Modified bone replacement material

Abstract

The invention relates to a method for modifying a bone replacement material or a surface coating for an implant in order to form a product with osteotropic properties from a solid microporous starting material, having the steps of comminuting a modification material, which is made of a solid source for strontium, fluoride, magnesium, manganese, zinc, and / or gallium atoms, to an average diameter of maximally 1.0 mm or less and applying the comminuted modification material onto the starting material in order to produce an intermediate product; and thermally treating the intermediate product at a treatment temperature below the melting point of the modification material and of the bone replacement material or of the surface coating of the implant for a treatment time in a device for a thermal treatment in an open atmosphere so that moisture can escape in order to produce the product, wherein calcium atoms of the hydroxylapatite are replaced with atoms of the modification material. In the process, the modification material of the intermediate product has a maximum moisture content of 10%, and the treatment temperature and the treatment time lie in a range which has a lower boundary of at least 400 °C for the treatment temperature and at least 30 min for the treatment time and which is further defined by a treatment temperature of at least 1150 °C and a treatment time of at least 2 min. Lastly, a step is carried out of cleaning the product of unincorporated modification material using mechanical, chemical, or physical cleaning methods.

Description

[0001] Modified bone substitute material

[0002] The invention relates to a method for modifying a bone replacement material or a surface coating of an implant to a product with osteotropic properties from a solid, microporous starting material which essentially comprises hydroxyapatite (Ca5[OH|(PO4)3).

[0003] In the context of the invention, the starting materials mentioned may also be understood to mean materials which have a structure analogous to the starting materials but are synthetically produced.

[0004] Many currently used bone substitute materials made from natural bone, including autologous, allogeneic, and xenogeneic bone, coral, algae, and even fully synthetic hydroxyapatite bone substitutes, which are used as bone implants or as bone substitutes in bone augmentation, have only osteoconductive properties. This means that while existing calcium phosphate or hydroxyapatite bone substitute materials provide a suitable biocompatible surface for the direct growth of bone tissue on the implant surface, they do not directly stimulate new bone formation in the immediate bone environment of the implant.

[0005] Hydroxyapatite or calcium phosphate materials are fundamentally only osteoconductive. They therefore permit bone growth and serve as a guiding structure, but do not themselves stimulate the proliferation or differentiation of bone-forming cells, such as osteoblasts or their precursors. Direct growth, within the meaning of the invention, can be understood in particular as growth without an "intermediate tissue layer" between the implant surface and the bone tissue. To exert an osteoinductive effect, bone substitute materials or organic substances, such as collagens, are currently supplemented with additional proteins, peptides, or other molecules. Examples of these are growth factors such as various BMPs, IGF1 / 2, FGF, or similar, or even serum products. The problem here is that these substances often remain in the implant or at the implant site for unclear periods of time, as they are usually quickly washed away from the implant bed or degraded.As a result, the osteoinductive properties are only present for a short time and cannot really be dosed, and systemic effects throughout the organism are also possible, which are generally not desired.

[0006] Natural bone contains trace elements of certain ions in the crystalline structure of calcium phosphate, which ultimately constitute the inorganic composition of bone hard tissue. These incorporated ions, such as strontium (Sr), magnesium (Mg), manganese (Mn), or zinc (Zn), individually or in combination, are known to play a fundamental role in bone development. Strontium is present in significant amounts in natural bone, particularly in regions of increased metabolic turnover. Its presence is associated with an increase in osteoclast apoptosis and the enhancement of osteoblastic cell proliferation and collagen synthesis, which subsequently maintain bone formation and inhibit bone resorption.

[0007] Strontium has been proven to possess osteotropic and osteoinductive properties. Therefore, increasing the proportion of strontium, a natural trace element in a bone substitute material or implant surface to stimulate bone-forming cells, is of great interest. Such an increase in the proportion of strontium imparts the desired osteotropic and osteoinductive properties to a bone substitute material or implant surface.

[0008] This also applies to the elements zinc, magnesium, manganese, gallium, and fluorine, whose bone growth-stimulating properties are also described in the literature. Two processes exist for the production of such strontium-enriched bone substitute materials. First, EP 3 777 904 A1 describes the production of a bone substitute material from calcareous algae or mammalian bones as the starting material, and US 10,688,218 B2 describes the production of a bone substitute material from wood as the starting material. Both processes are based on a known, highly energy-intensive hydrothermal process, which was first described in US 3,929,971 and EP 230 570 B1.The further development of the teachings of the processes of the first-mentioned documents EP 3 777 904 A1 and US 10,688,218 B2 consists in the additional incorporation of strontium ions into the crystal lattice by a modification of the original process from the documents US 3,929,971 and EP 230 570 B1.

