DD295983A5 - RESORBABLE, PHOSPHATED FORMKOERPER AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

The invention relates to a resorbable phosphate-containing molding and its preparation. The molding material to be used as the implant material consists of 10 to 90 parts by mass in% collagen and 90 to 10% of a glassy or glassy crystalline material with fast solubility, which before melting melts to a mixture consisting of 20-55% CaO; 5-25% Na 2 O; 0-15% K2O; 0-15% MgO; 30-50% P2O5; 0-15% SiO 2; 0-40% Na2SO4 and / or K2SO4. The form body is absorbed within 2 to 20 months in the human / animal body. Production takes place by processing the collagen, suspending the melted and comminuted material in a dry collagen suspension and drying the material. {Material, glassy; Material, glassy-crystalline; Formkoerper; implant; Bone replacement; collagen; absorbability; Solubility}

Description

Field of application of the invention

The invention relates to a graded resorbable, phosphate-containing shaped body, which can be used in the broadest sense to fill cavities in human medicine, especially in the surgical disciplines of orthopedics, ENT, dentistry, internal medicine and traumatology ,

Characteristic of the known state of the art

For the filling of cavities in the human organism collagen in the most diverse property and application form. However, filling bone defects with only collagen leads to connective tissue formation and the desired bone formation remains. This problem has been known for some time, and various variants have been presented in the literature, including a combination of collagen with apatites, tricalcium phosphates and generally with calcium phosphates, so that this disadvantage is overcome. These inorganic substances are known to be somewhat conducive to bone regeneration.

If you fill with such combined materials cavities that have no contact with the bone, - if the proportion of inorganic material is not too high, d. h., about greater than 60%, connective tissue is formed. There is no ectopic bone formation.

In this sense, it can already be stated here that a material which is suitable for filling up bone defects can, in principle, also be used in areas in which a connective tissue induction is required (this does not apply in reverse).

If one looks through the existing literature on the mentioned combination of materials, the following general aspects result.

For example, EP 0030583 refers to a bone substitute material that is uniformly mixed with apatite powder or apatite grains. There is no mention of a minimal amount of apatite so that this combination of materials can even act as a bone substitute. Other combination materials are also mentioned and not specified, such as plastics, textiles, metals, ceramics, etc. In the meantime, however, it has been agreed that only selected materials (so-called "bioactive") are suitable for a solid bone composite from apatite powder appears questionable from today's perspective.

In DE-OS 3203957 reference is made to the admixture of hydroxyapatite and / or calcium phosphate.

In EP 0164483 a method is presented by means of which a bone substitute material of collagen and hydroxyapatite is produced, in which, however, it is necessary to resort to formaldehyde or glutaraldehyde. Although only very small amounts are used here in contrast to solutions suggested even later, the handling of these substances alone involves, in some cases, locally highly crosslinked, even plastic-like products, which at least do not promote bone formation.

In WO 86/03671 combinations of TCP, apatite, collagen, a polypeptide, metals, etc. are described.

Again, as with all the aforementioned known solutions for connective tissue or. Bone substitute, but there is the defect that the absorption usually affects without exception first or the collagens and resorption times of these substances are between a few days to weeks. As the newly formed (endogenous) cell tissue progresses, the previously combined inorganic material is simply pushed together, which delays the further absorption of the inorganic material and, above all, directly hampers further tissue engorgement. It comes to a solid connective tissue or bony deposition, which adversely affects the further absorption of the material and thus tissue formation, since the healing process is brought to a stop and the further penetration of the tissue takes place only in the context of the naturally occurring Gewebeumbildungsprozesses. This is simply made clear when one considers the absorption times of the materials used, such as apatites, tricalcium phosphates, calcium phosphates, etc., with months or years. It was from the today's point of view but more or less devious combinations with metals, etc. even ignored.

It must therefore be the object of the invention to seek a combination of materials in which the tissue formation process is dynamically continued after the first collagen resorption. This has the advantage that the tissue formation is accelerated overall compared to previous solutions with simultaneous successful (complete) resorption of newly formed bone arises, which integrates functionally. The aim of the application of the solution according to the invention relates primarily to bone replacement; However, it is also possible to use the material for filling cavities, which are ultimately only to be substituted by the body's own connective tissue. Furthermore, with the method according to the invention advantageous forms of application are offered, which meet the surgeon during the procedure by easy handling.

Explanation of the essence of the invention

In the surgical practice of various disciplines, the question arises again and again about a suitable filling of defects. In particular, the search for a suitable resorbable bone replacement material is focused.

Significant differences in the application result from the sizes of the defects to be filled. While there are no problems with bony growth at defect sizes up to approx. 3 m ³ , this is not the case with larger defects. The proposed combination of materials focuses especially on these larger defects.

The invention is therefore based on several subtasks, so first to provide inorganic materials that have a much higher solubility than the apatites or tricalcium phosphate granules used previously and show similar effect in terms of bone formation, but which are more stable compared to collagen resorption, further the task of a suitable collagen supply and a method for application-oriented production of the material combination.

For the different applications or defect sizes, there are also different requirements with regard to the solubility of these materials. These substances must be biocompatible and must not counteract bone formation. Thereby it is e.g. It is not possible to use metaphosphate glasses, although they are known to have high solubility.

