Artificial bone repair material, porous magnesium-containing tricalcium phosphate powder and preparation method therefor

Abstract

An artificial bone repair material and a preparation method therefor, and a preparation method for a porous magnesium-containing tricalcium phosphate powder for the artificial bone repair material. The artificial bone repair material is a composite material having a porous structure, and the raw materials of the artificial bone repair material comprise collagen and a porous magnesium-containing tricalcium phosphate powder, wherein the porous magnesium-containing tricalcium phosphate powder is formed by subjecting a precipitate obtained after the reaction of a calcium salt solution, a magnesium salt solution and a phosphate solution to spray drying, and the particle size of the magnesium-containing tricalcium phosphate powder is 1-20 μm. The mass percentage of magnesium-containing tricalcium phosphate in the artificial bone repair material is 50-95%. The artificial bone repair material has a relatively high ceramic component content, and the binding property and dispersity of the ceramic component in collagen are relatively good, such that the artificial bone repair material has relatively high biological activity and degradability, and the new bone tissue can grow inside until a bone defect part is completely replaced, while the artificial bone repair material is degraded in vivo.

Description

Artificial bone repair material, porous magnesium-containing tricalcium phosphate powder and preparation method thereof Related applications

[0001] This application claims priority to Chinese patent applications No. CN2023110914215 and No. CN2023110962420 filed on August 29, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present disclosure relates to a bone repair material and its raw materials and preparation method, specifically a porous magnesium-containing tricalcium phosphate and a collagen / magnesium-containing tricalcium phosphate artificial bone repair material prepared using collagen and porous magnesium-containing tricalcium phosphate as raw materials. Background Art

[0003] As the aging population continues to intensify, the incidence of bone injuries due to various chronic diseases, traffic accidents, work-related injuries, and sports injuries is increasing year by year. There is an urgent need to develop new artificial bone materials for bone defect repair. In recent years, a number of calcium phosphate-based artificial bone repair materials, represented by hydroxyapatite and tricalcium phosphate, have been widely used. While the chemical composition of calcium phosphate materials is similar to the inorganic components of human bone and exhibits good biocompatibility, they still face challenges such as non-degradability in the body, a mismatch between their degradation rate and the osteogenesis cycle, and low bioactivity, making it difficult to meet the growing market demand.

[0004] Existing bone repair materials are mostly based on hydroxyapatite, which exhibits some biocompatibility after implantation, but also degrades slowly in vivo. Studies have shown that hydroxyapatite remains unchanged in the bone defect even after years of implantation, hindering new bone ingrowth. See reference 1: Dorozhkin SV, Epple M. Biological and medical significance of calcium phosphates. Angew. Chem. Int. Ed. 2002, 41: 3130-3146.

[0005] After implantation, dense hydroxyapatite materials only form new bone tissue on the surface and lack the ability to induce bone formation. Compared with hydroxyapatite, tricalcium phosphate materials have better degradation performance and can form chemical bonds with bone after implantation in the body, but they still lack sufficient biological activity and cannot further promote the formation of new bone. At the same time, tricalcium phosphate materials require high-temperature calcination to prepare, which greatly increases the cost of bone repair materials. See reference 2: Yadav MK, Pandey V. and et al. A low-cost approach to develop silica doped Tricalcium Phosphate (TCP) scaffold by valorizing animal bone waste and rice husk for tissue engineering applications. Ceram. Int. 2022, 48: 25335-25345.

[0006] Some researchers have enhanced the bioactivity of calcium phosphate materials by incorporating collagen molecules. Collagen, a key component of human bone, exhibits excellent osteoinductivity, inducing osteoblast proliferation and differentiation. (See reference 3: Jiang QS, Wang LR and et al. Canine ACL reconstruction with an injectable hydroxyapatite / collagen paste for accelerated healing of tendon-bone interface. Bioact. Mater. 2023, 20:1-15.)

[0007] However, relying solely on collagen molecules to provide bioactivity is far from sufficient. The composite process of collagen and hydroxyapatite requires blending collagen powder with hydroxyapatite and then hot-pressing at 90-130°C. This product exhibits significant deficiencies in terms of degradation performance (hydroxyapatite is difficult to degrade in vivo) and pore structure (compared to a denser structure after hot pressing). Mainstream technologies in the industry include freeze-drying collagen / hydroxyapatite composites and freeze-drying of porous tricalcium phosphate ceramics. The nanoscale hydroxyapatite powder used in the freeze-drying method has a content of 20-80%, resulting in poor dispersibility and inability to achieve a higher ceramic phase content. Furthermore, hydroxyapatite is difficult to degrade in vivo, hindering new bone formation and ingrowth. Freeze-drying of porous tricalcium phosphate ceramics utilizes a sintered calcium phosphate ceramic matrix with insufficient toughness, making it impossible to achieve the unique shaping properties of collagen. Summary of the Invention

[0008] The present disclosure relates to an artificial bone repair material and its preparation method. The artificial bone repair material has a high ceramic component content, and the ceramic component has good binding and dispersibility in collagen, avoiding shedding and inflammation during in vivo use. The artificial bone repair material has high bioactivity and degradability. As the artificial bone repair material degrades in the body, new bone tissue can grow into the defect until the bone defect is completely replaced. The present disclosure also relates to a method for preparing a porous magnesium-containing tricalcium phosphate powder for use in bone repair materials. The reaction conditions are relatively mild, reducing production costs. The resulting bone repair raw material is a low-density porous powder material that has good binding properties with polymer materials such as collagen.

[0009] A first aspect of the present disclosure provides an artificial bone repair material, which is a composite material with a porous structure. The raw materials of the artificial bone repair material include collagen and porous magnesium-containing tricalcium phosphate powder. The porous magnesium-containing tricalcium phosphate powder is formed by spray-drying a precipitate obtained by reacting a calcium salt, a magnesium salt, and a phosphate solution. The particle size of the porous magnesium-containing tricalcium phosphate powder is 1 to 20 μm. The mass percentage of the porous magnesium-containing tricalcium phosphate in the artificial bone repair material is 50 to 95%.

[0010] In one embodiment, the mass percentage of magnesium tricalcium phosphate in the artificial bone repair material is 85-95%, that is, the content of ceramic components in the obtained artificial bone repair material can reach more than 85%.

[0011] In one embodiment, the mass ratio of the collagen to the porous magnesium-containing tricalcium phosphate powder in the raw material is 0.05-1.

[0012] In one embodiment, the mass percentage of porous magnesium-containing tricalcium phosphate in the artificial bone repair material is 50-95%.

[0013] In one embodiment, the porosity of the artificial bone repair material is 70-95%.

[0014] In one embodiment, the artificial bone repair material is prepared by cross-linking and composite molding of collagen and porous magnesium-containing tricalcium phosphate powder.

[0015] In one embodiment, the mass percentage of magnesium element in the porous magnesium-containing tricalcium phosphate powder is less than or equal to 3%.

[0016] In one embodiment, the porous magnesium-containing tricalcium phosphate powder is prepared by the following steps:

[0017] A mixed solution of calcium salt and magnesium salt is prepared as the first solution; a phosphate solution is prepared and the pH is adjusted to 9.5-10.5 with alkaline solution to form the second solution;

[0018] heating and mixing the first solution and the second solution, and reacting them at 60-95° C. with stirring;

[0019] The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed and spray-dried to obtain a porous magnesium-containing tricalcium phosphate powder.