[0009] All of the above-mentioned processes describe a technically and energetically very complex hydrothermal process. In this process, the starting material, after the addition of chemical additives and sometimes highly toxic solutions, is exposed to temperatures of up to approximately 230°C and the resulting pressure for an extended period of time in a closed container. This can take several hours, or even days, depending on the applied temperature. Under these conditions, the desired ion exchange of calcium ions with strontium ions is achieved within the crystal lattice of the starting material. In this process, the strontium ions are absorbed into the starting material rather homogenously, but in very small quantities. Therefore, only a small amount of strontium is available at the surface of the starting material treated in this way to stimulate the bone cells.This is therefore only a case of the occasional exchange of calcium ions by strontium ions, but there can be no talk of the conversion of a hydroxyapatite into a strontium apatite.

[0010] Nevertheless, a bone substitute material produced in this way exerts a local osteotropic and osteoinductive effect, which primarily and essentially only occurs in the implant site. Thus, such a bone substitute material has a local, but not a systemic, effect. A further advantage is that such a bone substitute material exerts its osteoinductive or osteotropic effects throughout its entire stay in the implant site and only ceases once it is replaced by native bone tissue. Thus, even a slight increase in the strontium content can achieve faster and more sustainable bone healing of a bone defect.The invention is therefore based on the object of providing a method for modifying a bone replacement material or a surface coating of an implant to a product with osteotropic properties, as well as an osteotropic bone replacement material or an osteotropic surface coating which has long-acting, locally limited osteotropic and osteoinductive properties.

[0011] This object is achieved according to the invention by a method for modifying a bone replacement material or a surface coating of an implant having the features of claim 1 and an osteotropic bone replacement material or an osteotropic surface coating having the features of claim 11.

[0012] Advantageous embodiments of the invention are specified in the subclaims.

[0013] According to the invention, a bone substitute material or a surface coating of an implant is modified into a product with osteotropic properties. The product is to be made of a solid, microporous starting material, which essentially comprises hydroxyapatite (Ca5[OH|(PO4)3).

[0014] The starting material of the invention consists of small, porous solids in the form of approximately 0.2 to 2.0 mm granules or larger molded bodies, which are synthetically produced or of natural origin. They are already present in a macroscopically visible crystalline form, and this macroscopic form is not altered by the application of the process.

[0015] Their properties provide volume and act as a kind of "grid" or "guiding structure" for bone growth, and they should therefore retain their shape even in clinical use. This material should not be confused with the bone cements often described in the literature. These are used to secure orthopedic prostheses such as hip or femoral neck prostheses, and are then injected into fractured vertebrae to stabilize them. Bone cements are made from finely ground powders that are mixed with solutions immediately before application to the patient. They are then incorporated into the prosthesis in a low or high viscosity (liquid or pasty). In a chemical exothermic reaction with heat generation, these powders set and harden, forming extremely fine crystalline structures.

[0016] Such bone cements are used to fill gaps or inaccuracies between the bone and the prosthesis, such as a titanium hip prosthesis. This ensures a stable fit of the prosthesis within the bone thanks to the precise fit achieved. Furthermore, they can fill cavities in osteoporotic fractured vertebrae, thus preventing further fractures by restabilizing the vertebral body.

[0017] This type of stabilization cannot be achieved with bone substitute material, as bone must first form around the material. The material itself therefore does not provide stability like bone cement can. Bone substitute material, as described and used here, consists of small solid bodies whose porous and interconnecting structures are used to enable growth on and ingrowth between the granular solid bodies. The bone substitute material is ultimately fully incorporated into the newly formed bone and, if necessary, resorbed over the years as part of the natural bone remodeling processes and replaced by real bone. Its crystalline microstructure and macroscopic shape already exist before use and should be retained as far as possible after use. Unlike bone cements, no new crystals form through a chemical reaction involving the generation of heat during application to the patient.

[0018] In summary, bone cements are powders that, at the time of application, are mixed into a liquid or pasty mass by adding solutions. They set and harden through a chemical reaction with heat generation and the formation of tiny crystalline structures. They compensate for inequalities in the fit between two material boundaries or serve as immediately load-bearing supports for vertebral fractures. In-growth of new bone is virtually impossible. In contrast, bone substitute materials are already available in crystalline form as granules. They do not react chemically upon application and have no stabilizing function, but merely a volume-enhancing and conductive function in new bone formation.

