Bone regeneration materials

Abstract

The present invention relates to a bone regenerating material consisting essentially of a solid phase of macroporous naturally occurring hydroxyapatite, as well as a method for producing the same and a method for repairing bone defects.

Description

[Technical field]

[0001] The present invention relates to a bone regeneration material consisting essentially of a solid phase of macroporous, naturally occurring hydroxyapatite.

[0002] The present invention further relates to a method for producing a bone regenerating material consisting essentially of a solid phase of macroporous, naturally occurring hydroxyapatite.

[0003] The invention finally relates to a method for repairing a bone defect in a patient using a bone regenerating material consisting essentially of a solid phase of macroporous, naturally occurring hydroxyapatite.

[0004] Bone regenerating materials of this kind are used for the treatment of bone deterioration in various fields, especially in restorative and cosmetic surgery. [Background technology]

[0005] Hydroxyapatite is an osteoconductive calcium phosphate with the formula Ca5(PO4)3(OH) and is the major mineral component of bone. In fact, hydroxyapatite belongs to the crystallographic family of apatites, which are isotypic compounds with the same hexagonal crystal structure.

[0006] Hydroxyapatite is the most common crystalline calcium phosphate and is the main mineral component of bone, tooth enamel, and dentin, and therefore this compound has been widely used as a biomaterial in various medical fields for many years.

[0007] Moreover, hydroxyapatites, especially those of natural origin, have good biocompatibility and specific adsorption properties for cells or proteins, making their use perfectly suitable in the field of reconstructive, restorative or aesthetic surgery of bones, especially oral bones.

[0008] It has therefore been recognised that hydroxyapatite of natural (animal) origin is not only osteoconductive but also has a crystal structure and morphology identical to that of natural human bone material, making it perfectly suitable for implants, particularly intraoral implants, and is currently used to stimulate bone reconstruction and regeneration in missing or deteriorated bone sites.

[0009] Moreover, bone regenerative materials consisting essentially of a solid phase of naturally occurring hydroxyapatite, devoid of organic material (proteins, prions, peptides, lipids), have been shown to allow better bone regeneration compared to synthetic hydroxyapatite solid phases. Indeed, when the bone regenerative material is implanted in the patient, it is essential to remove all traces of organic material to promote its integration in the body, osseointegration at the implant site, biocompatibility, and to allow it to interact with the biological environment while avoiding unnecessary rejection reactions.

[0010] Bone colonization depends on the porous properties of the bone regenerating material and the number and size of its interconnected macropores. These interconnections form tunnels that allow the passage of cells and blood flow between the pores, facilitating new bone formation.

[0011] In this regard, the prior art is known from the document US Pat. No. 5,417,975, which discloses the product BioOss®, a bone regeneration material comprising a solid phase of naturally occurring hydroxyapatite having nanopores, micropores and pores with a diameter of 50 μm or more.

[0012] WO 2015 / 049336 is also known as prior art, and this document also discloses a bone regeneration material comprising a solid phase of naturally occurring hydroxyapatite having pores with a diameter of 50 μm or more, preferably pores with a diameter of 50 to 100 μm. Summary of the Invention [Problem to be solved by the invention]

[0013] Unfortunately, although these products have many advantages, their mechanical properties leave room for improvement.

[0014] The present invention relates to a method for producing a hydroxyapatite solid phase having a crystal size of 20 to 120 nm and a specific surface area of ​​8 to 20 m. 2 The object of the present invention is to overcome the drawbacks of the prior art by providing a bone regeneration material as described above, characterized in that it is a crystalline solid phase of hydroxyapatite having a molecular weight of 1000 to 15000 / g. [Means for solving the problem]

[0015] The bone regeneration material according to the present invention is particularly advantageously obtained after a sintering step at a temperature of from 800°C to 1200°C, preferably from 800°C to 1150°C, more preferably from 800°C to 1100°C, even more preferably from 800°C to 1050°C, still more preferably from 800°C to 1000°C, especially preferably from 800°C to 950°C, even more especially preferably from 800°C to 900°C, particularly preferably from 800°C to 850°C, for example from 810°C to 830°C, for example 820°C.