[0020] In one embodiment, the alkaline solution is aqueous ammonia or sodium hydroxide.

[0021] A second aspect of the present disclosure provides a method for preparing an artificial bone repair material, comprising: dissolving collagen in an acid solution, adding porous magnesium-containing tricalcium phosphate powder, stirring uniformly to form a mixed slurry, and drying and shaping the mixture to obtain the artificial bone repair material; wherein the porous magnesium-containing tricalcium phosphate powder is formed by spray drying a precipitate obtained by reacting a calcium salt, a magnesium salt, and a phosphate solution, and has a particle size of 1 to 20 μm.

[0022] In one embodiment, the preparation method specifically comprises the following steps:

[0023] S101, dissolving collagen in an acid solution, adding porous magnesium-containing tricalcium phosphate powder, and stirring evenly to prepare a mixed slurry;

[0024] S102, adding a cross-linking agent to the mixed slurry, injecting the mixed slurry into a molding mold, and freeze-drying to obtain a molded composite material;

[0025] S103, removing the residual cross-linking agent in the composite material with an eluent solution, washing with pure water for multiple times, and drying to obtain the artificial bone repair material.

[0026] In one embodiment, the mass ratio of collagen to porous magnesium-containing tricalcium phosphate powder is 0.05-1.

[0027] In one embodiment, the mass percentage of magnesium element in the porous magnesium-containing tricalcium phosphate powder is less than or equal to 3%.

[0028] In one embodiment, the acid solution includes a hydrochloric acid solution or an acetic acid solution with a concentration of 0.1-2 wt %.

[0029] In one embodiment, the concentration of the collagen in the acid solution is 0.5-5 wt %.

[0030] In one embodiment, the collagen includes one or more of type I collagen, type II collagen, and recombinant collagen, and has a weight average molecular weight of 100,000 to 350,000 Da.

[0031] In one embodiment, step S102 is specifically implemented as follows: 1 to 100 ppm of a cross-linking agent is added to the mixed slurry and then injected into a molding mold, the mold is shaken to make the slurry liquid level reach a level, and then the mold is placed in a -4 to -80 ° C environment and frozen, and then demolded to obtain a molded composite material by a freeze-drying method; wherein the cross-linking agent includes one or a combination of glutaraldehyde and genipin, and the freeze-drying temperature is -20 to -80 ° C.

[0032] In one embodiment, step S103 is specifically implemented as follows: soaking the composite material in an eluent solution for 0.5 to 24 hours, placing the eluted composite material in pure water and stirring and washing it at a speed of 200 to 600 rpm for 6 to 24 hours, and then vacuum drying the composite material with a water content greater than 90 wt % to obtain a collagen / magnesium-containing tricalcium phosphate artificial bone repair material; wherein the eluent includes a combination of one or more of polyvinyl alcohol and sodium borohydride, with a concentration of 0.05 to 3 wt.%; the vacuum degree of the vacuum drying treatment is 1 to 50 Pa, and the cold trap temperature is -40 to -80°C.

[0033] In one embodiment, the preparation method further includes a preparation step of preparing the porous magnesium-containing tricalcium phosphate powder, and the preparation step specifically includes:

[0034] A mixed solution of calcium salt and magnesium salt is prepared as the first solution; a phosphate solution is prepared and the pH is adjusted to 9.5-10.5 with alkaline solution to form the second solution;

[0035] heating and mixing the first solution and the second solution, and reacting them at 60-95° C. with stirring;

[0036] The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed and spray-dried to obtain a porous magnesium-containing tricalcium phosphate powder.

[0037] In one embodiment, the molar ratio of calcium ions to magnesium ions in the first solution is 6 to 10; after the first solution and the second solution are mixed, the molar ratio of calcium ions to phosphate ions is 1.1 to 1.5; the calcium salt includes a combination of one or more selected from anhydrous calcium chloride, calcium chloride dihydrate, and calcium nitrate tetrahydrate, the magnesium salt includes magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate, and the phosphate includes a combination of multiple selected from one of disodium hydrogen phosphate, diammonium hydrogen phosphate, and sodium hydrogen phosphate.

[0038] In one embodiment, the washed precipitate is spray-dried using a spray dryer, wherein the air inlet temperature of the spray dryer is 240-300° C., the air outlet temperature is 120-150° C., and the feed rate is 30-200 mL / min.

[0039] Another aspect of the present disclosure provides a method for preparing porous magnesium-containing tricalcium phosphate powder for artificial bone repair material, comprising the following steps:

[0040] (i) preparing a mixed solution of calcium salt and magnesium salt as a first solution; preparing a phosphate solution and adjusting the pH to 9.5-10.5 with an alkaline solution as a second solution;

[0041] (ii) heating and mixing the first solution and the second solution, and reacting them at 60-95° C. with stirring;

[0042] (iii) The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed and spray-dried to obtain a porous magnesium-containing tricalcium phosphate powder.

[0043] In one embodiment, the molar concentration ratio of calcium ions to magnesium ions in the first solution is 6-10.

[0044] In one embodiment, the molar concentration of calcium ions in the first solution is 0.01 to 0.9 mol / L, more preferably 0.1 to 0.8 mol / L, and even more preferably 0.2 to 0.6 mol / L. For example, the molar concentration of calcium ions is 0.01 mol / L, 0.05 mol / L, 0.08 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L, 0.6 mol / L, 0.7 mol / L, or 0.8 mol / L.

[0045] In one embodiment, the molar concentration of magnesium ions in the first solution is 0.001-0.15 mol / L, more preferably 0.01-0.15 mol / L, further preferably 0.01-0.1 mol / L, and particularly 0.05-0.08 mol / L. For example, the molar concentration of magnesium ions is 0.001 mol / L, 0.005 mol / L, 0.008 mol / L, 0.01 mol / L, 0.02 mol / L, 0.03 mol / L, 0.04 mol / L, 0.05 mol / L, 0.06 mol / L, 0.07 mol / L, 0.08 mol / L, 0.09 mol / L, 0.1 mol / L, 0.12 mol / L, or 0.15 mol / L.

[0046] In one embodiment, the concentration of the calcium salt is 1-100 g / L, more preferably 30-100 g / L, further 50-100 g / L, further 60-90 g / L, and particularly 80-90 g / L; for example, 80 g / L, 82 g / L, 84 g / L, 86 g / L, 88 g / L, or 90 g / L by weight.

[0047] In one embodiment, the concentration of the magnesium salt is 0.4-40 g / L, more preferably 0.4-30 g / L, further 5-30 g / L, further 15-30 g / L, and particularly 20-30 g / L; for example, 20 g / L, 22 g / L, 24 g / L, 25 g / L, 27 g / L, or 29 g / L.

[0048] In one embodiment, after the first solution and the second solution are mixed, the molar ratio of calcium ions to phosphate ions is 1.1-1.5.

