WO2021083369A1 - 镁锶 - 磷酸硅盐材料及制备方法、包含其的结构可控的多孔骨修复复合支架材料 - Google Patents

镁锶 - 磷酸硅盐材料及制备方法、包含其的结构可控的多孔骨修复复合支架材料 Download PDF

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WO2021083369A1
WO2021083369A1 PCT/CN2020/125505 CN2020125505W WO2021083369A1 WO 2021083369 A1 WO2021083369 A1 WO 2021083369A1 CN 2020125505 W CN2020125505 W CN 2020125505W WO 2021083369 A1 WO2021083369 A1 WO 2021083369A1
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composite scaffold
strontium
magnesium
bone repair
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PCT/CN2020/125505
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French (fr)
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张鹏
李健
白雪岭
成文翔
王新峦
赖毓霄
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深圳先进技术研究院
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Definitions

  • the invention belongs to the technical field of biomedical tissue engineering, and relates to a magnesium strontium-silicon phosphate salt material and a preparation method, and a porous bone repair composite scaffold material with a controllable structure containing the magnesium strontium-silicon phosphate material.
  • silicate bioceramic materials are very similar to natural bone minerals in physical and chemical properties, have good biocompatibility and osteoconductivity, and can promote direct chemical bonding with bone, which has been studied in the field of bone tissue engineering.
  • silicate ceramics can adjust the chemical composition, by introducing different contents of ions that promote bone angiogenesis into the ceramic components, not only can the mechanical strength and degradation rate of the material be adjusted and controlled, but also the ceramic material can be improved in bone repair. In terms of biological effects, it can improve bone tissue regeneration.
  • SPS strontium-phosphosilicate
  • Sr 5 (PO 4 ) 2 SiO 4 bioceramics
  • Sr functions similarly to Ca in bones.
  • Magnesium (Mg 2+ ) is an essential element for the human body, and its content is the 10th element in the human body. About 65% of magnesium is present in bones and teeth. Studies have shown that magnesium (Mg 2+ ) can not only induce vascular endothelial cells to produce nitric oxide and enhance endothelial cell migration and proliferation; it can also mobilize endothelial progenitor cells (EPCs), increase the production of VEGF, promote the formation of new blood vessels, and maintain blood vessels. Function play an important physiological function (Katakawa M, Fukuda N, Tsunemi A, Mori M, Maruyama T, Matsumoto T, et al.
  • bioceramic scaffold materials have limited their clinical applications due to their weak mechanical strength, fracture toughness, and high brittleness. Therefore, multi-functional composite scaffold materials have begun to appear widely in basic research and clinical applications of tissue repair.
  • polymer-bioactive ceramic composite materials because they have the advantages of each component, make composite scaffold materials show good clinical performance in terms of histocompatibility, mechanical strength, bone conduction and osteoinductivity.
  • the application prospect has become a hot spot in bone tissue engineering research and a new clinical treatment method.
  • the purpose of the present invention is to provide a magnesium strontium-silicate phosphate material and preparation method, and a porous bone repair composite scaffold material with a controllable structure containing the same.
  • the composite scaffold material provided by the present invention has excellent biocompatibility and degradability
  • the strontium (Sr) and magnesium (Mg) ions released by transplantation into the body have the activity of promoting osteogenic angiogenesis.
  • the degradation products of the composite scaffold can also promote the proliferation, differentiation and mineralization of osteoblasts, while inhibiting the activity of osteoclasts. Because of its anti-osteoporosis effect, the composite scaffold material provided by the present invention shows great application potential in preparing bone defect repair, especially osteoporotic bone defect repair scaffolds.
  • the present invention provides a magnesium strontium-silicon phosphate material
  • the magnesium strontium-silicon phosphate material has the following structural formula:
  • the 0 ⁇ x ⁇ 5 can be 0.01, 0.05, 0.1, 0.2, 0.4, 0.5, 0.8, 1, 1.2, 1.4, 1.5, 1.8, 2.0, 2.2, 2.5, 2.8, 3.0, 3.2, 3.4, 3.5, 3.8 , 4.0, 4.2, 4.5, 4.8, 4.9, etc.
  • magnesium ions and strontium ions have a synergistic effect.
  • the two work together to promote the proliferation and differentiation of osteoblasts, which is beneficial to osteogenesis and osteogenesis in the process of bone repair.