According to the invention, this object has been achieved by developing rapidly absorbable inorganic materials whose solubility can be adjusted within a wide range, and they are always more soluble than apatites and / or tricalcium phosphate.

Melting the mixture of the composition (in parts by mass in%):

0-14 K ₂ O, preferably 0.1-14;

0-15 MgO, preferably 0.1-15; 30-55 P ₂ O ₆

0-15SiO ₂ , preferably 0.1-15;

0-40 Na ₂ SO ₄ and / or K ₂ SO ₄ , preferably 0.1-35

a, sheds or frits them, one obtains spontaneously crystallized glass-ceramics, which surprisingly contain a so far in the ASTM file and in the relevant literature not designated crystalline phase, which is referred to in the context of this description with "X", or obtained Mixed crystals of this phase "X".

By X-ray diffractometry this phase becomes "X" or mixed crystals of this phase are roughly characterized by the following d-values and intensities:

Composition example с

d-value: 3,945 3,650 3,384 3,199 2,885 2,717 2,552 2,351 2,239 2,164 1,980 1,827 1,597 1,569 1,517

Intensities: 20 20 2 8 90 100 10 10 20 8 40 8 10 10 10

Composition Example

d value: 3.904 3.618 3.347 3.189 2.851 2.679 2.529 2.321 2.209 2.141 1.953 1.808 1.578 1.547 1.498

Intensities: 20 20 2 8 90 100 10 10 20 8 40 8 10 10 10

Composition example d

d value: 3,892 3,611 3,338 3.15 2,844 2,667 2,523 2,310 2,199 2,135 1,945 1,804 1,571 1,539 1.495

Intensities: 15 20 2 8 90 100 10 10 20 8 40 8 10 10 10

Composition Example b

d-value: 3,875 3,600 3,325 3,12 2,835 2,663 2,514 2,303 2,195 2,131 1,941 1,800 1,569 1,537 1,491

Intensities: 20 20 2 8 90 100 10 10 20 8 40 8 10 8 8

This crystalline phase is thus similar to the phase referred to in the literature as phase "A" (see also: Andro, J .; Matsuno, S .: Ca ₃ (PO ₄ J ₂ -CaNaPO ₄ System, Bulletin Chem. Soc., Japan 41 [1968] 342-347), but differs from them by significant line shifts and intensity changes as well as the absence of a strong diffraction line at the network plane 421. Phase A has been described by Ando as a superstructure of hexagonal catium sodium orthophosphate, where he calls both the high and the low temperature form of CaNaPO ₄ alpha- and beta-rhenanite, respectively, and the mere formulation rhenanit thus includes both forms, which we will follow in the present description for this language usage or definition of rhenanite.

The structure type of "A" is also the phase "X" assigned, although apparently over half of the sodium can be replaced by potassium and also calcium can be partially substituted by magnesium in this structure. These substitutions are generally referred to herein as mixed crystal formation.

The materials containing this phase also show the desired properties in terms of a defined fast solubility.

The new materials are in the cooled state at room temperature as a glass or glass crystalline material, but can in principle be converted into the glass crystalline state and have essentially physiological constituents. The rate of dissolution of the materials is adjusted in accordance with the application within wide limits, as described in more detail below, so that no toxic reactions or overconcentrations of any constituents are implied.

An expansion of the melting range leads beyond the "X" phase to further crystalline phases known per se

The phase "A" or its mixed crystals, rhenanite or its mixed crystals may additionally or in each case be present in the material produced according to the invention in its own right These composition variations are also suitable for application in the named fields of application in terms of the objective, as well as incorporation the known isomorphism of the sulphates of potassium and sodium.

This extended composition area thus extends to the already mentioned components in their mass fractions in%:

0-40 Na ₂ SO ₄ and / or K ₂ SO ₄

However, a further increase in the Calciumorthophosphatanteils leads to increasingly heavier or non-meltable and non-pourable materials, thus approaching the known materials both from their production process and in their properties (solubilities) or depart from the objectives of the present invention. Particularly advantageous embodiments are therefore in the concentration ranges (mass fractions in%)

21-50 CaO, especially 23-50

5-20 Na ₂ O, especially 6-20

0.1-14 K ₂ O, especially 2-14

0.1-12 MgO, especially 0.5-10

32-48 P ₂ O ₅ , especially 35-48

0.1-15 SiO ₂ , in particular 1-10

0.1-35 Na ₂ SO ₄ and / or K ₂ SO ₄ , in particular 0.1-20

Another preferred embodiment of the material according to the invention consists of

22-55 CaO, 6-12 Na ₂ 0.3-14 K ₂ O, 2-8 MgO, 37-43 P ₂ O ₆ , 0.5-10 SiO ₂ , 0.5-20 Na ₂ SO ₄ and / or K ₂ SO ₄ .

The material according to the invention is further characterized in that it can be converted at a temperature in the range of 1200 ⁰ C to 155O ⁰ C in a pourable enamel. Further characteristics of the material are that the melt can be converted into the glassy state at room temperature at a cooling rate greater than about 150 ^° C. per minute, and that the melt, when cooled below a normal cooling rate or at a cooling rate slower than about 35 ° C per minute, spontaneously crystallized. This forms a fine crystalline structure.

It has furthermore been found that spontaneously crystallized material of the same chemical composition as the corresponding glass (obtained under extreme cooling conditions) or the crystalline material produced from the glass by tempering each have different solubilities.