[0049] In one embodiment, the molar concentration of phosphate in the second solution is 0.008-0.8 mol / L, preferably 0.01-0.8 mol / L, further 0.05-0.8 mol / L, and particularly 0.1-0.5 mol / L. For example, the molar concentration of phosphate is 0.008 mol / L, 0.009 mol / L, 0.01 mol / L, 0.02 mol / L, 0.03 mol / L, 0.04 mol / L, 0.05 mol / L, 0.06 mol / L, 0.07 mol / L, 0.08 mol / L, 0.09 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L, 0.6 mol / L, 0.7 mol / L, or 0.8 mol / L.

[0050] In one embodiment, the concentration of phosphate in the second solution is 1-100 g / L, more preferably 30-100 g / L, further 50-90 g / L, further 70-90 g / L, and particularly 80-90 g / L; for example, 81 g / L, 83 g / L, 84 g / L, 85 g / L, 87 g / L, or 88 g / L.

[0051] In one embodiment, the first solution and the second solution are mixed in equal volumes.

[0052] In one embodiment, the solvent of the first solution is water, and the solvent of the second solution is water. In one embodiment, the solvent of the first solution includes a combination of one or more selected from methanol, ethanol, and water, and the solvent of the second solution includes a combination of one or more selected from methanol, ethanol, and water.

[0053] In one embodiment, the calcium salt includes a combination of one or more selected from anhydrous calcium chloride, calcium chloride dihydrate and calcium nitrate tetrahydrate, the magnesium salt includes a combination of one or more selected from magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate, and the phosphate includes a combination of one or more selected from disodium hydrogen phosphate, diammonium hydrogen phosphate and sodium hydrogen phosphate.

[0054] In one embodiment, the alkaline solution is ammonia water or sodium hydroxide.

[0055] In one embodiment, in step (i), the pH of the second solution is adjusted to 9.8-10.2 using aqueous ammonia. More preferably, the pH of the second solution is 9.8-10.0.

[0056] In one embodiment, in step (ii), the first solution and the second solution are heated to 60-95° C. and then mixed.

[0057] In one embodiment, in step (ii), the stirring rate is 100-500 rpm.

[0058] In one embodiment, in step (ii), the reaction is carried out under normal pressure.

[0059] In one embodiment, in step (iii), the washed precipitate is spray-dried using a spray dryer, wherein the inlet air temperature of the spray dryer is 240-300° C., the outlet air temperature is 120-150° C., and the feed rate is 30-200 mL / min.

[0060] In one embodiment, in step (iii), the precipitate is added to water and centrifuged and washed multiple times, the washed precipitate is added to 5 to 20 times the mass of water, stirred evenly to form a slurry, and then spray-dried.

[0061] In one embodiment, the preparation method is implemented as follows:

[0062] dissolving a calcium salt and a magnesium salt in water to obtain a first solution, wherein the concentration of the calcium salt is 1 to 100 g / L and the concentration of the magnesium salt is 0.4 to 40 g / L;

[0063] dissolving phosphate in water and adjusting the pH to 9.5-10.5 with aqueous ammonia to obtain a second solution, wherein the concentration of phosphate is 1-100 g / L;

[0064] Equal volumes of the first solution and the second solution were heated to 60-95°C and then mixed, and reacted under normal pressure with stirring at a rate of 100-500 rpm to form a suspension;

[0065] The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed 4 to 8 times with water. The washed precipitate is added to 5 to 20 times its mass of water and stirred evenly to form a slurry. The slurry is processed into a micron-sized porous tricalcium phosphate powder using a spray dryer to obtain the bone repair raw material. The inlet air temperature of the spray dryer is 240 to 300°C, the outlet air temperature is 120 to 150°C, and the feed rate is 30 to 200 mL / min.

[0066] The artificial repair material disclosed herein uses degradable collagen and magnesium-containing tricalcium phosphate as raw materials, achieving a fully degradable design in vivo. It is expected that as the material degrades in the body, new bone tissue will grow in until the bone defect is completely replaced. Magnesium-containing tricalcium phosphate is a micron-sized, low-density porous powder that will not exhibit stratification or precipitation after being dispersed in a collagen solution. This significantly increases the content of calcium phosphate ceramic components (50-95%), resulting in uniform dispersion and good bonding properties, thus avoiding shedding and inflammation during application. Furthermore, it has high activity, effectively promoting the osteogenic differentiation of bone tissue cells and promoting new bone formation.

[0067] The method for preparing porous magnesium-containing tricalcium phosphate powder disclosed herein is to directly react a calcium / magnesium mixed solution with a phosphate solution at 60-95°C under normal pressure to generate a magnesium-containing tricalcium phosphate suspension, which is then shaped by spray drying to obtain a low-density porous magnesium-containing tricalcium phosphate powder with a particle size of 1-20 μm. The reaction conditions are mild and the preparation process is simple, avoiding the use of a high-temperature calcination process or preparation by solid-phase reaction. The porous structure can provide better binding force and dispersibility in the process of preparing bone repair bodies. The obtained powder material effectively promotes the osteogenic differentiation of bone tissue cells and promotes new bone formation. In the process of preparing bone repair bodies from the powder material, the special porous structure can enable tricalcium phosphate to form an interlocking structure with polymers (such as collagen), significantly improving the binding of the body and solving the problems of shedding and inflammation that may occur during the application of nano tricalcium phosphate powder. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] In order to more clearly illustrate the technical solution of the present disclosure, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present disclosure. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0069] FIG1 is an XRD pattern of the porous magnesium-containing tricalcium phosphate powder material in Example 1 of the present disclosure.

[0070] FIG2 is a SEM microscopic morphology of the porous magnesium-containing tricalcium phosphate powder material in Example 1 of the present disclosure.

[0071] FIG3 is a photograph of the artificial bone repair material prepared in Example 1 of the present disclosure.

[0072] FIG4 is a SEM microscopic morphology of the artificial bone repair material prepared in Example 1 of the present disclosure.

[0073] FIG5 is a diagram of the interpenetrating microstructure of porous magnesium-containing tricalcium phosphate and collagen in the artificial bone repair material prepared in Example 1 of the present disclosure.

[0074] FIG6 is a photograph of the powder and debris in deionized water after the artificial bone repair material prepared in Comparative Example 1 was soaked in deionized water for 1 hour and repeatedly squeezed 50 times.

[0075] FIG7 shows the mixed solution prepared in Comparative Example 2, in which there is an obvious stratification phenomenon.

[0076] FIG8( a ) and FIG8 ( b ) are microscope photos of MC3T3-E1 bone progenitor cells cultured with the artificial bone repair material prepared in Example 1 of the present disclosure for 1 day and 3 days, respectively; FIG8 ( c ) and FIG8 ( d ) are microscope photos of MC3T3-E1 bone progenitor cells cultured in the blank control group for 1 day and 3 days, respectively.

[0077] FIG9 is an XRD pattern of the powder material prepared in Example 4 of the present invention.

[0078] Figure 10 is the XRD pattern of the powder material prepared in Comparative Example 3.

[0079] FIG11 is an XRD pattern of the powder material prepared in Comparative Example 4. DETAILED DESCRIPTION

[0080] The preferred embodiments of the present disclosure are described in detail below with reference to the accompanying drawings to make the advantages and features of the present disclosure more easily understood by those skilled in the art. It should be noted that the descriptions of these embodiments are intended to facilitate understanding of the present disclosure and do not constitute a limitation of the present disclosure. In addition, the technical features involved in the various embodiments of the present disclosure described below may be combined with each other as long as they do not conflict with each other.