  • Vascular function shortens the repair time of bone defects.
  • magnesium ions and strontium ions are based on Sr 5-x Mg x (PO 4 ) 2 SiO 4 provided in this application. It has a better effect on promoting the proliferation and differentiation of osteoblasts for bone repair.
  • the present invention provides a method for preparing the magnesium strontium-silicate phosphate material according to the first aspect, and the preparation method includes the following steps:
  • the molar ratio of the Sr source and the Mg source is (5-x):x, 0 ⁇ x ⁇ 5, such as 4.99:0.01, 4.5:0.5, 4:1, 3:2, 2:3, 1 :4, 0.5:4.5, 0.01:4.99.
  • the solvent of the mixed solution of the Sr source and the Mg source is double distilled water.
  • the Sr source is selected from strontium nitrate; the Mg source is selected from magnesium nitrate hexahydrate.
  • the molar ratio of the P source and the Si source is 2:1.
  • the P source is selected from triethyl phosphate
  • the Si source is selected from ethyl orthosilicate.
  • the mixing time is 1-3 h, such as 1.5 h, 1.8 h, 2.0 h, 2.5 h and the like.
  • the aging temperature is room temperature, and the time is 24-30 h, such as 25 h, 28 h, 29 h, etc.
  • the temperature of the reaction is 80-90°C, such as 82°C, 85°C, 88°C, etc.
  • the time is 16-20 h, such as 17 h, 18 h, 19 h, etc.
  • the temperature of the polycondensation is 75-85°C, such as 78°C, 80°C, 82°C, etc.
  • the time is 5-10 h, such as 6 h, 7 h, 8 h, 9 h, etc.
  • the drying is first drying at 100-120°C (for example, 105°C, 110°C, 115°C) for 5-8 h (for example, 6 h, 7 h, etc.), and then drying at 850-900°C (for example, 860°C). , 870°C, 880°C, 890°C, etc.) for 2-3 h (for example, 2.2 h, 2.5 h, 2.8 h, etc.).
  • the invention synthesizes the bioceramic material containing magnesium ion and strontium ion by using the sol-gel method.
  • the present invention provides an application of the magnesium strontium-silicate phosphate material according to the first aspect in the preparation of a bone repair composite scaffold material.
  • the present invention provides a porous bone repair composite scaffold material with a controllable structure.
  • the porous bone repair composite scaffold material with a controllable structure includes polyhydroxyalkanoate and the magnesium strontium-phosphate described in the first aspect. Silicon salt material.
  • the polyhydroxy fatty acid ester used in the present invention has good biocompatibility and degradability.
  • the degradation product 3-hydroxybutyric acid (3HB) is one of the main components of the ketone body in the mammalian body. It can promote the proliferation, differentiation and mineralization of osteoblasts. It can also inhibit the activity of osteoclasts and has anti-osteoporosis effects.
  • the present invention combines polyhydroxy fatty acid esters and magnesium strontium-silicon phosphate materials to ensure the advantages of bioceramic scaffold materials, and uses polyhydroxy fatty acid esters to make up for the lack of mechanical properties, so that the present invention provides While the composite scaffold material has good biocompatibility, it can promote osteogenesis and angiogenesis, and has good mechanical strength, which can meet application requirements.
  • the mass ratio of the polyhydroxy fatty acid ester and the magnesium strontium-silicon phosphate material is (0.5-5):1, such as 1:1, 1.5:1, 2:1, 2.5:1, 3:1 , 3.5:1, 4:1, 4.5:1, etc., preferably (1-3):1.
  • the polyhydroxy fatty acid ester is selected from poly-3-hydroxybutyrate, poly-3-hydroxyvalerate, poly-3-hydroxyhexanoate, 3-hydroxybutyrate-3-hydroxyvalerate Any one or a combination of at least two of the copolyester or 3-hydroxybutyrate-3-hydroxyhexanoic acid copolyester.
  • the polyhydroxy fatty acid ester selected in the present invention has good mechanical strength, and when it is used in a bone repair composite scaffold material, its mechanical strength is good, and it has a good application effect.
  • the porous bone repair composite scaffold material with controllable structure has a porosity of 60-80%, such as 62%, 64%, 66%, 68%, 70%, 72%, 75%, 78%, etc.