[0016] This sintering process makes it possible to "weld" the crystals of the solid phase, especially of naturally occurring hydroxyapatite, resulting in a very large reduction or complete disappearance of nano- and micropores, an increase in the size of the crystals, and a decrease in the specific surface area. However, a significant reduction or disappearance of nano- and micropores in bone regenerative materials is considered detrimental, since it would prevent the material from vascularizing and colonizing, which could lead to incomplete or poor quality bone regeneration in the future.

[0017] Indeed, it is generally recognized that the absence of microporosity in bone regenerating materials is detrimental to bone growth and osteoconduction formation.

[0018] In spite of this drawback, the sintering process according to the invention is particularly advantageous since it allows the surface shape of the regenerated material to be preserved, thereby reinforcing its strength while preserving the potential for bone regeneration.

[0019] For example, the material sintering process according to the invention makes it possible to form substantially spherical elements on the surface of the material.

[0020] Thus, the material according to the invention has substantially spherical / ball-like / pseudo-spherical elements of hydroxyapatite with a size (diameter or equivalent diameter) of ≥ 150 nm to ≤ 350 nm, preferably ≥ 175 nm to ≤ 325 nm, more preferably ≥ 200 nm to ≤ 300 nm. The substantially spherical / ball-like / pseudo-spherical elements together form the rough surface of the bone regeneration material according to the invention, unlike the performance of sintering processes at temperatures above 1200°C, which lead to melting of the hydroxyapatite on the surface of the material, resulting in an excessively smooth surface that is detrimental to the bone regeneration potential.

[0021] Particularly surprisingly, the inventors have found that the bone regeneration material according to the present invention has a crystal size of 20 to 120 nm and a specific surface area of ​​8 to 20 m after the sintering process, i.e., the sintering step. 2 / g, have a harder, stronger structure, and have a rougher surface morphology, yet are colonized by bone tissue in a manner similar to the prior art method.

[0022] Indeed, the bone regeneration material according to the invention is intended to be implanted for the reconstruction and / or regeneration of bone defects or bone deterioration, more particularly in the dental field, where the forces exerted by chewing are high and repeated over a long period of time.

[0023] Thus, the bone regeneration material of the present invention has the same properties and advantages as the prior art in terms of bone regeneration capacity, osseointegration and osteoconduction, but is particularly advantageous in that it is harder, stronger and has a surface roughness which maintains or enhances bone regeneration capacity.

[0024] The dependent claims refer to further advantageous embodiments.

[0025] Advantageously, the size of the crystals of the crystalline solid phase of hydroxyapatite in the bone regeneration material of the present invention is 30 nm or more and 120 nm or less, preferably 40 nm or more and 100 nm or less, more preferably 45 nm or more and 80 nm or less, even more preferably 50 nm or more and 80 nm or less, and particularly preferably 50 nm or more and 60 nm or less.

[0026] Advantageously, the specific surface area of ​​the solid phase of hydroxyapatite in the bone regeneration material according to the invention is greater than 10 m 2 / g or more 20m 2 / g or less, preferably 10m 2 / g or more 18m 2 / g or less, more preferably 12m 2 / g or more 16m 2 / g or less.

[0027] This has the advantage of providing a bone regeneration material according to the present invention which offers at least the same bone regeneration properties as prior art methods, whilst having improved strength and stiffness, making it particularly suitable for the dental field where mechanical constraints are great.

[0028] Suitably, the porosity of the bone regenerating material according to the present invention is 70% or more and 85% or less, preferably 75% or more and 85% or less, and more preferably 80% or more and 85% or less.

[0029] This has the advantage that the bone regenerating material according to the present invention can be provided with significantly improved bone formation ability.

[0030] Preferably, the particle size distribution of the bone regeneration material according to the present invention is 10 is 350 μm or more and 500 μm or less, preferably 370 μm or more and 480 μm or less.

[0031] Preferably, the particle size distribution of the bone regeneration material according to the present invention is 50 is 500 μm or more and 800 μm or less, preferably 550 μm or more and 780 μm or less.

[0032] Preferably, the particle size distribution of the bone regeneration material according to the present invention is 90is 850 μm or more and 1250 μm or less, preferably 850 μm or more and 1100 μm or less, and more preferably 850 μm or more and 1000 μm or less.

[0033] The bone regeneration material according to the present invention having such a particle size distribution has the advantage that it has an optimal pore volume that enables bone regeneration.