[0081] The artificial bone repair material disclosed herein is a composite material with a porous structure. Its raw materials include collagen and porous magnesium-containing tricalcium phosphate powder. The porous magnesium-containing tricalcium phosphate powder is formed by spray-drying the precipitate after the reaction of calcium salt, magnesium salt and phosphate solution. The particle size of the magnesium-containing tricalcium phosphate powder is 1 to 20 μm. The mass percentage of magnesium-containing tricalcium phosphate in the artificial bone repair material is 50 to 95%; preferably, the mass percentage of magnesium-containing tricalcium phosphate in the artificial bone repair material is 70 to 95%; more preferably, the mass percentage of magnesium-containing tricalcium phosphate in the artificial bone repair material is 85 to 95%.

[0082] The mass ratio of the collagen to the porous magnesium-containing tricalcium phosphate powder in the raw material is 0.05 to 1. The collagen includes a combination of one or more of type I collagen, type II collagen, and recombinant collagen, and has a weight-average molecular weight of 100,000 to 350,000 Da.

[0083] Furthermore, the artificial bone repair material is prepared by cross-linking collagen and porous magnesium-containing tricalcium phosphate powder, wherein the cross-linking agent comprises one or a combination of glutaraldehyde and genipin.

[0084] Furthermore, the mass percentage of magnesium element in the porous magnesium-containing tricalcium phosphate powder is less than or equal to 3%, preferably 1-2%, and more preferably 1.3%-1.9 wt%.

[0085] Existing collagen and calcium phosphate composites primarily use hydroxyapatite as a primary component, significantly different from the concept of complete degradation and regeneration in this application. However, if degradable tricalcium phosphate is used, since most can only be prepared through high-temperature calcination, the resulting micron-sized, dense particles are difficult to stably disperse in collagen solutions, making effective composites with collagen difficult. The active tricalcium phosphate powder material in this application is a micron-sized, low-density, porous powder, which ensures uniform dispersion of the powder in the collagen and significantly increases the content of calcium phosphate ceramic powder (50-95%).

[0086] Compared with hydroxyapatite, tricalcium phosphate material has better degradation performance, so it has significant advantages in the application of bone repair materials. Tricalcium phosphate raw materials usually need to be prepared by high-temperature calcination or solid-phase reaction at a temperature of more than 1000 degrees, which requires a lot of energy and the product particles are in the micron level, with high density and irregular surface. At present, although some manufacturers can stably produce tricalcium phosphate powder raw materials, most of them calcine the raw materials through solid-phase reaction method and crush the powder through mechanical grinding, which is expensive. After sintering, the grains are large and have irregular geometric shapes, and the fluidity is poor in the process of preparing liquid-phase composite materials. The magnesium-containing tricalcium phosphate powder of the present application is prepared based on wet chemical reaction. It directly reacts wet chemically at 60~95℃ under normal pressure to generate a magnesium-containing tricalcium phosphate suspension, and a low-density porous magnesium-containing tricalcium phosphate powder of 1~20 μm is obtained through a special molding method of spray drying. This special micron-scale porous structure enables tricalcium phosphate powder to form an interlocking structure with collagen during the preparation of composite materials. It combines with the binding properties of collagen and has good dispersibility in the collagen solution, solving the problems of shedding and inflammation that may occur during the application of nanotricalcium phosphate powder, and has important practical application value.

[0087] This application overcomes the problem of low-temperature preparation of tricalcium phosphate. By manipulating the ion binding pathway in a liquid-phase reaction, a low-temperature chemical synthesis process for tricalcium phosphate has been developed, allowing reaction temperatures as low as 60-95°C, significantly reducing production costs by over 90%. This process avoids the harsh reaction conditions of high-temperature calcination (above 1000°C) and hydrothermal synthesis (160-250°C, 1.5 MPa). Furthermore, the powder material produced in this application is doped with active magnesium, which effectively promotes osteogenic differentiation of bone tissue cells and promotes new bone formation. To address the weak binding force and poor dispersibility of tricalcium phosphate materials during application, the active tricalcium phosphate material synthesized by this application's low-temperature wet chemical method is spray-dried to form a micron-sized, low-density porous powder. This unique porous structure enables the tricalcium phosphate powder to form an interlocking structure with polymers such as collagen during the preparation of bone repair materials, resulting in excellent dispersibility and binding properties. This solves the problems of shedding and inflammation that can occur with nano-tricalcium phosphate powders during application, and has important practical application value.

[0088] The artificial bone repair material disclosed herein is prepared by the following method: collagen is dissolved in an acid solution, porous magnesium-containing tricalcium phosphate powder is added, stirred evenly to form a mixed slurry, and dried and formed to obtain the artificial bone repair material; wherein the porous magnesium-containing tricalcium phosphate powder is formed by spray drying a precipitate obtained after the reaction of calcium salt, magnesium salt and phosphate solution, and has a particle size of 1 to 20 μm.

[0089] The above preparation method specifically comprises the following steps:

[0090] S101, dissolving collagen in an acid solution, adding porous magnesium-containing tricalcium phosphate powder, and stirring evenly to prepare a mixed slurry;

[0091] S102, adding a cross-linking agent to the mixed slurry, injecting the mixed slurry into a molding mold, and freeze-drying to obtain a molded composite material;

[0092] S103, removing the residual cross-linking agent in the composite material with an eluent solution, washing with pure water for multiple times, and drying to obtain the artificial bone repair material.

[0093] In step S101, the mass ratio of collagen to porous magnesium-containing tricalcium phosphate powder is 0.05 to 1, preferably 0.1 to 0.4, and more preferably 0.1 to 0.2. For example, the mass ratio of collagen to porous magnesium-containing tricalcium phosphate powder can be 0.05, 0.08, 0.1, 0.2, 0.3, 0.4, or 0.5.

[0094] The acid solution includes a hydrochloric acid solution and / or an acetic acid solution, with a concentration of 0.1 to 2 wt %. The concentration of collagen in the acid solution is 0.5 to 5 wt %, preferably 1 to 5 wt %, more preferably 1 to 3 wt %, and further 1.2 to 2 wt %. For example, the concentration of collagen in the acid solution is 0.5 wt %, 1.0 wt %, 1.2 wt %, 1.5 wt %, 2 wt %, 3 wt %, or 5 wt %. The collagen includes a combination of one or more of type I collagen, type II collagen, and recombinant collagen, and has a molecular weight of 100,000 to 350,000 Da.