[0019] According to the method according to the invention, a modifying material from a solid source of strontium, fluorine, magnesium, manganese, zinc and / or gallium atoms is ground to an average diameter of no more than 1.0 mm or smaller, and the comminuted modifying material is applied to the starting material to produce an intermediate product. The intermediate product is then thermally treated at a treatment temperature below the melting point of the modifying material and the bone replacement material or the surface coating of the implant for a treatment time in a thermal treatment facility in an open atmosphere so that moisture can escape, in order to produce the product, whereby calcium atoms of the hydroxyapatite are partially replaced by atoms of the modifying material.The modification material of the intermediate product has a maximum moisture content of 10%, and the treatment temperature and treatment time lie within a range whose lower limit is at least 400°C treatment temperature and at least 30 minutes treatment time. The range is further defined by the combinations of at least 500°C treatment temperature and at least 10 minutes treatment time, at least 600°C treatment temperature and at least 7 minutes treatment time, at least 700°C treatment temperature and at least 5 minutes treatment time, at least 900°C treatment temperature and at least 3 minutes treatment time, and at least 1150°C treatment temperature and at least 2 minutes treatment time. Finally, the product is cleaned of any unincorporated modification material using mechanical, chemical, or physical cleaning processes.

[0020] With the method according to the invention, it has been possible for the first time to incorporate strontium, fluorine, magnesium, manganese, zinc, and / or gallium ions into the surface of the apatite facing bone growth, in particular the hydroxyapatite, rather than merely depositing them or distributing them in low concentrations throughout the solid. Thus, they are available in increased concentrations directly on the surface of the bone replacement material, especially during the important initial phase of bone growth during the first days and weeks. With purely superficial deposition, as described, for example, in JP 2021029750, which describes crystal growth of strontium apatite on a surface, detachment of the deposited substances could occur. With uniform distribution throughout the solid, as in the known hydrothermal process of EP 3 777 904 A1, the distribution of the ions is homogeneous and the concentration at the surface is very low.However, the method according to the invention makes it possible to bind the above-mentioned ions, which have osteotropic, i.e., osteoinductive, antiresorptive, and / or bone tissue-promoting properties, to the resulting apatite structure in such a way that they cannot be easily dissolved out. This is the case with the described method because the chemical composition of the apatite surfaces, particularly the hydroxyapatite, that have come into contact with the strontium, fluorine, magnesium, manganese, zinc, and / or gallium sources is selectively altered.

[0021] For example, in the process according to the invention, when using strontium fluoride as a strontium source, superficial "islands" and "band-like areas" of strontium phosphate are formed in the contact area on the surface of a hydroxyapatite after heat treatment according to the described process. These "islands" represent areas in which a conversion of calcium phosphate to strontium phosphate has occurred through ion exchange. In these clearly demarcated areas, hydroxyapatite has been converted into the bioactive strontium apatite through the application of energy.

[0022] The treatment time and the treatment temperature are interrelated. This means that a lower treatment temperature can be selected for a long treatment time than for a short treatment time. According to the invention, this physico-chemical relationship between time and energy input is clarified by specifying the treatment time and treatment temperature according to the invention using a range defined by its limits. The lowest described combination is 400°C treatment temperature and at least 30 minutes treatment time. If the treatment temperature is increased, the treatment time can be reduced. This means that the invention cannot be successfully implemented with a treatment temperature of 400°C and a treatment time of only 20 minutes.Further points for defining the possible combinations are at least 500°C treatment temperature and at least 10 minutes treatment time, at least 600°C treatment temperature and at least 7 minutes treatment time, at least 700°C treatment temperature and at least 5 minutes treatment time, at least 900°C treatment temperature and at least 3 minutes treatment time, and at least 1150°C treatment temperature and at least 2 minutes treatment time. This is further explained in the figure description for Figure 45. Below 400°C, no or almost no reaction takes place. Above 1150°C, depending on the selected modification material, it either melts or sinters.

[0023] In principle, the comminuted modifying material can be applied to the starting material in any way. However, it has been recognized that various methods yield particularly good results. For example, the comminuted modifying material can be at least partially dissolved in a liquid, preferably water, and applied to the starting material, with subsequent drying to remove the liquid. The liquid thus serves as a carrier medium for the modifying material. After drying, the modifying material remains on the starting material.

[0024] Another possibility is to add small amounts of a liquid to the crushed modifying material to create a slurry-like consistency, and then apply this slurry to the starting material. Here, too, the liquid is used as a carrier medium, and by creating a slurry-like consistency, a sufficiently good application to the starting material is achieved.

[0025] If a liquid is used to apply the modifying material to the starting material, it may be helpful to remove excess ground modifying material using physical steps before thermally treating the intermediate. This has been shown to produce better results in the final product.

[0026] However, it is not absolutely necessary to use a liquid to apply the modifying material to the starting material. It is also possible to apply the comminuted modifying material to the starting material by embedding the starting material in the comminuted modifying material and thus thermally treating it. Alternatively, dry, comminuted modifying material can also be applied to the starting material.