[0034] Advantageously, the bone regeneration material according to the invention is enriched with a second synthetic solid phase of calcium phosphate with a Ca / P molar ratio between 0.2 and 2, preferably between 0.3 and 1.8, more preferably between 0.5 and 1.65, said second synthetic solid phase having a solubility product Ks greater than the solubility product Ks of the first phase of solid hydroxyapatite of natural origin.

[0035] In particularly advantageous embodiments, this results in increased calcium (e.g., free extracellular Ca 2+ ionic form) and phosphorus (e.g., free extracellular PO4 3- Since an adequate release of the hydroxyl group (in the form of ions) into the surroundings of the bone regeneration site is ensured, the latter can act as a promoter of regrowth of the surrounding biological tissues by significantly promoting the proliferation and differentiation of bone cells as well as mineralization.

[0036] Preferably, the bone regeneration material of the present invention comprises at least one therapeutic agent selected from the group consisting of antibiotics, antivirals, anti-inflammatory drugs, hormones such as steroids, growth factors such as BMPs, anti-rejection agents, stem cells, and mixtures thereof.

[0037] Advantageously, the bone regeneration material according to the invention is a sterile material.

[0038] Further embodiments of the bone regeneration material according to the invention are set out in the accompanying claims.

[0039] The present invention also relates to a method for producing the bone regenerating material according to the present invention, comprising the steps of: - contacting the bone material comprising hydroxyapatite and organic matter with an aqueous extraction solution having a temperature between 150°C and 300°C and a pressure between 1500 and 3500 kPa, to obtain a first liquid phase comprising said organic matter and possibly impurities extracted from said bone material, and a second solid hydroxyapatite phase. - separating the liquid phase and the solid hydroxyapatite phase. - (mild) sintering of the separated solid hydroxyapatite phase at a temperature between 800°C and 1200°C. - forming said bone regeneration material by sintering said hydroxyapatite phase.

[0040] The method of the present invention makes it possible, in a particularly surprising and advantageous manner, to provide sintered bone regeneration materials which have at least the same properties as the prior art in terms of bone regeneration capacity, osseointegration and osteoconduction, but which are harder, stronger and, due to their surface roughness, maintain or improve their bone regeneration capacity.

[0041] In particular, sintering conditions below 800°C do not improve the mechanical strength of the material, and temperatures above 1200°C and even above 900°C have a negative effect on the surface morphology and bone regeneration ability of the material, while sintering conditions between 800°C and 1200°C and even below 900°C appear to make it possible to obtain strong, robust and strong bone regeneration materials with the desired bone regeneration ability that can be implanted into patients.

[0042] Advantageously, the method according to the invention further comprises, between said separation step and said sintering step, a sequence of sieving steps of said solid hydroxyapatite phase over a sequence of sieves, preferably said sequence of sieving steps comprising a first sieving step over a sieve of at least 1 mm and a second sieving step over a sieve of at least 0.25 mm.

[0043] For example, the post-extraction solid hydroxyapatite phase derived from bone material, which has already been rendered brittle by the extraction process, is deposited on a sieve set including, from bottom to top, a collection basket, a 0.25 mm sieve and a 1 mm sieve.

[0044] Further advantageously, the series of sieving steps of the method according to the invention between the separation step and the calcination step is a series of sieving steps comprising the steps of adding metal balls to said series of sieves and moving said metal balls over said series of sieves.

[0045] Indeed, by adding metal balls to the sieve set and using an apparatus to move the sieve set, the balls can further fragile the hydroxyapatite phase, facilitating its passage through the sieve to obtain particles of the desired size.

[0046] Advantageously, the aqueous extraction solution of the method according to the invention has a temperature of from 170°C to 280°C, preferably from 190°C to 260°C, more preferably from 210°C to 240°C, particularly preferably from 220°C to 230°C.

[0047] Preferably, the aqueous extraction solution of the method according to the present invention is subjected to a pressure of from 2000 kPa to 3500 kPa, preferably from 2500 kPa to 3500 kPa, more preferably from 3000 kPa to 3500 kPa, even more preferably from 3200 kPa to 3500 kPa, and particularly preferably from 3400 kPa to 3500 kPa.

[0048] In fact, the supercritical extraction step of the method according to the invention, at temperature conditions of 220-230°C and pressure conditions of 3200-3500 kPa, shows the best results for obtaining a pure solid hydroxyapatite phase, freed of organic material (proteins, prions, peptides, lipids), thus reducing possible subsequent undesirable rejection reactions.