[0095] Step S101 is specifically implemented as follows: Use an analytical balance to weigh collagen and micron-sized low-density porous magnesium-containing tricalcium phosphate powder. Use a balance to weigh the acid solution, add all the collagen to the solution, and use a polytetrafluoroethylene stirring paddle to stir at 300-1200 rpm until the collagen is completely dissolved. Then, add all the micron-sized low-density porous magnesium-containing tricalcium phosphate powder to the collagen solution and continue stirring for 5-30 minutes until the mixture is uniform. The porous magnesium-containing tricalcium phosphate powder used is prepared by the following steps:

[0096] (1) Dissolving a calcium salt and a magnesium salt in water to obtain a first solution, wherein the concentration of the calcium salt is 1 to 100 g / L, and the concentration of the magnesium salt is 0.4 to 40 g / L. Furthermore, the molar ratio of calcium ions to magnesium ions is 6 to 10; the concentration of the calcium salt is more preferably 30 to 100 g / L, further 50 to 100 g / L, further 60 to 90 g / L, and particularly 80 to 90 g / L; for example, 80 g / L, 82 g / L, 84 g / L, 86 g / L, 88 g / L, or 90 g / L. Optionally, the concentration of the magnesium salt is more preferably 0.4-30 g / L, further 5-30 g / L, further 15-30 g / L, particularly 20-30 g / L; for example, 20 g / L, 22 g / L, 24 g / L, 25 g / L, 27 g / L or 29 g / L.

[0097] (2) Dissolve phosphate in water and adjust the pH to 9.5-10.5, or further to 9.8-10.0, using an alkali solution (preferably ammonia or sodium hydroxide) to obtain a second solution, wherein the concentration of phosphate is 1-100 g / L. The concentration of phosphate in the second solution is more preferably 30-100 g / L, or further 50-90 g / L, or further 70-90 g / L, or particularly 80-90 g / L; for example, 81 g / L, 83 g / L, 84 g / L, 85 g / L, 87 g / L, or 88 g / L. More preferably, the pH is adjusted to 9.8-10.2 using ammonia. The inventors have found that the pH value has an important influence on the preparation of porous magnesium-containing tricalcium phosphate powder. According to X-ray diffraction results, a pH value that is too high or too low will produce more impurity phases, resulting in the porous magnesium-containing tricalcium phosphate powder containing more calcium hydrogen phosphate impurity phases or hydroxyapatite.

[0098] (3) Equal volumes of the first solution and the second solution were heated to 60-95°C and then mixed, and a wet chemical reaction was carried out at 60-95°C under stirring conditions at normal pressure, wherein the stirring rate was 100-500 rpm and the molar ratio of calcium ion to phosphate ion was 1.1-1.5.

[0099] (4) The suspension after the wet chemical reaction is centrifuged to obtain a precipitate, which is then washed 4 to 8 times with water. The washed precipitate is added to 5 to 20 times the mass of water and stirred evenly to form a slurry. The slurry is processed into micron-sized porous tricalcium phosphate powder using a spray dryer to obtain the bone repair raw material, wherein the inlet air temperature of the spray dryer is 240 to 300 °C, the outlet air temperature is 120 to 150 °C, and the feed rate is 30 to 200 mL / min.

[0100] The calcium salt includes a combination of one or more selected from anhydrous calcium chloride, calcium chloride dihydrate and calcium nitrate tetrahydrate; the magnesium salt includes a combination of one or more selected from magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate; and the phosphate includes a combination of one or more selected from disodium hydrogen phosphate, diammonium hydrogen phosphate and sodium hydrogen phosphate.

[0101] The micron-sized porous tricalcium phosphate powder has a particle size of 1 to 20 μm and a microscopically porous structure. The magnesium content therein is 1 to 2 wt%, preferably 1.3% to 1.9 wt%, showing excellent biological activity and effectively promoting new bone formation.

[0102] In step S102 , the cross-linking agent includes one or a combination of glutaraldehyde and genipin, and the concentration of the cross-linking agent in the mixed slurry is 1-100 ppm.

[0103] Step S102 is specifically implemented as follows: add a cross-linking agent with a concentration of 0.1-10 ppm to the mixed slurry and inject 1-50 mL into a container with a bottom area of ​​1-25 cm 2 The slurry is placed in a mold and shaken to level the surface. The mold is then placed in a freezer at -4 to -80°C and then removed from the mold and freeze-dried to produce a preformed composite material. The freeze-drying temperature is -20 to -80°C, and mold materials include, but are not limited to, silicone, polytetrafluoroethylene, and medical stainless steel.

[0104] Step S103 is specifically performed as follows: the composite material is immersed in an eluent solution for 0.5 to 24 hours, the eluted composite material is placed in pure water and stirred and washed at 200-600 rpm for 6 to 24 hours, and the composite material having a water content of 90-97 wt % is then vacuum dried to obtain a collagen / magnesium-containing tricalcium phosphate artificial bone repair material. The eluent includes, but is not limited to, polyvinyl alcohol, sodium borohydride, and the like, with a concentration of 0.05-3 wt %. The vacuum degree during the vacuum drying process is 1-50 Pa, and the cold trap temperature is -40 to -80°C.

[0105] The prepared collagen / magnesium-containing tricalcium phosphate artificial bone repair material has a porosity of 70-95%, a maximum pore size greater than 300 μm, and a magnesium-containing tricalcium phosphate content of 50-95 wt %, preferably 85-95 wt %. Example 1

[0106] (1) Preparation of porous magnesium-containing tricalcium phosphate powder

[0107] Weighing and dissolving: Weigh 900 g of anhydrous calcium chloride and 270 g of magnesium chloride hexahydrate, dissolve in 10 L of water to obtain solution A; weigh 830 g of diammonium hydrogen phosphate, dissolve in 10 L of water, and adjust the pH of the solution to 10.0 with ammonia water to obtain solution B.

[0108] Heat and mix: Heat solution A and solution B to 70°C and mix, stirring continuously at 100 rpm to form a suspension.

[0109] Wet chemical reaction: The mixed suspension was heated and stirred at 70°C and 100 rpm for 12 hours.

[0110] Centrifugal washing: The suspension after the wet chemical reaction was centrifuged at 2000 rpm for 3 minutes to obtain the precipitate, and water was added and centrifuged for washing 5 times.

[0111] Spray Drying: Add the cleaned precipitate to 10 L of water and stir to form a slurry. Set the spray dryer's inlet air temperature to 250°C and the outlet air temperature to 120°C. Spray dry the slurry at a rate of 50 mL / min to obtain a micron-sized, low-density, porous tricalcium phosphate powder with a particle size distribution of 1 to 20 μm.

[0112] Testing: The X-ray diffraction results of micron-sized, low-density, porous magnesium-containing tricalcium phosphate powder are shown in Figure 1, where the mass percentage of magnesium is 1.9%. The microscopic morphology of the micron-sized, low-density, porous tricalcium phosphate powder is shown in Figure 2. The powder exhibits a porous structure. This unique porous structure enables the magnesium-containing tricalcium phosphate powder to form an interlocking structure with the polymer during the preparation of composite materials.

[0113] (2) Preparation of artificial bone repair materials

[0114] Weighing and Dissolving: Use an analytical balance to weigh 0.4g of type I collagen. Also weigh 20g of 0.1% dilute hydrochloric acid solution. Add all of the collagen to the solution and stir at 400rpm using a PTFE stirrer for 1 hour to prepare a collagen solution. Also use an analytical balance to weigh 2.4g of the porous magnesium-containing tricalcium phosphate powder prepared above.