It has furthermore been found that the spontaneously crystallized glass-ceramic as crystalline main constituents at least one of the phases of Rhenanits, mixed crystals of Rhenanits, the phase "A", mixed crystals of the phase "A", the above-mentioned new phase "X" and / or mixed crystals contains the phase "X". The material may additionally contain glaserite and / or crystalline potassium sulfate.

If the main crystalline constituents of the material are rhenanite or mixed rhenanite crystals, the composition of the material in the mixture is as follows (in% by mass and calculated on an oxide basis):

30-40 CaO; 15-20 Na ₂ O; 0-1 K ₂ O, preferably 0.01-0.1 K ₂ O; 0-5 MgO, preferably 0.1-5 MgO; 40-55 P ₂ O ₆ ; 0-15 SiO ₂ ; preferably 0.1-8 SiO ₂ ; 0-30 Na ₂ SO ₄ and / or K ₂ SO ₄ , preferably 0.1-25 Na ₂ SO ₄ and / or K ₂ SO ₄ .

By "crystalline main ingredient" is meant that the percentage of the component is higher than the proportion of other components present in the material.

If the material contains the phase "A" as main crystalline constituents, the composition of the material in the mixture is as follows (in parts by mass in% and calculated on an oxide basis):

40-50 CaO; 8-20 Na ₂ O; 0-1 K ₂ O, preferably 0.1-1 K ₂ O; 0-5 MgO, preferably 0.1-5 MgO; 40-50 P ₂ O ₅ ; 3-20 SiO ₂ ; 0-30 Na ₂ SO ₄ and / or K ₂ SO ₄ , preferably 0.1-25 Na ₂ SO ₄ and / or K ₂ SO ₄ .

If the material contains the phase "X" or mixed crystals of the phase "X" as main crystalline constituents, the composition of the material in the batch is as follows (in% by weight and calculated on an oxide basis):

22-45 CaO; 8-20 Na ₂ O; 0-14 K ₂ O, preferably 0.1-14 K ₂ O; 0-15 MgO, preferably 0.1-15 MgO; 30-55 P ₂ O ₆ ; 0-15 SiO ₂ , preferably 0.1-15 SiO ₂ ; 0-40 Na ₂ SO ₄ and / or K ₂ SO ₄ , preferably 0.1-35 Na ₂ SO ₄ and / or K ₂ SO ₄ .

A particular advantage of the invention is that the material is biocompatible, sometimes even bioactive in the sense of a direct bone attachment or under constant release allows the formation of new bone tissue. On the other hand, it also promotes connective tissue formation. The material can be used for example as granules with a grain size in the range of 63-500 μπι.

The object of the invention was further achieved in that, in addition to rapidly absorbable inorganic materials, collagen preparations have also been developed whose absorption behavior can be regulated over a wide range and whose absorption times are to a certain extent consistent with those of the rapidly absorbable inorganic materials. Coincidence of the resorption times of the collagens and the inorganic materials prevents the structural and inertness of the inorganic portion of collagen-ceramic combinations resulting from premature resorption of collagen in older specimens and the associated collapse of the inorganic material during the advance of the newly formed endogenous cell tissue.

Even if the residue-free absorption behavior of the collagen fraction in the gradually absorbable phosphate-containing moldings, which can be regulated in wide ranges, is an essential criterion for its suitability as a material mix component, the problem-free application of the moldings is bound to further quality features of the collagen. For the ability to combine materials of distinctly different chemical structures and physical properties, which also do not enter into chemical bonds, but are to form a stable, malleable, dimensionally stable composite, the components of which are homogeneously distributed in one another until residue-free absorption is based on the preservation of the highest degree of nativity of the skieroprotein collagen with its adhesion and scaffolding favoring micro- and macrofibrillar structure attach great importance.

Elution of the albumins and globulins, elimination of lipoproteins and other non-collagenous components of the animal starting materials must be carried out very intensively according to the invention, but the necessary chemical process steps for isolation of desired collagen types must only take place under conditions which ensure the greatest possible nativity, but also desantigenization and haemostasis. It has been ensured according to the invention that the uniqueness of the collagen fiber braiding is maintained, which alone ensures optimum combinability with bioceramics. While in every other weaving a certain regularity of interweaving is recognizable, free fiber ends can be detected and individual fibers isolated, collagen fibers are three-dimensionally intertwined and intergrown so that never a beginning or end of fibers can be detected and only fragments of fibers can be isolated. The collagen fibers are made up of fiber bundles and these in turn are made of the finest collagen fibrils, in which the parallel ordered fibrils can again meet in sub-bundles, in order to separate soon afterwards in new sub-bundles and reunite. A continuous single fibril can thus soon belong to the one bundle of fibrils, that is to say one fiber and soon the other. This network of fibers is further completed and solidified by transverse collagen fibrils which irregularly and randomly connect the individual fiber bundles.