[0049] The duration of the supercritical extraction step is advantageously adjusted depending on the amount of bone material. Advantageously, the sintering step of the method according to the invention is carried out for a period of between 40 minutes and 4 hours, preferably between 1 hour and 3 hours, more preferably between 1 hour and 2 hours, and particularly preferably between 1 hour and 1.5 hours.

[0050] Furthermore, the sintering step includes a temperature ramp sub-step combined with a hot plate step, which sintering step lasts in total, for example, 1 hour and 20 minutes.

[0051] Preferably, the sintering step of the method according to the invention is carried out at a temperature of from 800°C to 1150°C, preferably from 800°C to 1100°C, more preferably from 800°C to 1050°C, even more preferably from 800°C to 1000°C, especially preferably from 800°C to 950°C, even more preferably from 800°C to 900°C, particularly preferably from 800°C to 850°C, for example from 810°C to 830°C.

[0052] Preferably, the heating step of the sintering step allows a temperature of 800° C. to 1150° C., advantageously 800° C. to 850° C., for example 810° C. to 830° C., to be reached in a period of 20 minutes to 2 hours, preferably 20 minutes to 1 hour, more preferably 20 minutes to 45 minutes, even more preferably 25 minutes to 35 minutes.

[0053] For example, the sintering temperature can reach 820° C. in 30 minutes by the temperature increasing process.

[0054] Preferably, during the temperature ramping step, the temperature increase with time is substantially linear.

[0055] This allows for a temperature ramp-up that is not too long and is reproducible.

[0056] Indeed, the inventors have noted that relatively long heating steps, especially at temperatures above 600° C., already affect bone. This is not necessarily a disadvantage, but must be taken into account when determining the length of the plate step at temperatures between 800° C. and 1200° C., preferably between 800° C. and 1150° C., more preferably between 800° C. and 850° C., for example between 810° C. and 830° C.

[0057] Furthermore, the hot plate step of the sintering process is carried out at a temperature of 800° C. to 1200° C., advantageously 800° C. to 850° C., for example 810° C. to 830° C., for a period of 20 minutes to 2 hours, preferably 30 minutes to 1 hour and 30 minutes, more preferably 45 minutes to 1 hour, even more preferably 46 minutes to 58 minutes.

[0058] For example, the hot plate process at a sintering temperature of 820° C. is carried out for 45 to 58 minutes.

[0059] Furthermore, the sintering step of the method according to the invention has some flexibility with respect to sintering temperature and sintering time, however the temperature setting of the heating plate step in the sintering step is the most critical setting and would benefit from being more closely controlled.

[0060] Advantageously, the method according to the invention further comprises, between said sieving step and said sintering step, a step of treating said solid hydroxyapatite phase with a peroxide, preferably with hydrogen peroxide.

[0061] Preferably, the method according to the invention further comprises a (mild) drying step between said peroxide treatment step and said sintering step.

[0062] Advantageously, the method according to the invention further comprises a step of enriching the bone regeneration material with calcium and phosphorus by at least one separate first immersion and at least one second immersion, successive to one another in any order, said at least one first immersion being carried out in a first solution containing calcium at a concentration of 1 M and said at least one second immersion being carried out in a second solution containing phosphorus at a concentration of 0.5 M.

[0063] Advantageously, the first soaking of the enrichment step of the method according to the invention is carried out in a first solution of Ca(NO3)2.4H2O, CaCl2.2H2O, CaSO4.2H2O and CaCO3.

[0064] Advantageously, the second immersion of the enrichment step of the method according to the invention is carried out in a second solution of Na3PO4, Na2HPO4, NaH2PO4.H2O, K3PO4, K2HPO4, KH2PO4, K2HPO4, (NH4)3PO4, (NH4)2HPO4 or NH4H2PO4.

[0065] Preferably, the method according to the invention further comprises the step of sterilizing the bone regeneration material and / or the enriched bone regeneration material, preferably by sterilization by ionization.

[0066] Further embodiments of the manufacturing method according to the invention are set out in the accompanying claims.

