfonyl chloride, adipic acid and their derivatives such as Dimethyladipinnidate and the like. Important when choosing the Crosslinking agent is that complete crosslinking is achieved and an insoluble product is produced. Preferably serve as crosslinking agent diazomethane (CH₂N₂) or Thionyl chloride (SOCl₂), with diazomethane being particularly preferred becomes. Diazomethane is under the chosen conditions (aqueous System, room temperature) quite active, generated exclusively physiologically harmless methylene bridges without that Denature protein, and the one that occurs in the reaction Nitrogen can be easily removed from the system. Thionyl chloride also proves to be mild but effective Cross-linking agent, the physiologically harmless bridges generated. Preferably with an excess of crosslinking agent worked on a full three-dimensional networking of the plasma protein. One after graduation amount of crosslinking agent remaining in the reaction be removed by dialysis.

The crosslinking reaction is preferably cuboid or cube-shaped containers carried to the later To facilitate compression of the crosslinking product. After this the crosslinking agent added and evenly distributed in the batch has been left standing still for a few hours, to a three-dimensional networking of the entire approach to reach. A whitish, gelatinous mass is obtained, the is still deformable when wet. The whole, in the original Amount of water contained is bound or built into the network; neither can be suitable from one Pour free water into the crosslinked product Application of vacuum a noteworthy, on evaporation of Water indicative weight reduction can be achieved.

In an essential aspect of the present invention it is necessary to compress this gelatinous mass. The compression causes a reduction in volume by at least partial, preferably extensive removal of the solvent. The polymer strands become one another approximated, and water emerges from the base.

On a laboratory scale, there has been a two-stage compression proven useful. In the first stage, the entire preferably cube-shaped in an adapted shape with cube-shaped mold cavity, and with an absorbent Stamp applied mechanical pressure to a cube face To squeeze out water. The approach was then taken and successively applied mechanical pressure to each cube face. For example, a fresh one can be used as an absorbent stamp Burnt clay plate. In this way, one causes isostatic compression. Other compaction measures and devices are possible. For example be worked with an isostatic press that has the exit of solvent, but the cross-linked protein essentially withholds.

The partially compressed approach then became more suitable in pieces Size divided that after the complete compression Had the dimensions of the desired implant. These pieces are placed individually in a suitable form. The shape became inserted into a press tool. With the interposition of a plastic sieve, to ensure the leakage of liquid was further compacted uniaxially using a lever operated ram. The pressure applied by physical force was 10 to 30 bar. Alternatively, this could also be the second Compression stage using an isostatic press or the like.

All compaction measures are carried out at room temperature carried out under normal conditions. Preferably the Compression at room temperature, at least at temperatures performed below 35 ° C to damage the plasma protein to avoid. Also, the compression is preferably not performed suddenly, but gradually according to that Fluid accumulation around the network structure of the protein matrix not to destroy.

To carry out the compression according to the invention, on the gelatinous mass exerted mechanical pressure on them Reduce volume and to squeeze out solvents. The pressure can be applied in various devices, for example with a disk-shaped stamp in a cylindrical shape or in an isostatic press. The stamp and / or wall material is preferably a micro-porous material with such a small pore size that only the small solvent molecules can penetrate. On a laboratory scale, for example, a stamp is made of a porous one Clay plate has been used.

The compression continues until a very substantial one Volume reduction is reached. Aim of compression is the water with a corresponding volume reduction largely completely squeezed out of the cross-linked protein matrix. Even with approaches with a high protein concentration should be the volume of the gelatinous obtained after crosslinking Mass to be reduced to at least half a bone substitute material with sufficient mechanical workability and maintain strength. Preferably the cross-linked Mass compacted to at least 1/3 of their initial volume. At protein concentrations of 15 to 30 g plasma protein in the liquid batch, compression has proven itself well, which is the volume of the crosslinked gelatinous mass reduced to 1/2 to 1/5 of the initial volume. A such a degree of compaction is preferably used. With more dilute starting solutions, the compression continued until an even larger reduction in volume is reached; for example, the volume of the networked mass down to 1/10 and less of the initial volume be reduced. Such compression can be done under usual Laboratory conditions in the course of 3 to 4 hours under one Pressure of 10 to 30 bar can be reached.

A particularly high compression is provided if particularly hard bone replacement pieces with a long dwell time be desired in the living organism.

The molded body obtained after the compression is physiological Milieu insoluble. When reintroduced into He swells only slightly; the volume increase is less than 3%.