[0027] Preferably, the respective substances themselves or chemical compounds, preferably their salts, containing these atoms are used as sources for strontium, fluorine, magnesium, manganese, zinc, and / or gallium atoms, in particular selected from: strontium fluoride, magnesium fluoride, zinc fluoride, manganese, and gallium oxide. This allows for good incorporation or exchange of the atoms with the atoms of the starting material.

[0028] It is also advantageous to select compounds as the strontium, fluorine, magnesium, manganese, zinc, and / or gallium source that are non-toxic for processing, have sufficient solubility in a non-toxic solution, or can be in fine powder form, have melting points that are as low as possible and ideally below the melting point of the starting material, and whose residual products and residues after the annealing process are also non-toxic and can be easily removed by mechanical, physical, or chemical cleaning methods. In the case of strontium, a strontium salt, namely strontium fluoride, has proven effective. In experiments, strontium fluoride was moderately soluble in distilled water. This could be improved by applying heat up to the boiling point of the distilled water.

[0029] In principle, the thermal treatment of the intermediate product can be carried out in any desired manner. Heating and / or cooling intervals can be provided to achieve the desired treatment temperature or room temperature.

[0030] It is preferable if the heating and / or cooling temperature change is a maximum of 10°C per minute, preferably less than 5°C per minute. Such temperature changes have been shown to have the least impact on the durability of the final product. A cooling interval of one hour at room temperature has also been shown to be gentle on the material.

[0031] This gentle process prevents embrittlement or the transition to a glassy phase of the materials. Lower temperatures are associated with longer annealing times and a lesser effect on the desired surface change, but this also allows for good control over the composition of the new material.

[0032] In general, prolonged heating of the material to be modified at relatively low temperatures is preferred in order to modify the starting material gently. According to the invention, it has been found that heating to 900°C for 30 minutes already produces excellent results, so even longer heating or higher temperatures do not necessarily lead to significantly better results.

[0033] When using hydroxyapatite in the form of bone substitute material from bovine bone or from algae as starting material and strontium fluoride as strontium source, temperatures of 400°C to 1150°C and an annealing time of at least 2 minutes to a maximum of 300 minutes have proven to achieve the desired result, namely a conversion of hydroxyapatite (calcium phosphate) into the desired strontium apatite (strontium phosphate) in the direct contact area with the ion source strontium fluoride, without causing damage to the starting material.

[0034] However, it is also possible to introduce the intermediate product directly into a treatment facility which essentially has the treatment temperature.

[0035] According to the investigations on which the invention is based, particularly good results could be achieved when the treatment temperature was below the melting point of the starting material and the ion source.

[0036] Apatite, in particular hydroxyapatite, calcium phosphate, tricalcium orthophosphate or tricalcium phosphate, calcium hydroxide, calcium oxide, aragonite, calcite in the form of fired, unfired and / or chemically processed biological skeletons or vertebrate or mammalian bones after or before pyrolytic or chemical maceration can be used as bone substitute material.

[0037] Aragonite or calcite, e.g., from calcareous algae, can be used in fired, unfired, and / or chemically treated form. When using vertebrate or mammalian bones, they are advantageously subjected to pyrolytic or chemical maceration beforehand, i.e., the removal of immunogenic material.

[0038] It is preferable if the starting material, in the case of organic origin, has already been subjected to a pyrolytic treatment and / or chemical purification prior to the treatment according to the invention, thus removing organic components. This does not apply to synthetically produced materials.

[0039] The invention further relates to an osteotropic bone replacement material or an osteotropic surface coating of an implant produced by the method according to the invention. Calcium atoms of the hydroxyapatite are partially replaced by strontium, fluorine, magnesium, manganese, zinc, and / or gallium atoms.

[0040] The osteotropic and osteoinductive surface of such a bone substitute material or implant, which essentially comprises apatite, exhibits, on the surface facing bone growth, island-like or band-like, sharply defined areas of crystal transformation of the hydroxyapatite into specific crystals of the corresponding ions of the strontium, fluorine, magnesium, manganese, zinc, and / or gallium source. These areas develop osteotropic and osteoinductive properties after implantation into an animal or human body. In addition to apatite, especially hydroxyapatite, small amounts of calcium phosphate, especially tricalcium phosphate, and calcium carbonate, especially calcite or aragonite, may also be present.