[0067] The present invention also relates to a method for repairing a bone defect in a patient, comprising the steps of: - measuring the defect to be filled. - positioning a synthetic coating device obtained by additive manufacturing and arranged to promote bone regeneration in a bone defect, said synthetic coating device comprising at least one shell formed of a porous matrix having a series of pores with a size between 50 μm and 1000 μm and at least one strut connected to said porous matrix on the one hand and supporting the bone surface of said bone defect on the other hand, said coating device being arranged to define a cavity itself arranged to accommodate the bone volume to be regenerated. - filling the cavity created by the coating device with the bone regeneration material according to the invention.

[0068] Advantageously, the method according to the invention is non-therapeutic restorative and / or cosmetic.

[0069] Advantageously, the method according to the invention is a method for the repair of bones subjected to strong mechanical stresses, preferably bones involved in the functioning of the masticatory system.

[0070] Further embodiments of the method for repairing a bone defect according to the invention are provided in the accompanying claims.

[0071] Other characteristics, details and advantages of the invention will become apparent from the following description, given in a non-limiting manner with reference to the drawings and examples. An example is shown below. [Brief description of the drawings]

[0072] [Figure 1] FIG. 1 is a scanning electron microscope (SEM) image showing the structure of a prior art bone regeneration material sintered at a temperature above 1200° C. [Figure 2A] 2A and 2B are images obtained by scanning electron microscopy (SEM) at magnifications of 5000 and 10000, respectively, of the structure of a bone regeneration material according to the invention sintered at a temperature of 820° C. [Figure 2B] 2A and 2B are images obtained by scanning electron microscopy (SEM) at magnifications of 5000 and 10000, respectively, of the structure of a bone regeneration material according to the invention sintered at a temperature of 820° C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0073] Example 1 - Bone regeneration material according to the present invention A bone regeneration material consisting essentially of a solid phase of hydroxyapatite has been produced in accordance with the present invention, in this example the material being sterilized. Three samples of the bone regeneration material according to the invention were subjected to a series of analyses including measurements of the solid phase composition, crystal size, volume porosity, particle size and specific surface area.

[0074] Samples 1, 2 and 3 all have a solid phase composition of 100% hydroxyapatite, that is, the bone regenerating material according to the present invention is essentially composed of a solid phase of hydroxyapatite. The crystal size of sample 1 is 54.6 nm, that of sample 2 is 54.2 nm, and that of sample 3 is 54.4 nm. Therefore, the average crystal size of the bone regeneration material according to the present invention is 54.4 nm. With regard to the volumetric porosity, the porosity of sample 1 is 82.3%, that of sample 2 is 82.1%, and that of sample 3 is 82.5%. Therefore, the average volumetric porosity of the bone regenerating material according to the present invention is 82.3%.

[0075] Regarding particle size, the particle size distribution of sample 1, d 10 is 381 μm, d 50 is 553 μm, d 90 The particle size distribution of sample 2 is 877 μm. 10 is 452μm, d 50 is 782μm, d 90 The particle size distribution of sample 3 is 1243 μm. 10 is 474μm, d 50 is 756μm, d 90 Therefore, the average particle size distribution d of the bone regeneration material according to the present invention is 1115 μm. 10 is 436μm, d 50 is 697 μm, d 90 is 1079 μm. The specific surface area of ​​samples 1, 2, and 3 is 16 m 2 / g, the average specific surface area is 16m 2 / g.

[0076] Furthermore, the bone regeneration material according to the invention is obtained in a particularly advantageous manner after a sintering step at a temperature of 820°C with a heating plate time of 45 to 60 minutes, making it possible to obtain a material with a harder and more robust structure having a rough surface morphology, thus improving the bone regeneration capacity.

[0077] Indeed, as depicted in Figures 2A and 2B, the material according to the invention has substantially spherical / ball-like / pseudo-spherical elements of hydroxyapatite with a size (diameter or equivalent diameter) of 150-350 nm, preferably 175-325 nm, more preferably 200-300 nm, which together form a rough surface, unlike the bone regeneration material shown in Figure 1, which is sintered at temperatures above 1200°C and has a smooth surface that is detrimental to the possibility of bone regeneration.

[0078] Example 2 - Preparation of bone regeneration material according to the present invention Batches of bone regenerating material according to the present invention were prepared by harvesting bovine bone and cutting the bovine bone to form bone material.