The structure of the collagen fiber bundles from normalmicroscopic visible individual fibers, the fibers of ultramicroscopically visible subfibrils or filaments, the filaments of molecular size protofibrils results for skin collagen a very large reactive fiber surface in the order of 500m ² to 2500m ² per kg of collagen. According to the invention care has been taken that this order of magnitude of the surface in the nonwovens made of collagen, the inorganic portion of the shaped body for physical bonding is available. It is also important that protofibrils consist of three helical twisted polypeptide chains and that polypeptide chains also self-assemble helically, with an average of 3.6 amino acids accounted for by a helix interconnected by peptide bonds and by other amino acids in preceding and following hydrogen bonds between NH groups and the oxygen atoms of the CO groups are connected. The side chains of the amino acids are located on the outside of the screw radially to the axis. The carriers of the reactivity of the proteins are the side-valently acting peptide groups characterized by their polar character and the terminal or side chain amino and carboxyl groups.

According to the invention, the reactivity of the collagen is reduced by blocking its reactive groups. In the clear case, irreversible solidifications of the molecular lattice between peptide groups of parallel-stored polypeptide chains can be achieved by incorporation of methylene bridges. After many studies, the finding is confirmed that z. B. aldehyde crosslinks of the collagen take place both with the amino groups of the side chains and with the peptide groups.

With the degree of blocking reactive groups in the collagen, it is now possible to get into areas of absorbability of collagen, which correspond to the absorption times of the particularly rapidly absorbable inorganic phosphate-containing moieties in the molding according to the invention. Thus, overall, the goal of the graded absorbability of the molded body is achieved. Almost comparable resorption times of the organic macrostructured and the inorganic microstructured portions cause dimensional stability during the entire exposure time of the ceramic-collagen combinations and thus a favorable course of osteogenesis. Optionally, it is also possible to replace part of the rapidly absorbable material according to the invention by pure and / or surface-modified tricalcium phosphate and / or hydroxyapatite. Thus, the concept of graduated absorbability is not broken. The addition of these substances can be carried out in the particle size of 63 to 1000 цt, with the particle size of 100 to 200pm is preferred.

The invention further relates to a process for the preparation of a graded resorbable, phosphate-containing molded body, which consists in homogeneously distributing the inventive glassy or glassy crystalline material with rapid solubility in a collagen. The preparation of the glassy or glassy crystalline material is carried out by mixing a mixture consisting of (in% by mass and calculated on an oxide basis);

20-55 CaO; 5-25 Na ₂ O; 0-15 K ₂ O; 0-15 MgO; 30-55 P ₂ O ₅ ; 0-15 SiO ₂ ; 0-40 Na ₂ SO ₄ and / or K ₂ SO ₄

melts for at least 10 minutes at a temperature of about 1200 to 1580T and the melt cools. Prefers

it is possible to use the preferred compositions already mentioned above.

As already explained above, cooling can take place with a very high cooling rate of at least 150,

better, however, 5 × 10 ^2o C per minute done while a glassy material can be obtained.

However, the main route to the production of rapidly soluble materials according to the invention is melting

subsequent spontaneous crystallization. Therefore, in the further all embodiments should preferably be aligned with this procedure. In this case, the melt is cooled at a rate of less than about 35 ° C per minute, wherein the spontaneous crystallization occurs. Advantageously, the spontaneously crystallized material is a conventional annealing process

subjected. This is done in the temperature range of about 600 to 1200 ⁰ C, depending on the chemical composition and the crystal phase to be generated, the crystalline portion - usually it is the crystalline

Main phase-still further increase. The relationship between chemical composition and crystal phase has already been generally described above. It come through the treatment according to the invention, the crystal phases of the rhenanite, the phase "A", mixed crystals of the phase "A", the phase "X", mixed crystals of the phase "X", glaserite and / or crystalline potassium sulfate

Appearance.

It is advantageous for the process according to the invention to use P ₂ Os in the form of phosphoric acid.

An advantageous material form is the granular form, so that the cooled and optionally tempered material is comminuted and classified by conventional methods.

When the content of Na ₂ SO ₂ and / or K ₂ SO _{4 is} about equal to or more than 3 mass% in the starting mixture, it is advantageous to add the granules to a treatment with distilled water over a period of 0.1 to 10 hours elevated temperature, preferably at about 80 to 100 ⁰ C suspend. As a result, an increase in the inner surface of the material is achieved, which is expressed in an increase in the solubility, and the sulfate content can, if it is not desired, reduced

become.

In order to compare the in vitro solubility of various materials according to the invention (as well as the tri- and trichlorethylene)

To be able to draw tetracalcium phosphate) were two different ways label, once the solubility in one

Differential circulating cell and on the other a quick method, which should be noted here:

The material to be investigated is comminuted, and the particle size chosen for the determination becomes 315-00,000

taken. The sample material is washed with ethanol and then dried at 110 ⁰ C. 10 samples of each 2 g of the test substance are weighed out on the analytical balance. Bidistilled water is heated to 37 ° C, and

200ml each in the beaker are mixed with the weighed about 2g. This sample remains in the incubator at 37 ^° C. for 24 h,

covered with a watch glass, stand. After this time, the samples are quantitatively transferred to pre-weighed fries.

Thereafter, the filters are dried at 110 ⁰ C with the sample substance. After cooling in the desiccator, the new weighing is carried out to determine the weight loss after:

(Weighing in mg-Weighing in mg) · 1000 / Weighed in mg = Result in mg Substance lost / g Weighing

Then the standard deviation is calculated.