After the cross-linked, gelatinous mass in the desired Extent has been compacted, the compacted product freeze-dried to remove residual solvent remove. Freeze drying can be carried out under normal conditions respectively.

After the molded body following freeze drying has been brought back to room temperature mechanically processed, for example sawn, cut, be milled, filed and / or drilled for fine adjustment to perform on a particular bone defect, or to to reproduce a certain piece of bone. For example a millimeter-exact replica of a section of one Pine crown has been created.

The molded body can then be sterilized; for example gas sterilization can take place overnight. Thereupon the molded body can be implanted on the patient the following day will. Alternatively, the molded body can already be in a closed Packaging sterilized and then stored. At 4 ° C, the sterile packaged molded body is practically arbitrary long shelf life.

Preferably, the solid, mechanically processable molded body obtained, consisting essentially of protein, is further adapted to its intended use as a bone replacement material. It is advisable to protect the protein matrix from proteolytic degradation. The presence of one or more fibrinolysis inhibitor (s) is expedient for this purpose. Exemplary fibrinolysis inhibitors are plasminogen activator inhibitor, one or more antiplasmins, such as α ₁-antiplasmin, α ₂-macroglobulin or aprotinin, and ε- aminocaproic acid and / or trypsin inhibitor. Both aprotenin and antiplasmin are preferably used because this combination of physiological inhibitors has a universal activity against all of the body's proteases. For example, 20,000 to 1,000,000 units (so-called KIE, namely Kalikrein inactivator units) of aprotinin and / or 500 to 2000 units of antiplasmins can be provided on 1 g of plasma protein. The fibrinolysis inhibitor (s) are preferably already added to the mixture of plasma protein, calcium phosphate particles and solvent in order to ensure a uniform distribution within the finished molded article. In the crosslinking reaction, the fibrinolysis inhibitor is additionally anchored to the matrix material.

Despite its comparatively high density of at least 0.6 g / cm³, preferably of at least 0.8 g / cm³ is the inventive Bone replacement material to support the formation of new vessels and promote tissue cell infusion. For this purpose the presence of growth factors desirable, at least are distributed in the peripheral zone of the bone substitute material. Examples of such growth factors are thrombin, Platelet extract, angionesis factor, endothelial cell growth f. or platelet growth factor and the like.

Suitable thrombin to (so-called. NIH units according to the standard of N ational I nstitute of H ealth the USA) under known, standardized conditions at least one biological activity of 10, 000 units per 1 mg comprise thrombin. Suitable preparations are commercially available, for example suitable thrombin can be obtained in microcrystalline form with a biological activity of at least 3,000 NIH units / mg preparation (which contains stabilizing agents and carrier materials known in addition to thrombin).

Angionesis factor is a protein that, for example, from tumor cells is formed and the connection of the tissue to the capillaries blood supply guaranteed. For production, for example animal tissue, preferably from the lungs or Spleen homogenized, and mechanical cell lysis (for example by repeated freezing and thawing) will. The insoluble fraction is centrifuged at high speed, and then the liquid supernatant separated and over a Sepharose 4 B-pillar fractionated. The middle fraction contains the desired angionesis factor. The effectiveness can be tested on animals checked, for example on rabbits by implantation of pieces of tissue into the eye socket.

Endothelial cells are used to obtain endothelial cell growth factor isolated, grown, propagated and isolated from umbilical cord. The cell material is homogenized and the liquid supernatant worked up by column chromatography. The effectiveness of individuals Fractions is based on influencing cellular growth tested by fibroblasts.

The growth factor (s) should preferably be in the Border area of the bone substitute material to be present around the sprout to promote tissue cells and vessels. Such Distribution can be countered by dialysis of the cross-linked material achieve a solution to the growth factor. For example the gelatinous mass obtained after crosslinking can Be kept at 4 ° C in an aqueous thrombin solution overnight. Then the networked, enriched in the growth factor Mass compacted.

It is also possible to insert one into the bone replacement material or incorporate several antibacterial agents. In In this regard, gentamycin sulfate, penicillin, tetracycline and / or streptomycin well proven. To others, optionally provided additives include neomycin and kanamycin. These active ingredients are preferably the initial ones Approach added to achieve a homogeneous distribution.