[0079] Bone material containing hydroxyapatite and organic matter is contacted with an aqueous extraction solution under supercritical temperature and pressure conditions, for example, at 220°C to 230°C and at a pressure of 3200 kPa to 3500 kPa, to obtain a first liquid phase containing the extracted organic matter and impurities and a second phase of solid hydroxyapatite, and then these two phases are separated to preserve the solid hydroxyapatite phase.

[0080] The solid hydroxyapatite phase embrittled by the supercritical extraction process is sieved through a first sieve of 1 mm to perform the first sieving, and then through a second sieve of 0.25 mm to perform the second sieving. Advantageously, metal balls are sieved together with the solid hydroxyapatite phase to facilitate crushing and sieving. The sieving process can be carried out once or multiple times, for example twice or three times.

[0081] The solid hydroxyapatite phase after sieving was collected and subjected to a sintering step at a temperature between 800 and 1200°C, ideally at 820°C, during a hot plate step at 820°C for 45 to 60 minutes.

[0082] In this way, the sintered solid hydroxyapatite phase forms the bone regeneration material of the present invention, which has a harder structure, is stronger and has a rougher surface morphology, thereby improving bone regeneration capacity.

[0083] Furthermore, the sintered solid hydroxyapatite phase forming the material according to the invention can also be washed and / or enriched with calcium and phosphorus by separate soaking and then sterilized, preferably by ionization.

[0084] Of course, it should be understood that the invention is in no way limited to the embodiments described above, but that many modifications are possible without departing from the scope of the appended claims.

Claims

1. A bone regeneration material essentially consisting of a solid phase of macroporous naturally occurring hydroxyapatite, having pores with a diameter of 50 μm or more, preferably 50 μm to 100 μm, wherein the solid phase of hydroxyapatite is a crystalline solid phase of hydroxyapatite with a crystal size of 20 nm to 120 nm, and a specific surface area of ​​8 m ２ / g or more 20m ２ / g or less.

2. The bone regeneration material according to claim 1, wherein the crystal size of the hydroxyapatite crystalline solid phase is 30 nm or more and 120 nm or less, preferably 40 nm or more and 100 nm or less, more preferably 45 nm or more and 80 nm or less, even more preferably 50 nm or more and 80 nm or less, and particularly preferably 50 nm or more and 60 nm or less.

3. The specific surface area of ​​the hydroxyapatite solid phase is 10 m ２ / g or more 20m ２ / g or less, preferably 10m ２ / g or more 18m ２ / g or less, preferably 12m ２ / g or more 16m ２ The bone regeneration material according to claim 1, wherein the Cr content is 0.015 / g or less.

4. 2. The bone regeneration material according to claim 1, wherein the porosity is 70% or more and 85% or less, preferably 75% or more and 85% or less, more preferably 80% or more and 85% or less.

5. Particle size distribution d １０ The bone regeneration material according to claim 1, wherein the particle size is 350 μm or more and 500 μm or less, preferably 370 μm or more and 480 μm or less.

6. Particle size distribution d ５０ The bone regeneration material according to claim 1, wherein the particle size is 500 μm or more and 800 μm or less, preferably 550 μm or more and 780 μm or less.

7. Particle size distribution d ９０ The bone regeneration material according to claim 1, wherein the particle size is 850 μm or more and 1250 μm or less, preferably 850 μm or more and 1100 μm or less, more preferably 850 μm or more and 1000 μm or less.

8. 2. The bone regeneration material of claim 1, which is enriched with a second synthetic solid phase of calcium phosphate having a Ca / P molar ratio of 0.2 or more and 2 or less, preferably 0.3 or more and 1.8 or less, more preferably 0.5 or more and 1.65 or less, and which has a solubility product Ks greater than the solubility product Ks of the first phase of the naturally occurring solid hydroxyapatite.

9. The bone regeneration material of claim 1, comprising at least one therapeutic agent selected from the group consisting of antibiotics, antiviral drugs, anti-inflammatory drugs, hormones such as steroids, growth factors such as BMPs, anti-rejection agents, stem cells, and mixtures thereof.