The following values result from this method:

Material or Mateial Code *

mg loss of substance / g weight

Ca ₃ (PO ₄ I ₂

4CaO · P ₂ O ₅

Batch 1 3.1 ± 0.39 Batch 2 3.0 ± 0.63 Batch 3 2.9 ± 0.60 Batch 4 2.2 ± 0.16 Batch 1 1.8 ± 0.72 Batch 1 5.9 ± 0.27 Batch 2 6.6 ± 0.55 Batch 3 6.2 ± 0.28 5.7 ± 0.84 14.7 ± 0.77 Batch 1, untreated 93.6 ± 3.57 Batch 2, untreated 87.6 ± 1.22 Lot 1, treated 23.1 ± 1.23 untreated 36.6 ± 1.68 treated 3.8 ± 0.77 (glassy, quenched) 54.9 ± 7.12 9.8 ± 1.98 Lot 10, untreated 188.0 ± 0.99 (n = 5) Lot 10, untreated 244.9 + 0.5 (n = 6)

* Compositions see Table 1

According to the results of the rapid method for the determination of the solubility, it is apparent that a coarse division of the materials after the main crystal phases can be carried out: Rhenanite or mixed crystals of rhenanite approx. 3 ... 10 mg / g

Phase "A" or mixed crystals of phase "A" about 1 to 4 mg / g

Phase "X" or mixed crystals of phase "X" about 7 ... 15 mg / g.

Of course, with the addition of the sulphate components or after carrying out a corresponding treatment (leaching) of materials with high sulphate contents, this classification no longer has any validity, these values are then exceeded as desired.

It should be noted, however, in general that particularly materials containing the (new) phase "X" or mixed crystals of the phase "X" are particularly well suited for the production of the pure and the sulfonated mixed melts and products derived therefrom. This expresses u. a. in the good pourability of the melts, the homogeneity of the materials, the leaching ability in the presence of sulfates, etc. from.

In general, for the preparation of the graded resorbable materials of the invention, it can be stated that the solubility is in the period of about 15 days to about 20 months, can be extended by addition of TCP and / or hydroxyapatite (HAp) according to the proportion, and within the o.g. Period in the order of Crystal Phase "X" -> Rhenanite -> Crystal Phase "A" solubility decreases (see table above and conclusions therefrom). This means that a high proportion of crystal phase "X" ensures faster solubility than a high rhenanite content, with corresponding sulfate levels further increasing solubility and allowing TCP and / or HAp levels to lengthen it The invention furthermore relates to the process for producing nonwovens based on collagen from animal tendons, hollow organs and hides and their combination with the inorganic resorbable biocompatible material prepared according to the invention.

The essence of the nonwoven production process is, on the one hand, the unique macroscopic and microstructural structure of collagen with its exceptionally large internal surface area of 500m ² to 2000m ² per kg of collagen, the polar character of peptide formation, and the reactive amino and carboxyl groups in the side chains in To obtain the highest possible nativity, on the other hand by mechanical crushing of the compact collagenous material to the order of the microscopically visible individual fibers and their joining to fleece space for the inorganic, rapidly absorbable biocompatible materials to make difficult to itself absorbability of the collagen, that the Resorption times of the collagen correspond to those of the particularly rapidly resorbable, biocompatible material and finally by desantigenization intolerance symptoms, for example antibody formation in the human body after implantation to avoid. According to the invention the object is achieved in that after mechanical removal of non-collagenous components is first removed by mild alkali and acid treatment Interfibrillarsubstanz from the collagen of animal origin, followed by the desantigenization with oxygen-evolving substances, preferably hydrogen peroxide, connects. It has been experimentally demonstrated that the collagen treated in the manner described so far exhibits very high reactivity, which, among other things, besides the ability to quench bleeding, is also documented in the property which is extremely important for the intended use, the inorganic, rapidly absorbable, biocompatible material with surprisingly high strength adhesively bind. The disadvantage of the high degree of responsiveness of collagen is the relatively short absorption time of the nonwovens produced from pure collagen after their implantation in the human body. The osteogenic and shape-forming efficacy of the generally less absorbable inorganic biocompatible materials would be greatly reduced in this case due to the too quickly occurred structural and inertness of the implant granules. However, the chemist has the ability, by crosslinking the collagen with, for example, aldehydes, phenolic condensation products and / or other substances, to drastically prolong the absorption times of the nonwoven webs made from cross-linked collagen after implantation into the human body. However, experimentally confirmed the theoretically derivable prognosis, according to which in 100% networked! Collagen the ability for adhesive bonding of inorganic, rapidly absorbable, biocompatible material is greatly reduced. Fully crosslinked nonwoven collagen trickles out the inorganic, rapidly absorbable, biocompatible material almost quantitatively. Under the premise of the broad agreement of the absorption times of inorganic and organic constituents or the graded absorbability of the moldings according to the invention, it is now possible to create optimally effective combinations. Extremely rapidly absorbable, inorganic, biocompatible material is thus conveniently combined with non-cross-linked collagen fleeces, while slowly resorbable, inorganic, biocompatible material should be combined with webs of proportionately cross-linked collagen. The same applies if inorganic, biocompatible materials with graded absorbability are combined. The apparent disadvantage of reduced adhesive binding of more highly absorbable, inorganic, biocompatible material in a combination containing greater proportions of crosslinked collagen is offset by the crosslinked collagen taking over partial functions of the inorganic material.