[0115] Mixing preparation: Add all the weighed porous magnesium-containing tricalcium phosphate powder to the collagen solution, stir with a PTFE stirring paddle at 400 rpm for 10 minutes until the mixture is uniformly stirred to prepare a mixed solution.

[0116] Cross-linking molding: 20 μL of 25% glutaraldehyde solution was added to the mixed solution. Stirring was performed at 400 rpm using a PTFE stirrer for 1 minute. The mixture was then poured into a polytetrafluoroethylene mold and gently shaken until the liquid surface was flat. The mold was then frozen in a -20°C freezer for 6 hours. The mold was then demolded and freeze-dried at -70°C for 48 hours to obtain a pre-formed composite material.

[0117] Cleaning: Immerse the composite material in a 1 wt % sodium borohydride solution for 0.5 hours to remove residual crosslinker. Then, rinse again with 10 times the volume of pure water at 400 rpm for 24 hours.

[0118] Freeze drying: The cleaned sample was placed in a -20°C refrigerator and frozen for 6 hours, and then freeze-dried for 36 hours to finally obtain the collagen / magnesium-containing tricalcium phosphate artificial bone repair material.

[0119] Detection: The micromorphology of the collagen / magnesium-containing tricalcium phosphate artificial bone repair material is shown in Figure 3. The results show that collagen is well combined with magnesium-containing tricalcium phosphate and maintains a micron-scale porous magnesium-containing tricalcium phosphate microstructure. As shown in Figure 4, the collagen / magnesium-containing tricalcium phosphate artificial bone repair material has obtained an excellent flaky fiber microstructure through a physical and chemical synergistic cross-linking process. As shown in Figure 5, the micron-scale low-density porous magnesium-containing tricalcium phosphate powder forms an interpenetrating microstructure with collagen. The porous magnesium-containing tricalcium phosphate powder has good binding properties with collagen, avoiding the problems of shedding and inflammation of the tricalcium phosphate powder during application. The mass percentage of magnesium-containing tricalcium phosphate in the artificial bone repair material is 85%. Example 2

[0120] Weighing and Dissolving: Weigh 0.25 g of type I collagen using an analytical balance. Weigh 20 g of 0.5% acetic acid solution using a balance. Add all of the collagen to the solution and stir using a PTFE stirrer at 1000 rpm for 0.3 hours to prepare a collagen solution. Weigh 1 g of the porous magnesium-containing tricalcium phosphate powder prepared in Example 1.

[0121] Mixing configuration: Add all the porous magnesium-containing tricalcium phosphate powder to the collagen solution, stir with a PTFE stirring paddle at 1000 rpm for 10 minutes until the mixture is uniformly stirred to prepare a mixed solution.

[0122] Cross-linking molding: Add 10 μL of 25% glutaraldehyde solution to the mixed solution. Stir at 1000 rpm using a PTFE paddle for 1 minute, then pour into a silicone mold and gently shake until the liquid surface is flat. The mold is then frozen in a -20°C freezer for 6 hours. After demolding, the mold is freeze-dried at -70°C for 48 hours to obtain a pre-formed composite material.

[0123] Cleaning: Immerse the composite material in 0.15 wt % sodium borohydride solution for 1 hour to remove residual crosslinker. Then, rinse again with 10 times the volume of pure water at 400 rpm for 24 hours.

[0124] Freeze-drying: The cleaned sample was placed in a -20°C freezer for 6 hours, followed by freeze-drying for 36 hours to obtain a collagen / magnesium-containing tricalcium phosphate artificial bone repair material. The weight percentage of magnesium-containing tricalcium phosphate in the artificial bone repair material was 80%. Example 3

[0125] Weighing and Dissolving: Using an analytical balance, weigh 4g of type I collagen. Also weigh 80g of 0.1% dilute hydrochloric acid solution. Add the entire amount of collagen to the solution. Stir using a PTFE paddle at 800 rpm for 0.5 hours. Weigh 8g of the porous magnesium-containing tricalcium phosphate powder prepared in Example 1.

[0126] Mixing configuration: Add all the porous magnesium-containing tricalcium phosphate powder into the collagen solution, stir with a PTFE stirring paddle at 800 rpm for 10 minutes until the mixture is uniformly stirred to prepare a mixed solution.

[0127] Cross-linking molding: 40 μL of 25% glutaraldehyde solution was added to the mixed solution. Stirring was performed at 800 rpm using a PTFE paddle for 1 minute. The mixture was then poured into a 316L medical stainless steel mold and gently shaken until the liquid surface was flat. The mold was then frozen in a -20°C freezer for 6 hours. The mold was then demolded and freeze-dried at -70°C for 48 hours to obtain a pre-formed composite material.

[0128] Cleaning: Immerse the composite material in a 0.5 wt.% sodium borohydride solution for 1 hour to remove any residual chemical crosslinking reagents. Then, rinse again with 10 times the volume of pure water at 400 rpm for 24 hours.

[0129] Freeze-drying: The cleaned sample was placed in a -20°C freezer for 6 hours, followed by freeze-drying for 36 hours to obtain a collagen / magnesium-containing tricalcium phosphate artificial bone repair material. The weight percentage of magnesium-containing tricalcium phosphate in the artificial bone repair material was 67%. Comparative Example 1

[0130] Weighing and Dissolving: Using an analytical balance, weigh 0.4g of type I collagen. Also weigh 20g of 0.1% dilute hydrochloric acid solution. Add all of the collagen to the solution and stir at 400rpm using a PTFE paddle for 1 hour to prepare a collagen solution. Also weigh 2.4g of magnesium-containing tricalcium phosphate nanopowder, prepared according to Example 1 of Patent ZL201610290891.8, using an analytical balance.

[0131] Mixing preparation: Add all the weighed magnesium tricalcium phosphate nanopowder into the collagen solution, stir with a PTFE stirring paddle at 400 rpm for 10 minutes until the mixture is uniformly stirred to prepare a mixed solution.

[0132] Cross-linking molding: Add 20 μL of 25% glutaraldehyde solution to the mixed solution. Stir at 400 rpm using a PTFE paddle for 1 minute, then pour into a silicone mold and gently shake until the liquid surface is flat. The mold is then frozen in a -20°C freezer for 6 hours. After demolding, the mold is freeze-dried at -70°C for 48 hours to obtain a pre-formed composite material.

[0133] Cleaning: Immerse the composite material in a 1 wt % sodium borohydride solution for 0.5 hours to remove residual crosslinker. Then, rinse again with 10 times the volume of pure water at 400 rpm for 24 hours.

[0134] Freeze-drying: The cleaned sample was placed in a -20°C freezer for 6 hours and then freeze-dried for 36 hours to obtain a composite material. As shown in Figure 6, the resulting composite material was repeatedly squeezed 50 times in pure water and then removed. It exhibited disintegration and powder shedding in pure water. Comparative Example 2

[0135] Weighing and Dissolving: Using an analytical balance, weigh 1.6g of type I collagen. Also weigh 80g of 0.1% dilute hydrochloric acid solution. Add all of the collagen to the solution and stir at 400rpm using a PTFE stirrer for 1 hour to prepare a collagen solution. Also weigh 9.6g of tricalcium phosphate, prepared by calcining at 1100°C, using an analytical balance.