[0041] The osteotropic and osteoinductive bone substitute material produced according to the method according to the invention can be used, for example, to produce dimensionally stable blocks. Since the resulting osteotropic bone substitute material has a granular to powder-like form, the dimensionally stable blocks produced from it can be custom-made and thus adapted to bone defects. Surfaces of implants, whether metallic or ceramic, can also be subjected to a surface refinement in this way, provided they contain apatite, preferably hydroxyapatite or calcium phosphate, so that the formation of a bioactive, osteotropic, and osteoinductive surface promotes faster and more likely bone healing, i.e., osseointegration, of the respective implant in the bone.For example, hydroxyapatite-coated dental implants made of titanium or even dental implants made of all-ceramic could be subjected to such a heat treatment for the incorporation of bone cell-stimulating strontium, fluorine, magnesium, manganese, zinc and / or gallium ions for better healing in the jawbone.

[0042] Through the inventive surface modification of a starting material, whether in the form of bone substitute material or in the form of surfaces on implants, this material develops a local osteotropic and osteoinductive effect, which occurs primarily and essentially only in or at the implant site. Thus, the inventive bone substitute material has no systemic effect. A further advantage is that the inventive surface modification of a starting material, whether in the form of bone substitute material or in the form of surfaces on implants, develops its osteotropic and osteoinductive effects over the entire time it remains in the implant site and only ends once it is replaced by native bone tissue. This results in faster and more sustainable bone healing of a bone defect or the healing of an implant in the bone.

[0043] Another application example for the osteotropic bone substitute material according to the invention could be the acceleration of healing of osteoporotic, traumatic, and / or malignant vertebral fractures or compression fractures after their stabilization by stimulating bone regeneration. Another possibility would be to use the material produced according to the invention as a starting material for 3D printing processes.

[0044] In the following, the implementation of the method according to the invention is described by way of example and, finally, the corresponding analysis results are explained.

[0045] Reference is also made to the figures, which show:

[0046] Fig. 1 shows a secondary electron image of a first embodiment of the method according to the invention; Fig. 2 shows material contrasts of the first embodiment of the method according to the invention;

[0047] Figures 3 to 8 show element distribution maps of the first embodiment of the method according to the invention;

[0048] Figures 9 and 10 show single point and small area analyses of the first embodiment of the method according to the invention;

[0049] Fig. 11 is a secondary electron image of a second embodiment of the method according to the invention;

[0050] Fig. 12 Material contrasts of the second embodiment of the method according to the invention;

[0051] Figures 13 to 18 show element distribution maps of the second embodiment of the method according to the invention;

[0052] Figures 19 and 20 show single point and small area analyses of the second embodiment of the method according to the invention;

[0053] Fig. 21 is a secondary electron image of a third embodiment of the method according to the invention;

[0054] Fig. 22 Material contrasts of the third embodiment of the method according to the invention;

[0055] Figures 23 to 30 show element distribution maps of the third embodiment of the method according to the invention;

[0056] Figures 31 and 32 show single point and small area analyses of the third embodiment of the method according to the invention;

[0057] Fig. 33 is a secondary electron image of a fourth embodiment of the method according to the invention;

[0058] Fig. 34 shows material contrasts of the fourth embodiment of the method according to the invention; Figures 35 to 42 show element distribution maps of the fourth embodiment of the method according to the invention;

[0059] Figures 43 and 44 show single point and small area analyses of the fourth embodiment of the method according to the invention; and

[0060] Fig. 45 is a diagram illustrating the report of treatment temperature and time.

[0061] For this purpose, strontium fluoride was dissolved in distilled water, with the dissolving behavior being improved by applying heat up to the boiling point of the distilled water. Subsequently, a starting material made of hydroxyapatite in the form of granules of the bone substitute material BioOss from Geistlich and Algipore from Dentsply Sirona was introduced into the strontium fluoride solution.

[0062] Good wetting with the strontium source was achieved by stirring and heating. Excess water was removed by pouring it off over a sieve. The treated starting material was then dried by evaporation by placing it in a heating oven at 180°C until sufficiently dry.

[0063] The coarsest excess of the strontium source was removed by simple sieving. The dried material, freed of coarse excess of the strontium source, was then subjected to a thermal treatment, which can also be described as an annealing process. After cooling, the material was washed and sieved in distilled water to remove coarse and loose excess and residues of the strontium source.

[0064] During the annealing process, a high-temperature dental furnace with a firing chamber of approximately 15 x 10 x 17 cm and a heating module for programming heating intervals and holding stages as well as temperature control was used.

[0065] The pretreated and dried material was placed in a refractory ceramic dish in the combustion chamber, the air-permeable combustion chamber was closed, and the annealing program was started. The final products analyzed below were produced at holding temperatures of 900°C for 30 minutes or 60 minutes without a heating interval and without a defined cooling interval, simply cooling to room temperature. At these temperatures and annealing times, a sufficiently good conversion of the starting material was achieved. Additionally, as previously described, the aforementioned ions were incorporated and bonded to the apatite crystal lattice. Material analyses showed that the hydroxyapatite (calcium phosphate) of the starting material was converted to strontium apatite (strontium phosphate) on the surface at precisely those points where contact with the strontium fluoride had existed.The lower the oven temperature, the slower and less noticeable this phenomenon became. This fact could be used to control the composition of the desired final product.