The crosslinking of the collagen is conveniently still in its compact state. The desired degree of crosslinking can be achieved both by the fact that only the stoichiometrically necessary amount of crosslinking agent is offered to the collagen to be crosslinked, as well as that collagen crosslinks all binding possibilities until complete saturation and is combined in subsequent steps with uncrosslinked collagen in the desired ratio ,

Consequently, compact uncrosslinked or cross-linked collagen is to be comminuted into fiber suspensions, conveniently first coarsely to be coughed, then to be ground several times (up to five times) in colloid mills with the addition of water. The suspensions of crosslinked and uncrosslinked collagen are stirred into each other homogeneously in the desired ratio. It is possible to isolate individual types of collagen, their separate grinding under addition of water to fiber suspensions and their homogeneous mixing. In the suspensions prepared in the described manner, the granular, inorganic, rapidly absorbable, biocompatible material is distributed uniformly in the ratio of 10% by mass to 90% by mass, based on the total dry mass of the shaped bodies to be produced. Optionally, before mixing with the fiber suspension, the granulated, inorganic, rapidly absorbable, biocompatible material

sparingly soluble components consisting of pure and / or surface modified alpha tricalcium phosphate and / or hydroxyapatite. The ratio between the inorganic fast resorbable components and the inorganic long term stable components should generally be within the limits of 80 to 5 to 5 to 95. All of these preparations are to be transferred into precooled forms of physiologically harmless material, freeze-dried and double-welded in a known manner in polyethene film and sterilized.

Exemplary embodiments

The preceding embodiments, which show only the full scope of the invention are explained in more detail below by a few examples. First, the approaches mentioned in Table 1 were melted as rapidly absorbable materials and comminuted according to the following application tests. The crystalline phases were determined, the solubility tested by the described rapid method and in the differential cycle cell. Some of these results have already been presented in the preceding section.

In the following, examples will be given of some examinations with regard to the application. An overview of some of the tested material combinations is given in Table 2.

Example 1-19 (a to s)

Table 1 - List of composition examples:

Code- Oxide composition in% by mass MgO Na ₂ O K ₂ O P ₂ O ₅ SiO ₂ additions designation CaO 5.4 8.3 13.3 401 8.9 - a 24 5.52 13.70 6.94 41.48 7.38 - b 25.11 0 8.3 13.3 40.1 8.9 - с 31.5 5.4 8.3 13.3 40.1 8.9 10Na ₂ SO ₄ d 24 5.52 13.70 6.94 41.48 7.38 10Na ₂ SO ₄ e 25.11 6.04 9.27 14.12 34.05 9.05 - f 26.63 6.73 10.32 15.64 38.63 10.00 - G 18.68 4.64 11.27 17.48 40.85 - - H 25.76 4.64 11.27 17.48 40.85 - 8Na ₂ SO ₄ 25.76 - 13.7 6.94 41.48 7.38 - j 32.75 - 13.7 6.94 41.48 7.38 4Na ₂ SO ₄ к 32.75 5.52 8.84 13.54 40.54 7.21 - I 24.35 5.52 8.84 13.54 40.54 7.21 4K ₂ SO ₄ m 24.35 5.52 8.84 13.54 40.54 7.21 10K ₂ SO ₄ η 24.35 5.52 8.84 13.54 40.54 7.21 30 Na ₂ SO ₄ о 24.35 5.4 8.3 13.3 40.1 8.9 20 Na ₂ SO ₄ P 24.0 5.4 8.3 13.3 40.1 8.9 10Na ₂ SO _{4 and} 10K ₂ SO ₄ q 24 5.52 8.84 13.54 40.54 7.21 4.5 Na ₂ SO ₄ and 4.5 K ₂ SO ₄ г 24.35 4.64 11.27 17.48 40.85 _ 3Na ₂ SO ₄ and 18K ₂ SO ₄ S 25.76

Example 20-27 (I to V and VII to IX)

From a melt spontaneously crystallizing on cooling of the composition с a grain fraction of 200 to 500 was prepared. This material was mixed with a surface-modified tricalcium phosphate (TCP) of the same particle size and processed together with collagen into a nonwoven according to the information given above, the proportion of the components corresponding to the material combination I (see Table 2). The obtained fleece was implanted into artificially set bone defects of experimental animals (rats, rabbits and pigs). It was found after a period of 12 weeks, that in comparison to the implantation of pure TCP products, a higher degree of resorption and a higher bone perforation was done.

Table 2 section of the test program of the combination of materials according to the invention (proportion in%)

Code of Collagen or rapidly absorbable surfaces material collagens Materials (Together modified combination Substitution Code n. Tab. 1) tricalcium phosphate * I 20 10from с 70 Il 40 5 from с 55 III 40 50voncund Юѵопа - IV 20 20 of d 60 V 80 20 of d - VII 20 60vonaund20vonc - VIII 25 20 from a and 25 from с 30 IX 50 40vonound10vonr -

Material according to DD 258713 A3

Example 28

A nonwoven material corresponding to the material combination Il was implanted in artificially set bone defects of pigs. After a waiting period of 30 weeks hardly any TCP residues were detectable.

Example 29

Fleece according to the material combinations III, V and IX was implanted in the soft tissue of pigs and in places where previously organ parts were removed. It was found after 15 weeks that the fleece was completely resorbed in each case and in the case of filling the cavities through the fleece, these were filled with connective tissue.