[0136] Mixing: Add all the weighed tricalcium phosphate powder to the collagen solution and stir with a PTFE impeller at 400 rpm for 10 minutes until uniform. This creates a mixed solution. As shown in Figure 7, after standing for 0.5 hours, the mixed solution exhibited significant delamination, making it impossible to prepare the composite material.

[0137] Extract cell experiment

[0138] MC3T3-E1 bone progenitor cells were cultured with the collagen / porous magnesium-containing tricalcium phosphate composite material extract prepared in Example 1, as well as a blank control group. Microscopic observation was performed after one and three days of culture. The results are shown in Figures 8(a) through 8(d). Referring to the accompanying figures, the extract cell experiments demonstrated that the artificial repair material of Example 1 exhibited good cell growth during application, was non-cytotoxic, and exhibited excellent biocompatibility.

[0139] The collagen / porous magnesium-containing tricalcium phosphate composite material of this embodiment realizes a fully degradable design in vivo by using degradable collagen and tricalcium phosphate materials as raw materials. It is expected that while the material degrades in vivo, new bone tissue will grow in until the bone defect site is completely replaced. The active magnesium element doped in the magnesium-containing tricalcium phosphate material can effectively promote the osteogenic differentiation of bone tissue cells and promote new bone formation. The porous powder structure of the porous magnesium-containing tricalcium phosphate will not show stratification and precipitation after being dispersed in the collagen solution, which significantly increases the content of calcium phosphate ceramic powder (65~95%); its particle size is 5~20 μm, and it maintains its agglomerated state during the molding process of the composite material. Example 4

[0140] Weighing and dissolving: Weigh 1800 g of anhydrous calcium chloride and 400 g of magnesium chloride hexahydrate, dissolve them in 20 L of water to obtain solution A; weigh 1700 g of diammonium hydrogen phosphate, dissolve it in 20 L of water, and adjust the pH of the solution to 9.8 with ammonia water to obtain solution B.

[0141] Heat and mix: Heat solution A and solution B to 90°C and mix, stirring continuously at 100 rpm to form a suspension.

[0142] Wet chemical reaction: The mixed suspension was heated and stirred at 90°C and 100 rpm for 4 hours.

[0143] Centrifugal washing: The suspension after the wet chemical reaction was centrifuged at 2000 rpm for 3 minutes to obtain the precipitate, and water was added and centrifuged for washing 5 times.

[0144] Spray Drying: Add the cleaned precipitate to 20 L of water and stir to form a slurry. Set the spray dryer's inlet air temperature to 270°C and outlet air temperature to 140°C. Spray dry the slurry at a rate of 100 mL / min to obtain micron-sized, low-density, porous tricalcium phosphate powder with a particle size distribution ranging from 1 to 20 μm.

[0145] Testing: The X-ray diffraction results of micron-sized low-density porous tricalcium phosphate powder are shown in Figure 9, where the mass percentage of magnesium is 1.3%. Comparative Example 3

[0146] Weighing and dissolving: Weigh 1800 g of anhydrous calcium chloride and 300 g of magnesium chloride hexahydrate, dissolve them in 20 L of water to obtain solution A; weigh 1700 g of diammonium hydrogen phosphate, dissolve it in 20 L of water, and adjust the pH of the solution to 9.3 with aqueous ammonia to obtain solution B.

[0147] Heat and mix: Heat solution A and solution B to 90°C and mix, stirring continuously at 100 rpm to form a suspension.

[0148] Wet chemical reaction: The mixed suspension was heated and stirred at 90°C and 100 rpm for 4 hours.

[0149] Centrifugal washing: The suspension after the wet chemical reaction was centrifuged at 2000 rpm for 3 minutes to obtain the precipitate, and water was added and centrifuged for washing 5 times.

[0150] Spray Drying: Add the cleaned precipitate to 20 L of water and stir to form a slurry. Set the spray dryer's inlet air temperature to 270°C and the outlet air temperature to 140°C. Spray dry the slurry at a rate of 100 mL / min to obtain a micron-sized, low-density, porous tricalcium phosphate powder.

[0151] Detection: The X-ray diffraction results of tricalcium phosphate powder are shown in Figure 10. As shown in Figure 10, the porous tricalcium phosphate powder contains impurity phases, mainly calcium hydrogen phosphate impurity phases. Comparative Example 4

[0152] The preparation process of Comparative Example 4 differs from that of Example 4 in that diammonium hydrogen phosphate is dissolved in water and then the pH value of the solution is adjusted to 10.8 with aqueous ammonia, and the other steps are the same.

[0153] The obtained powder material was subjected to XRD detection. According to the X-ray diffraction results shown in FIG11 , the powder material prepared in Comparative Example 4 contained a relatively large amount of hydroxyapatite.

[0154] As used in this specification and claims, the terms "comprises" and "include" merely indicate the inclusion of the steps and elements specifically identified, and these steps and elements do not constitute an exclusive list; a method or apparatus may also include other steps or elements. The term "and / or" as used herein includes any combination of one or more of the associated listed items.

[0155] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0156] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In the event of any conflict or inconsistency between the definitions used herein and those in other published documents, the definitions used herein shall prevail.

[0157] The above embodiment is only for illustrating the technical concept and features of the present disclosure and is a preferred embodiment. Its purpose is to enable people familiar with this technology to understand the content of the present disclosure and implement it accordingly, and it is not intended to limit the scope of protection of the present disclosure.

Claims

1. An artificial bone repair material, which is a composite material with a porous structure, and its raw materials include collagen and porous magnesium-containing tricalcium phosphate powder, wherein the porous magnesium-containing tricalcium phosphate powder is formed by spray drying a precipitate obtained after a reaction between a calcium salt, a magnesium salt and a phosphate solution, and the particle size of the porous magnesium-containing tricalcium phosphate powder is 1-20 μm; the mass percentage of the porous magnesium-containing tricalcium phosphate in the artificial bone repair material is 50-95%.

2. The artificial bone repair material according to claim 1, characterized in that: The mass ratio of the collagen to the porous magnesium-containing tricalcium phosphate powder in the raw material is 0.05-1.

3. The artificial bone repair material according to claim 1 or 2, characterized in that: The mass percentage of porous magnesium-containing tricalcium phosphate in the artificial bone repair material is 85-95%, and the porosity of the artificial bone repair material is 70-95%.

4. The artificial bone repair material according to any of the preceding claims, characterized in that The artificial bone repair material is prepared by cross-linking and composite molding of collagen and porous magnesium-containing tricalcium phosphate powder.

5. The artificial bone repair material according to any of the preceding claims, characterized in that The mass percentage of magnesium element in the porous magnesium-containing tricalcium phosphate powder is less than or equal to 3%.

6. The artificial bone repair material according to any of the preceding claims, characterized in that The porous magnesium-containing tricalcium phosphate powder is prepared by the following steps: A mixed solution of calcium salt and magnesium salt is prepared as the first solution; a phosphate solution is prepared and the pH is adjusted to 9.5-10.5 with alkaline solution as the second solution; The first solution and the second solution are heated and mixed, and reacted at 60-95° C. with stirring; The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed and spray-dried to obtain a porous magnesium-containing tricalcium phosphate powder.