[0066] For analysis, the samples prepared as described above were embedded in epoxy resin. Since the samples were intended for analysis using a scanning electron microscope, these non-conductive specimens were first made conductive with a thin layer of carbon.

[0067] The samples were placed in a scanning electron microscope (LEO 440) with a tungsten cathode. Images were acquired at an excitation voltage of 20 kV and various beam currents. The SE images (secondary electron images) shown represent topographic contrasts.

[0068] The BSE (back-scattered electron) images shown in the figures reveal material contrasts. The brighter a pixel in the BSE image, the higher the average atomic number of the material found at that location.

[0069] For example, in the samples presented here, one spot is significantly brighter where the Ca present in the apatite has been substituted by Sr in significant quantities.

[0070] The chemical analysis in the SEM was performed using an X-Max 150 detector. This is an energy-dispersive detector capable of simultaneously detecting the analyzable elements.

[0071] To characterize the samples, elemental distribution maps were first created for each location. These maps mapped out an area of ​​interest at a resolution of 1024 x 768 pixels. Based on these elemental distribution maps, individual analyses were then performed at specific points. This resulted in spectra with excellent statistics, allowing for the generation of chemical analysis with meaningful data.

[0072] The element distribution maps shown in the figures were selected selectively. Although other elements were also included, these turned out to be irrelevant to the research question under consideration here.

[0073] Sample bone material 0.5h / 900°C

[0074] The analyses shown in Figures 1-10 refer to bovine conch treated according to the inventive method for 0.5 h at 900°C. Figure 1 shows a secondary electron image. It can be seen that the polished sample has almost no relief. The majority of the sample is made up of the bone material used here, which appears in medium gray tones. The dark areas originate from the areas where the epoxy resin is located. The light gray grains are enclosed in this epoxy resin and are located close to the bone material.

[0075] Fig. 2 shows material contrasts. Within the bone material, clearly demarcated areas can be seen in the grayscale, showing slight differences. This is likely due to slight differences in the apatite's chemical composition or density at these locations.

[0076] The grains are so bright in the BSE image because they contain large amounts of the heavy element Sr. Some bright spots can also be seen in the upper part of the image, which come from grains containing Sr.

[0077] However, upon closer inspection, one can also see various bright spots within the bone material. This occurs primarily where the SrF2 grains are located close to the bone material. However, there are also bright spots where no SrF2 is visible. One might assume that SrF2 was present here at some point (before preparation).

[0078] The following explains the element distribution maps shown in Figures 3 to 8. In the images for the elements P (Figure 3) and Ca (Figure 4), the bone material is first visible. The concentrations of the elements appear to vary locally here—as already explained in the discussion of the BSE image. It appears that both elements exhibit higher and lower concentrations at the same locations. It is assumed that the bone material may exhibit variations in density at these locations.

[0079] However, another fact is striking. If you look at the areas in the element distribution map where the BSE image was brightened in the bone material, the P image suggests that there is less phosphorus there. As you continue, you'll see that this is only partially true. At the same time, you can see in the Ca image that the Ca is practically no longer visible in these areas. So, something has happened here.

[0080] The positions of the SrF2 grains can be seen in the images for Sr (Fig. 5) and F (Fig. 6). If one simultaneously examines the elemental distribution for oxygen (O) (Fig. 7) at these locations, one can see that in the center of the image, some of the grains exhibit a slight rim of increased oxygen concentrations. This is more pronounced in the upper middle section of the image. There, one can hardly see any F, but all the more O. Since the Sr was introduced in the form of SrF2 at the beginning of the experiment, it can be assumed that oxidation of the material occurred during the experiment. Fig. 8 shows an elemental distribution map for carbon (C).

[0081] Furthermore, it can be observed that significant concentrations of Sr are present in the bone material at locations where the Ca and P values ​​are lower. These are primarily the locations that – as already mentioned – are located spatially close to the SrF2 grains or their oxygen-rich transformation products. These locations, in particular, need to be documented and further characterized with subsequent single-point analyses.

[0082] Single point analyses

[0083] With the help of single-point and small-area analyses, as shown in Figures 9 and 10, the findings resulting from the element distribution maps were now substantiated in more detail.