10. The bone regeneration material according to claim 1 , which is a sterile material.

11. a step of contacting a bone material containing hydroxyapatite and organic substances with an aqueous extraction solution at a temperature of 150°C to 300°C and a pressure of 1500 kPa to 3500 kPa to obtain a first liquid phase containing the organic substances extracted from the bone material and, if necessary, impurities, and a second solid hydroxyapatite phase; separating the liquid phase from the solid hydroxyapatite phase; (mild) sintering the separated solid hydroxyapatite phase at a temperature between 800°C and 1200°C; forming a bone regeneration material from the sintered hydroxyapatite phase; The method for producing the bone regenerating material according to claim 1, comprising:

12. 12. The method according to claim 11, further comprising a series of sieving steps of the solid hydroxyapatite phase on a series of sieves between the separating step and the sintering step, preferably the series of sieving steps comprising a first sieving step on a sieve of at least 1 mm and a second sieving step on a sieve of at least 0.25 mm.

13. 13. The method of claim 12, wherein the series of sieving steps between the separating step and the sintering step is a series of sieving steps including adding metal balls to the series of sieves and moving the metal balls over the series of sieves.

14. The method according to claim 11, wherein the aqueous extraction solution is brought to a temperature of from 170°C to 280°C, preferably from 190°C to 260°C, more preferably from 210°C to 240°C, and even more preferably from 220°C to 230°C.

15. The method according to claim 11, wherein the aqueous extraction solution is subjected to a pressure of from 2000 kPa to 3500 kPa, preferably from 2500 to 3500 kPa, more preferably from 3000 to 3500 kPa, and even more preferably from 3200 to 3500 kPa.

16. 12. The method according to claim 11, wherein the sintering step is carried out for a period of from 40 minutes to 4 hours, preferably from 1 hour to 3 hours, more preferably from 1 hour to 2 hours, for example from 1 hour to 1.5 hours.

17. The sintering step is carried out at a temperature of from 800°C to 1150°C, preferably from 800°C to 1100°C, more preferably from 800°C to 1050°C, even more preferably from 800°C to 1000°C, particularly preferably from 800°C to 950°C, even more preferably from 800°C to 900°C, particularly preferably from 800°C to 850°C, for example from 810°C to 830°C.

18. 13. The method of claim 12, further comprising a step between the sieving step and the sintering step of treating the solid hydroxyapatite phase with a peroxide, preferably hydrogen peroxide.

19. 20. The method of claim 18, further comprising a drying step between the peroxide treating step and the sintering step.

20. 12. The method of claim 11 further comprising the additional step of washing the sintered hydroxyapatite phase.

21. 12. The method of claim 11, further comprising enriching the bone regeneration material with calcium and phosphorus by at least one first and at least one second separate immersion in succession in any order, wherein the at least one first immersion is performed in a first solution containing calcium at a concentration of 1 M and the at least one second immersion is performed in a second solution containing phosphorus at a concentration of 0.5 M.

22. The first soak of the enrichment step is ３ ) ２ .4H ２ O, CaCl ２ .2H ２ O, CaSO ４ .2H ２ O or CaCO ３ 22. The method of claim 21 , wherein the first solution is

23. The second steeping of the enrichment step is ３ P.O. ４ , Na ２ HPO ４ , NaH ２ P.O. ４ .H ２ O.K. ３ P.O. ４ , K. ２ HPO ４ , K.H. ２ P.O. ４ , K. ２ HPO ４ , (NH ４ ) ３ P.O. ４ , (NH ４ ) ２ HPO ４ , or NH ４ H ２ P.O. ４ 22. The method of claim 21 , wherein the second solution is

24. 12. The method of claim 11, further comprising the step of sterilizing the bone regeneration material and / or the enriched bone regeneration material, preferably by ionization.

25. measuring the defect to be filled; positioning a synthetic coating device arranged to promote bone regeneration in a bone defect, said synthetic coating device comprising at least one shell formed of a porous matrix obtained by additive manufacturing and having a series of pores with a size of between 50 μm and 1000 μm, and at least one strut connected to said porous matrix on the one hand and supporting the bone surface of said bone defect on the other hand, said synthetic coating device being arranged to define a cavity itself arranged to accommodate the bone volume to be regenerated; Filling the cavity formed by the synthetic coating device with the bone regeneration material according to any one of claims 1 to 10 or the bone regeneration material obtained according to any one of claims 11 to 24; 1. A method for repairing a bone defect in a patient, comprising:

26. 26. The method of claim 25, which is non-therapeutic restorative and / or cosmetic.

27. 26. A method according to claim 25, which is a method for the repair of bones subjected to strong mechanical stresses, preferably bones involved in the functioning of the masticatory system.

Images