Example 30

Fleece according to the material combinations IV and VII was implanted in artificially set bone defects in pigs. After a period of 30 weeks, the defects were largely filled with newly formed bones. Only with very large defects material residues could still be found in the case of the material combination IV.

Claims (46)

1. Resorbable phosphate-containing shaped body, characterized in that the shaped body contains 10 to 90 parts by weight in% collagen or collagen based on animal tendons, hollow organs and skins and 90 to 10 parts by weight in% of a glassy or glassy crystalline material with rapid solubility, prior to melting dating back to a mixture consisting of (in% by mass and calculated on an oxide basis) 20 to 55% CaO; 5 to 25% Na ₂ O; 0 to 15% K ₂ O; 0 to 15% MgO; 30 to 50% P ₂ O ₅ ; 0 to 15% SiO ₂ ; 0 to 40% Na ₂ SO ₄ and / or K ₂ SO ₄ 2. Shaped body according to claim 1, characterized in that the collagen is uncrosslinked and crosslinked type I collagen, II and / or III. 3. Shaped body according to claim 1 or 2, characterized in that the resorbable biocompatible material is a glassy or glass-crystalline material with rapid solubility, which results from the melting of a mixture with the following constituents (% by weight) CaO 21-50%, especially 23-50% Na ₂ O 5-20%, especially 6-20% K ₂ O 0.1-14%, especially 2-14% MgO 0.5-15%, in particular 0.5-10% P ₂ Os 32-48%, especially 35-48% SiO ₂ 0.1-15%, especially 2-15% Na ₂ SO ₄ 0.1-20%, in particular 0.1-12% and subsequent cooling. 4. Shaped body according to claim 3, characterized in that the mixture has the following composition 5. Shaped body according to one or more of claims 1 to 4, characterized in that the glass crystalline material as crystalline main constituents at least one of the phases from the group Rhenanit, mixed crystals of Rhenanits, phase "A", mixed crystals of the phase "A", phase " X "or mixed crystals of the phase" X "contains. 6. Shaped body according to one of claims 3 to 6, characterized in that the shaped body further contains pure alpha-tricalcium phosphate and / or hydroxyl apatite whose particle sizes are in the range of 63 to 800 micrometers. 7. Shaped body according to claim 1 or 2, characterized in that the resorbable biocompatible material is obtained by surface modification alpha tricalcium phosphate, the calcium release of the surface layer is higher than the calcium release of the body. 8. Shaped body according to claim 7, characterized in that it further contains pure alpha-tricalcium phosphate and / or hydroxyapatite. 9. Shaped body according to claim 2 to 5 and 7, characterized in that the resorbable biocompatible material is composed of the rapidly absorbable material and the obtained by surface modification of alpha-tricalcium phosphate. 10. Shaped body according to claim 9, characterized in that the resorbable biocompatible material is composed of the rapidly absorbable material, the obtained by surface modification alpha tricalcium phosphate and pure alpha tricalcium phosphate. 11. Shaped body according to claim 7, 9 or 10, characterized in that the material further contains hydroxylapatite. 12. Shaped body according to claim 8, 10 or 11, characterized in that the particle size of pure alpha-tricalcium phosphate or hydroxyapatite is in the range of 63 to 1000 micrometers. 13. Shaped body according to claim 3 to 5, 7 or 9, characterized in that the resorbable biocompatible material has a particle size in the range of 63 to 1000 micrometers. 14. Shaped body according to one or more of claims 1 to 13, characterized in that the resorbability in the range of 15 days to 52 weeks. 15. Shaped body according to claim 14, characterized in that the resorbability, starting from uncrosslinked collagen with increasing proportion of crosslinked collagen and / or rapidly absorbable material and / or surface-modified alpha-tricalcium phosphate and pure alpha-tricalcium phosphate and hydroxyapatite decreases in this order. 16. Shaped body according to claim 1 to 15, characterized in that it is present as a nonwoven or cut fleece or has a pillow or cuboid shape. 17. A process for the preparation of resorbable, phosphate-containing moldings based on the collagen of animal tendons, hollow organs and hardnesses, degreased in a conventional manner, chemically treated, optionally depilated, characterized in that the animal raw materials mechanically cleaned of unsuitable ingredients, then washed , subjected to an alkali treatment, then washed, subjected to an acid treatment with inorganic and / or organic acids and / or solutions of acidic salts, washed again, mixed with oxygen-evolving substances and finely comminuted mechanically with added water after repeated washing, the resulting protein fiber suspension optionally with Suspensions of crosslinked or uncrosslinked collagen of other types is mixed to homogeneity, obtained in the now present suspension by melting a batch and subsequent cooling of the melt glassy or glass-crystalline, biocompatible material with rapid solubility and / or a surface-modified alpha-tricalcium phosphate each of particle size to about 1000 microns are homogeneously distributed and transferred the preparations in precooled forms of physiologically acceptable material and freeze-dried. 18. The method according to claim 17, characterized in that the material with rapid solubility and / or the surface-modified alpha tricalcium phosphate additionally hydroxyapatite and / or pure alpha tricalcium phosphate are added. 19. The method according to claim 17 or 18, characterized in that the glassy or glass-crystalline material with rapid solubility is a material which results from the melting of a mixture with the following constituents (% by mass) CaO 21-50%, especially 23-50% Na ₂ O 5-20%, especially 6-20% K ₂ O 0.1-14%, especially 2-14% MgO 0.5-15%, in particular 0.5-10% P ₂ O ₅ 32-48%, especially 35-48% SiO ₂ 0.1-15%, especially 2-15% Na ₂ SO ₄ 0.1-20%, especially O, 1-12% and subsequent cooling. 