[0084] For this sample, points 1 to 4 (small area analyses) show that these are "normal" apatites with Ca and P. In addition, there are significant amounts of F and some CI. The Sr content is within the detection limit. This also applies to analysis point 5, which represents the beginning of a small profile up to point 9. The Sr content increases significantly, while the Ca value also decreases. At the last point of the profile (point 9), 71 wt.% SrO is found. Considering the atomic ratios, it appears that the P content remains roughly constant. Likewise, the sum of Ca and Sr remains roughly the same. This could mean that even in the Sr-rich areas, there is a phase that is stoichiometrically equivalent to apatite, but in which the Ca is successively replaced by Sr.

[0085] Another profile (points 10 to 15) shows identical behavior.

[0086] Analysis 17 shows a nearly ideal grain of SrF2, while analysis 16 already suggests some oxidation of SrF2.

[0087] Analysis points 18 to 23 show SrF2 grains that are transformed to varying degrees. It is not possible to determine what these are. Analysis points 20 and 21, for example, show significantly more oxygen than the known divalent cations Ca and Sr should normally contain.

[0088] Sample bone material 1.0h / 900°C

[0089] The analyses shown in Figures 11-20 refer to beef shanks treated according to the inventive method for 1 h at 900°C. The figures show the analyses analogous to those described above.

[0090] In the sample processed for 1 hour, the conditions are not much different from the sample treated for only half an hour. However, fewer remaining SrF2 grains were found. Where reactions involving Sr incorporation occurred, these grains appear to penetrate somewhat further.

[0091] The area of ​​the sample shown in the figures does not contain any relict SrF2.

[0092] However, the elemental distribution map of Sr clearly shows that significant amounts of SrF2 must have been present. However, they appear not to have survived the experiment, leaving only massive concentrations of Sr in the apatite.

[0093] The three single point profiles (from 1 to 6, from 7 to 11 and from 12 to 16) each clearly show the increase in the concentration of Sr towards the edge.

[0094] The C content in these profiles also appears to increase slightly toward the edge. This behavior was already indicated in previous sections, but is most clearly noticeable here.

[0095] Sample algae material 0.5h / 900°C

[0096] The analyses shown in Figures 21-32 refer to algal material treated by the process according to the invention for 0.5h / 900°C.

[0097] Fig. 21 shows a secondary electron image, and Fig. 22 again shows material contrasts. Fig. 23 shows an element distribution map for P, Fig. 24 shows an element distribution map for Ca, Fig. 25 shows an element distribution map for Mg, Fig. 26 shows an element distribution map for Na, Fig. 27 shows an element distribution map for Sr, Fig. 28 shows an element distribution map for F, Fig. 29 shows an element distribution map for O, and Fig. 30 shows an element distribution map for C. Figures 31 and 32 again show single-point and small-area analyses.

[0098] The algal material in this sample consists of a Ca phosphate.

[0099] While the BSE image only reveals hints of chemical inhomogeneities, the element distribution maps are much more informative.

[0100] Firstly, it is evident that there are local enrichments of Mg in the Ca phosphate. The Mg was likely incorporated as a substitute for Ca. It is also striking that the Mg also partially enriches at the edges of the grains. This indicates a significant mobilization of Mg during the heating process. It is quite possible that this mobilization is only achieved when the melting point of the material is approached. However, no definitive conclusion can be drawn here. Similar conclusions can be made for Na, which also has its highest concentrations at the edge of the algal material.

[0101] The element distribution map also clearly shows the enrichment of Sr at the edge of the algal material. Four profiles (1 to 5, 8 to 11, 12 to 15, and 16 to 20) were analyzed. All of these profiles show a significant increase in Sr at the expense of Ca.

[0102] The element chlorine plays no role in this algal material. Fluorine, however, is prominently represented.

[0103] Sample: Algae material 1.0h / 900°C

[0104] Finally, the algal material shown in Figures 33-44 relates to the algal material treated according to the method of the invention for 1 h at 900°C. The figures show the analyses analogous to those described above.

[0105] Here again, the same phenomena can be seen as mentioned above in the sample with a treatment duration of 0.5 hour.

[0106] The profiles (points 1 to 4, 6 to 8 and 19 to 23) each show the increase in Sr concentrations.

[0107] For profiles 19 to 23, small areas were analyzed instead of points, thus representing an integral analysis of the area. Here, too, the increase in Sr is evident.

[0108] In both SrF2 grains shown in the image, it can be seen that the Sr penetrates to a depth of about 50 pm into the porous algal material. This is significantly deeper than in the compact bone material.

[0109] In summary, it can be stated that in the present samples the incorporation of Sr into the bone material and into the algal material occurred to a very pronounced extent under the present experimental conditions.

[0110] It can be seen that the Sr sometimes penetrates quite deeply into the material, displacing the Ca from the lattice. The stoichiometric calculation of the atomic fractions suggests that a simple exchange of the two elements occurs here.