The bone substitute material can also contain glycosaminoglycans contain. As is known, the glycosaminoglycans form the Main component of the supporting and connective tissues and bodies High molecular weight, in solution viscous compounds that mainly from glucuronic acid and acetylgalactosamine or Acetylglycosamine exist. Exemplary representatives are Hyaluronic acid and chondroitin sulfate A, B, C. For isolation the chondroitin sulfate proteins can be cartilage with CaCal₂- or extract NaOH solution, and from the extract the protein-like Fill out accompanying substances with chloroform / amyl alcohol. For example, hyaluronic acid can come from human umbilical cord be won. Suitable preparations are in fine chemicals Trade accessible. The presence of such glycosaminoglycans increases elasticity, toughness and breaking strength of the finished bone replacement material even further. For example, in the approach of plasma protein, calcium phosphate Particles and water contain one or more glycosaminoglycans be stirred. The proportion of glycosaminoglycans can be up to make up about 10 wt .-% of the plasma protein content.

Finally, it can be useful in individual cases, in the Bone replacement material homologous bone material, for example autologous cancellous bone or lyophilized and powdered Work in pieces of bone.

The following examples serve for further explanation of the invention without restricting it.

Example 1

The raw materials, namely

5 g microcrystalline fibrinogen, 2.5 g hydroxyapatite with an average particle size of 5 μm, 100,000 AI units aprotin, 2,000 AI antiplasmins, and 200,000 units of gentamycin

were mixed together dry. The powder mixture obtained was made up to a total volume with demineralized water brought from 20 ml and the mixture stirred. After a period of stirring After about 1 hour at room temperature you get a cloudy Suspension.

This suspension comes in a stable plastic tub square base and poured with 2 ml of a 1- % Diazomethane solution added. The mixture is stirred for a further 10 min at room temperature and then keeps the neck still. The suspension gradually solidifies. After about 3 to The crosslinking reaction is complete for 4 hours and is obtained a whitish, gelatinous mass. The whole, originally Existing water volume is bound within the network. This gelatinous, already largely dimensionally stable mass is dialyzed overnight against an aqueous thrombin solution, to bring growth factor into the marginal area. For this dissolve about 9,000 NIH units of "topostasin" in 20 ml of water, fill into a suitable container, and hang the cube-shaped, cross-linked mass in this vessel so that all surfaces are covered with solution. From a back calculation of the after Dialysis treatment of thrombins still present in the solution it was found that about 20 to 30% of the thrombin in the Edge area of the networked mass have been anchored.

After the enrichment with growth factor, the networked, gelatinous mass compacted. For this the mass was again placed in the plastic tub and with a fresh clay tablet mechanical pressure on the exposed surface exercised and the mass compressed under water leakage. The Mass was turned, and successively pressure on each surface of the cube exercised. The clay tablets were replaced with fresh tablets exchanged after sucking up water.

This first stage of compression was completed after about 3 hours. The already largely dry, partially compacted Cubes were cut into 6 cuboids of approximately the same size. Each cuboid was individually cut into a mold with an adapted mold cavity laid out a free main area with a plastic strainer covered, and an adapted stamp applied. These The unit was then placed in a lever operated press and further compacted under manual force, until practically no further lever movement was possible.

The fully compacted moldings were removed from the mold and freeze-dried under normal conditions. The Moldings obtained thereafter were solid and had a light weight yellowish bone-like appearance. On these samples were determined the following properties.

density

Determination of density according to method A according to DIN 53 479 gave a value of approx. 1.1 g / cm³.

hardness

The determination of the Shore D hardness according to DIN 53 505 resulted a value of approx. 80.

Bending test

The bending test was based on DIN 53 452 3-point load carried out.

Sample dimensions: length 38.2 mm, width 7.55 mm, thickness 4.0 mm Support distance: 30 mm Loading speed: 3 mm / min

Here a bending strength of approx. 34 N / mm², an elongation at break of approx. 1.6% and a flexural modulus of elasticity of approximately 2,000 N / mm².

Pressure test:

The pressure test was carried out on two in accordance with DIN 53 454 smaller sections with a length of approx. 7 mm. The Loading speed was 0.1 mm / min. The determined Measurement results indicate a compressive strength of approx. 10 to 15 N / mm², on compression at break of approx. 3% and on close a pressure modulus of approx. 320 to 460 N / mm².