20. The method according to claim 19, characterized in that the mixture has the following composition 21. The method according to one or more of claims 17 to 20, characterized in that the glass crystalline material as crystalline main components at least one of the phases: rhenanite, mixed crystals of rhenanite, phase "A", mixed crystals of the phase "A", phase "X" or mixed crystals of the phase "X" contains. 22. The method according to claim 17 to 21, characterized in that in the case of using animal skins, the scar membrane is removed by splitting with a band knife splitting machine in a thickness of 0.1 to 0.3 mm. 23. The method according to claim 17 to 21, characterized in that in the case of using animal skins, the subcutaneous tissue is completely removed by cleavage with a band knife splitting machine. 24. The method according to claim 17 to 23, characterized in that for the alkali treatment about 0.001 to about 5 N aqueous solutions selected from the group of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, ammonia, alkali metal borates are used, in particular alkali metal hydroxides, preferably sodium hydroxide. 25. The method according to claim 17 to 24, characterized in that the duration of the alkali treatment of two hours up to 12 days, preferably from 18 hours to 48 hours. 26. The method according to claim 17 to 25, characterized in that the temperature of the alkali treatment is at most 35 ° C, preferably 20 ⁰ C to 25 ° C. 27. The method according to claim 17 to 26, characterized in that after the alkali treatment with distilled water to the alkalinity of less than pH 8.5 is washed. 28. The method according to claim 17 to 27, characterized in that the proteins treated according to the invention are treated with physiologically acceptable acids, in particular hydrochloric acid of concentration 0.01 mol / l to 5 mol / l. 29. The method according to claim 17 to 28, characterized in that the acid treatment is carried out over 30 minutes to 48 hours, preferably 18 hours to 36 hours. 30. The method according to claim 17 to 29, characterized in that the temperature of the acid treatment is at most 35 ° C, preferably 10 ° C to 25 ° C. 31. The method according to claim 17 to 30, characterized in that is washed after the acid treatment with distilled water to the acidity of greater than pH 4.2. 32. The method according to claim 17 to 31, characterized in that the proteins treated according to the invention are treated with solutions of oxygen-evolving substances, preferably peroxides, in particular with solutions of hydrogen peroxides of the concentration of 0.5 mol / l to 10 mol / l. 33. The method according to claim 17 to 32, characterized in that the treatment time with oxygen-evolving substances is 10 minutes to 24 hours, preferably 30 minutes to two hours. 34. The method according to claim 17 to 33, characterized in that the temperature of the solutions of oxygen-evolving substances is at most 35 ° C, preferably 20 ⁰ C to 28 ° C. 35. The method of claim 17 to 34, characterized in that following the treatment with oxygen-evolving substances is washed with distilled water until free of peroxide. 36. The method of claim 17 to 35, characterized in that in the case of co-use of crosslinked collagen, a proportionate or full crosslinking with phenol condensation products and / or aliphatic mono- or polyfunctional aldehydes and / or aliphatic alkyl sulfates takes place. 37. Method according to claim 36, characterized in that the uncrosslinked or cross-linked proteins treated according to the invention are mechanically comminuted to protein fiber suspensions in stages with the addition of 100% to 8000%, preferably 1000% distilled water, based on the mass of the proteins. 38. The method of claim 17 to 37, characterized in that optionally protein fiber suspensions of different types of collagen in the desired ratio are uniformly stirred into each other. 39. The method of claim 17 to 38, characterized in that crosslinked and uncrosslinked protein fiber suspension in the desired ratio are uniformly stirred into each other. 40. The method of claim 17 to 39, characterized in that the cooling of the melt is carried out at a rate of less than about 25 K per minute. 41. A method according to claim 17 to 39, characterized in that the cooling of the melt takes place at a rate of at least about 100 K per minute. 42. The method of claim 17 to 41, characterized in that the biocompatible, rapidly absorbing material in the ratio of 10Ma .-% to 90Ma .-%, based on the total dry weight of the shaped articles to be produced is distributed homogeneously in the protein fiber suspension. 43. The method of claim 17 to 42, characterized in that the biocompatible, rapidly absorbable material with surface-modified, powdered alpha-tricalcium phosphate mixed in the ratio of 95 to 5 to 95 and in the ratio of 10 wt .-% to 90 Ma .-% is distributed homogeneously in the protein fiber suspension based on the total dry mass of the shaped body to be produced. 44. The method according to claim 17, characterized in that the preparations in to -10 to -35 ° C, preferably -25 to -30 ⁰ C, cooled negative molds of physiologically inert material, preferably stainless steel, are transferred. 45. The method according to claim 44, characterized in that the preparations at least 2 hours at -38 ⁰ C to -40 ⁰ C and then at least 30 hours at 25 ° C and a pressure of 5Pa to 100Pa, preferably 15Pa, freeze-dried. 46. The method according to claim 17, characterized in that the shaped bodies are radiation sterilized.