[0111] The formation of oxygen-rich rims around the SrF2 grains is clearly evident. This extends to the complete displacement of SrF2. Whether this effect represents an intermediate step in the displacement of Ca from the apatite lattice cannot be determined.

[0112] Figure 45 shows a diagram illustrating the temperature and treatment time range according to the invention. According to the invention, the thermal treatment takes place under specific conditions. These are defined by a range determined by the treatment temperature and treatment time, as illustrated in Figure 45. The maximum temperature is determined by the melting point of the products used. Thus, the temperature and treatment time range in which the reaction according to the invention proceeds successfully is located above and to the right of the curve shown in the figure.

[0113] According to the invention, the inventive method can be carried out when the combination of treatment temperature and treatment time lies within the range whose lower limit is defined by the points 1150°C / 2 min, 900°C / 3 min, 700°C / 5 min, 600°C / 7 min, 500°C / 10 min, and 400°C / 30 min. In other words, the invention can be carried out at, for example, 500°C and 20 min, but at least not with the exceptionally good results as with 550°C and 30 min treatment. In contrast, the invention cannot be successfully carried out at 400°C and 20 min.

Claims

Claims 1. A method for modifying a bone substitute material or a surface coating of an implant into a product with osteotropic properties from a solid, microporous starting material which essentially comprises hydroxyapatite (Ca5[OH|(PO4)3] and is macroscopically visible in crystalline form, comprising the steps to be carried out in the following order: • Crushing a modification material from a solid source of strontium, fluorine, magnesium, manganese, zinc and / or gallium atoms to an average diameter of maximum 1.0 mm or smaller, • Applying the crushed modifying material to the starting material to produce an intermediate product, • thermally treating the intermediate product at a treatment temperature below the melting point of the modifying material and the bone replacement material or the surface coating of the implant for a treatment time in a thermal treatment facility in an open atmosphere so that moisture can escape, to produce the product, wherein calcium atoms of the hydroxyapatite are partially replaced by atoms of the modifying material, o wherein the modifying material of the intermediate product has a maximum moisture content of 10% and o wherein the treatment temperature and the treatment time are in a range whose lower limit is at least 400 °C treatment temperature and at least 30 min treatment time and wherein the range is further limited by the combinations of at least 500 °C treatment temperature and at least 10 min treatment time, at least 600 °C treatment temperature and at least 7 min treatment time,at least 700°C treatment temperature and at least 5 min treatment time, at least 900°C treatment temperature and, at least 3 min treatment time and at least 1150°C treatment temperature and at least 2 min treatment time is defined, • Cleaning the product of non-incorporated modification material by mechanical, chemical or physical cleaning processes.

2. Method according to claim 1, characterized in that for applying the comminuted modifying material to the starting material, the comminuted modifying material is at least partially dissolved in a liquid, preferably water, and is applied to the starting material, wherein subsequent drying is carried out to remove the liquid.

3. A method according to claim 1, characterized in that for applying the comminuted modifying material to the starting material, the comminuted modifying material is mixed with small amounts of a liquid in order to produce a sludge-like consistency and this sludge is applied to the starting material.

4. Process according to one of claims 1 to 3, characterized in that prior to the thermal treatment of the intermediate product, excess comminuted modifying material is removed by means of physical steps.

5. Method according to one of claims 1 to 4, characterized in that for applying the comminuted modifying material to the starting material, the starting material is embedded in the comminuted modifying material and is thus thermally treated.

6. The method according to any one of claims 1 to 4, characterized in that dry comminuted modifying material is applied to the starting material to apply the comminuted modifying material.

7. Method according to one of claims 1 to 6, characterized in that the respective substances themselves or chemical compounds, preferably their salts, which have these atoms are used as sources for strontium, fluorine, magnesium, manganese, zinc and / or gallium atoms, in particular selected from: strontium fluoride, magnesium fluoride, zinc fluoride, manganese, gallium oxide.

8. Method according to one of claims 1 to 7, characterized in that heating and / or cooling intervals are provided for the thermal treatment of the intermediate product in order to reach the desired treatment temperature or room temperature.

9. Method according to one of claims 1 to 8, characterized in that the heating and / or cooling temperature change is a maximum of 10°C per minute, preferably less than 5°C per minute.

10. Method according to one of claims 1 to 7, characterized in that for the thermal treatment of the intermediate product, the latter is introduced directly into a treatment device which essentially has the treatment temperature.

11. Osteotropic bone replacement material or osteotropic surface coating of an implant produced according to one of the processes 1 to 10, characterized in that calcium atoms of the hydroxyapatite are partially replaced by strontium, fluorine, magnesium, manganese, zinc and / or gallium atoms.

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