Example 2

The procedure of Example 1 was essentially repeated. Deviating from that after the first compression stage a partially compressed mass obtained is cut out, that after the final compression in one adapted shape approximates the dimensions of a jaw crown Had part. After freeze drying, this became Part mechanically reworked (carved and filed) and as close as possible to the patient’s jaw-crown defect customized. The finely machined crown section was sterilized and then implanted in the patient. The Bone replacement material was without rejection or inflammatory reactions absorbed by the organism. The rate of absorption is based on these experiences solely on the extent of compaction.

Example 3

The procedure of Example 1 was essentially repeated. Fibrinogen was deviated by the same amount Albumin replaced. The crosslinking reaction is just as smooth, like the networking of fibrinogen. The color of the finished product is a bit more yellow. The finished bone replacement material is a bit more crumbly and can be used for Plastics are used because the fit is easier due to simple Cancel can be achieved.

Example 4

The procedure of Example 1 was essentially repeated. A mixture of plasma proteins was used differently, namely dry plasma with predominantly albumin, glubolin and fibrinogen. The finished bone substitute is not like that mechanically stable, such as the material obtained according to Example 1.

Example 5

The procedure of Example 1 was essentially repeated. In addition, sales increased by 300 mg of chrondroitin sulfate (Na salt), added. Let the results of the bending test infer somewhat higher values.

Claims (18)

1. bone substitute material, consisting essentially of a matrix of cross-linked plasma protein in which calcium phosphate particles are homogeneously distributed, characterized in that the bone substitute material is obtainable by cross-linking an aqueous or predominantly aqueous suspension of the starting materials and subsequent mechanical compression of the cross-linking product and a solid , mechanically machinable molded body with a density of at least 0.6 g / cm³. 2. bone substitute material according to claim 1, characterized in that the bone replacement material has a density of at least 0.8 g / cm³ having. 3. bone substitute material according to claim 1 or 2, characterized in that the bone replacement material has a Shore D hardness of at least 40 has. 4. Bone replacement material according to one of claims 1 to 3, characterized in that the bone substitute material has a flexural strength of at least 20, preferably of at least 25 N / mm². 5. Bone replacement material according to one of claims 1 to 4, characterized in that 0.2 to 1.2 parts by weight for one part by weight of plasma protein Calcium phosphate particles are present. 6. bone substitute material according to one of claims 1 to 5, characterized in that as plasma protein fibrinogen, fibronectin, albumin and / or serve globulin. 7. Bone replacement material according to one of claims 1 to 6, characterized in that serves as plasma protein fibrinogen. 8. bone substitute material according to one of claims 1 to 7, characterized in that the bone substitute material additionally one or more Contains fibrinolysis inhibitor (s). 9. Bone replacement material according to one of claims 1 to 8, characterized in that the bone substitute material additionally one or more Contains growth factor (s). 10. Bone replacement material according to one of claims 1 to 9, characterized in that the bone substitute material additionally one or more glycosaminoglycan (s) contains. 11. Method of making a bone substitute material according to one of claims 1 to 10, where plasma protein, calcium phosphate particles and optionally optional additives in an aqueous or predominantly aqueous solvents are distributed homogeneously, the resulting suspension is mixed with a crosslinking agent and a crosslinking reaction is carried out, and the material finally obtained is frozen, freeze-dried, mechanically processed, sterilized if necessary and is soon implanted or stored, characterized in that the crosslinking product obtained after the crosslinking Exercise of mechanical pressure is compressed to solvent squeeze out and the volume of the crosslinking product to downsize. 12. The method according to claim 11, characterized in that mechanical pressure is exerted on the crosslinking product, to squeeze out solvents and to increase the volume at least half of the mass volume after crosslinking to reduce. 13. The method according to claim 11 or 12, with 15 to 30 parts by weight of plasma protein in 100 parts by weight Solvents have been distributed characterized in that mechanical pressure is exerted on the crosslinking product for so long until the volume - with liquid leakage - has been reduced to 1/2 to 1/5 of the initial volume. 14. The method according to any one of claims 11 to 13, characterized in that mechanical pressure is exerted on the crosslinking product for so long until the networked mass - under usual Conditions - no more liquid can be squeezed out can. 15. The method according to any one of claims 11 to 14, characterized in that a mechanical pressure of 10 on the crosslinking product up to 30 bar. 16. The method according to any one of claims 11 to 15, characterized in that the mechanical application of pressure by means of a movable Stamp made of fine-pored material. 17. The method according to any one of claims 11 to 16, characterized in that diazomethane is used as crosslinking agent. 18. The method according to any one of claims 11 to 17, characterized in that the networking product against a growth factor solution dialyzed and then the compression is carried out.