7. A method for preparing an artificial bone repair material, comprising: The collagen is dissolved in an acid solution, and porous magnesium-containing tricalcium phosphate powder is added, stirred evenly to form a mixed slurry, and dried to form an artificial bone repair material; wherein the porous magnesium-containing tricalcium phosphate powder is formed by spray drying a precipitate after the reaction of calcium salt, magnesium salt and phosphate solution, and has a particle size of 1-20 μm.

8. The method for preparing the artificial bone repair material according to claim 7, characterized in that: The preparation method comprises the following steps: S101, dissolving collagen in an acid solution, adding porous magnesium-containing tricalcium phosphate powder, and stirring evenly to obtain a mixed slurry; S102, adding a crosslinking agent to the mixed slurry, injecting the mixed slurry into a molding mold, and freeze-drying the mixed slurry to obtain a molded composite material; S103, removing the residual cross-linking agent in the composite material with an eluent solution, washing with pure water for multiple times, and drying to obtain the artificial bone repair material.

9. The method for preparing the artificial bone repair material according to claim 7 or 8, characterized in that: The mass ratio of collagen to porous magnesium-containing tricalcium phosphate powder is 0.05-1; the mass percentage of magnesium element in the porous magnesium-containing tricalcium phosphate powder is less than or equal to 3%.

10. The method for preparing an artificial bone repair material according to any one of claims 7 to 9, characterized in that: The acid solution includes a hydrochloric acid solution or an acetic acid solution, and the concentration is 0.1~2 wt %; the concentration of the collagen in the acid solution is 0.5~5 wt %; the collagen includes a combination of one or more selected from type I collagen, type II collagen and recombinant collagen, and the weight average molecular weight is 100000~350000 Da.

11. The method for preparing an artificial bone repair material according to claim 8, characterized in that: Step S102 is specifically implemented as follows: 1-100 ppm of a cross-linking agent is added to the mixed slurry and then injected into a molding mold, the mold is shaken to make the slurry liquid surface flat, and then the mold is placed in a -4 to -80 ° C environment to freeze, and then demolded to obtain a molded composite material through a freeze-drying method; wherein the cross-linking agent includes one or a combination of glutaraldehyde and genipin, and the freeze-drying temperature is -20 to -80 ° C.

12. The method for preparing the artificial bone repair material according to claim 8 or 11, characterized in that: Step S103 is specifically implemented as follows: soaking the composite material in an eluent solution for 0.5 to 24 hours, placing the eluted composite material in pure water and stirring and washing it at a speed of 200 to 600 rpm for 6 to 24 hours, and then vacuum drying the composite material with a water content greater than 90 wt % to obtain a collagen / magnesium-containing tricalcium phosphate artificial bone repair material; wherein the eluent includes a combination of one or more selected from polyvinyl alcohol and sodium borohydride, with a concentration of 0.05 to 3 wt %; the vacuum degree of the vacuum drying treatment is 1 to 50 Pa, and the cold trap temperature is -40 to -80 ° C.

13. The method for preparing an artificial bone repair material according to any one of claims 7 to 12, characterized in that: The preparation method further comprises a preparation step of preparing the porous magnesium-containing tricalcium phosphate powder, and the preparation step specifically comprises: A mixed solution of calcium salt and magnesium salt is prepared as the first solution; a phosphate solution is prepared and the pH is adjusted to 9.5-10.5 with alkaline solution as the second solution; The first solution and the second solution are heated and mixed, and reacted at 60-95° C. with stirring; The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed and spray-dried to obtain a porous magnesium-containing tricalcium phosphate powder.

14. The method for preparing an artificial bone repair material according to claim 13, characterized in that: The molar ratio of calcium ions to magnesium ions in the first solution is 6-10; after the first solution and the second solution are mixed, the molar ratio of calcium ions to phosphate ions is 1.1-1.5; the calcium salt includes a combination of one or more selected from anhydrous calcium chloride, calcium chloride dihydrate and calcium nitrate tetrahydrate, the magnesium salt includes a combination of magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate, the phosphate includes a combination of multiple selected from one of disodium hydrogen phosphate, diammonium hydrogen phosphate and sodium hydrogen phosphate, and the alkali solution is ammonia water or sodium hydroxide.

15. The method for preparing the artificial bone repair material according to claim 13 or 14, characterized in that: The washed precipitate is spray dried using a spray dryer, wherein the inlet air temperature of the spray dryer is 240-300°C, the outlet air temperature is 120-150°C, and the feed rate is 30-200 mL / min.

16. A method for preparing porous magnesium-containing tricalcium phosphate powder for artificial bone repair material, comprising the following steps: (i) preparing a mixed solution of calcium salt and magnesium salt as a first solution; preparing a phosphate solution and adjusting the pH to 9.5-10.5 with an alkali solution as a second solution; (ii) heating and mixing the first solution and the second solution, and reacting them at 60-95° C. with stirring; (iii) The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed and spray-dried to obtain a porous magnesium-containing tricalcium phosphate powder.

17. The preparation method according to claim 16, characterized in that: The molar ratio of calcium ions to magnesium ions in the first solution is 6-10.

18. The method for preparing bone repair raw material according to claim 15, characterized in that: The molar concentration of calcium ions in the first solution is 0.01-0.9 mol / L, and the molar concentration of magnesium ions is 0.001-0.15 mol / L.

19. The method for preparing a bone repair raw material according to any one of claims 16 to 18, characterized in that: After the first solution and the second solution are mixed, the molar ratio of calcium ions to phosphate ions is 1.1 to 1.

5.

20. The method for preparing bone repair raw material according to claim 19, characterized in that: The molar concentration of phosphate in the second solution is 0.008-0.8 mol / L.

21. The method for preparing a bone repair raw material according to any one of claims 16 to 20, characterized in that: The calcium salt includes a combination of one or more selected from anhydrous calcium chloride, calcium chloride dihydrate and calcium nitrate tetrahydrate, the magnesium salt includes magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate, the phosphate includes a combination of multiple selected from one of disodium hydrogen phosphate, diammonium hydrogen phosphate and sodium hydrogen phosphate, and the alkali solution is ammonia water or sodium hydroxide.

22. The method for preparing a bone repair raw material according to any one of claims 16 to 21, characterized in that: In step (i), the pH of the second solution is adjusted to 9.5-10.5 using aqueous ammonia.

23. The method for preparing a bone repair raw material according to any one of claims 16 to 22, characterized in that: In step (ii), the first solution and the second solution are heated to 60-95° C. and then mixed.

24. The method for preparing a bone repair raw material according to any one of claims 16 to 23, characterized in that: In step (ii), the stirring rate is 100-500 rpm.

25. The method for preparing a bone repair raw material according to any one of claims 16 to 24, characterized in that: In step (iii), the washed precipitate is spray dried using a spray dryer, wherein the inlet air temperature of the spray dryer is 240-300°C, the outlet air temperature is 120-150°C, and the feed rate is 30-200 mL / min.

26. The method for preparing the bone repair raw material according to claims 16 to 25, characterized in that: In step (iii), the precipitate is added to water and centrifuged for multiple washings, the washed precipitate is added to water with a mass of 5 to 20 times, stirred evenly to form a slurry, and then spray dried.

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