  • the porous bone repair composite scaffold material with controllable structure has a pore connectivity rate of 60-90%, such as 62%, 64%, 66%, 68%, 70%, 72%, 75%, 78%, 80%, 82%, 85%, 88%, etc.
  • the pore size of the porous bone repair composite scaffold material with controllable structure is 200-400 ⁇ m, for example, 220 ⁇ m, 250 ⁇ m, 280 ⁇ m, 300 ⁇ m, 320 ⁇ m, 350 ⁇ m, 380 ⁇ m, etc.
  • the present invention provides a method for preparing a porous bone repair composite scaffold material with a controllable structure according to the fourth aspect.
  • the preparation method includes the following steps:
  • the solvent of the polyhydroxy fatty acid ester solution is 1,4-dioxane and/or chloroform.
  • the concentration of the polyhydroxy fatty acid ester is 1-2 g/mL, such as 1.1 g/mL, 1.2 g/mL, 1.4 g/mL, 1.6 g/mL mL, 1.8 g/mL, etc.
  • the printing parameters are: a nozzle diameter of 50 ⁇ m, a nozzle moving speed of 10 mm/s, a spinning speed of 25 mm 3 /s, and a printing size of 20 ⁇ 20 ⁇ 30 mm.
  • the invention can realize the controllable structure of the porous bone repair composite scaffold material by controlling the printing parameters of the low-temperature printer.
  • controllable structure in the present invention refers to the controllable porosity, pore size, and pore connectivity rate of the composite scaffold.
  • freeze-drying Before the freeze-drying, it is first frozen at a temperature lower than -20°C (can be -25°C, -30°C, -40°C, -50°C, etc.) for at least 6 h (may be 6.5 h, 7 h, 8 h, 10 h, etc.).
  • the present invention provides an application of the porous bone repair composite scaffold material with a controllable structure according to the fourth aspect in the preparation of bone defect filling materials or bone defect repair materials.
  • the bone defect is an osteoporotic bone defect.
  • the present invention has the following beneficial effects:
  • magnesium ions and strontium ions have a synergistic effect.
  • the two work together to promote the proliferation and differentiation of osteoblasts, which is beneficial to the bone repair process.
  • the function of bone and vascularization shortens the repair time of bone defect.
  • the present invention uses polyhydroxy fatty acid esters and magnesium strontium-silicate phosphate materials to compound, while ensuring the advantages of bioceramic scaffold materials, and uses polyhydroxy fatty acid esters to make up for the shortcomings of its mechanical properties. While the composite scaffold material provided by the present invention has good biocompatibility, it can promote osteogenesis and angiogenesis, and has good mechanical strength, which can meet application requirements.
  • Fig. 1 is an XRD pattern of the magnesium strontium-silicate phosphate material provided in Examples 1-3.
  • FIG. 2A is an SEM image of the magnesium strontium-silicon phosphate material provided in Example 1.
  • FIG. 2B is an SEM image of the magnesium strontium-silicate phosphate material provided in Example 2.
  • 2C is an SEM image of the magnesium strontium-silicon phosphate material provided in Example 3.
  • FIG. 3A is an EDS diagram of the magnesium strontium-silicon phosphate salt material provided in Example 1.
  • FIG. 3A is an EDS diagram of the magnesium strontium-silicon phosphate salt material provided in Example 1.
  • FIG. 3B is an EDS diagram of the magnesium strontium-silicon phosphate material provided in Example 2.
  • FIG. 3B is an EDS diagram of the magnesium strontium-silicon phosphate material provided in Example 2.
  • 3C is an EDS diagram of the magnesium strontium-silicon phosphate material provided in Example 3.
  • FIG. 3C is an EDS diagram of the magnesium strontium-silicon phosphate material provided in Example 3.
  • Figure 4 is an apparent topography diagram of the porous bone repair composite scaffold provided in Example 1
  • Figure 5A is a graph showing the results of samples provided in Examples 1-3 and Comparative Example 1 for enhancing the osteogenic differentiation ability of mouse BMSCs (ALP expression staining activity).
  • Figure 5B is a graph showing the results of samples provided in Examples 1-3 and Comparative Example 1 for enhancing the osteogenic differentiation ability of mouse BMSCs (extracellular calcium nodule Alizarin Red staining).
  • Fig. 6 is an analysis diagram of the in vitro 6-hour microvessel-inducing ability of samples provided in Examples 1-3 and Comparative Example 1.
  • a magnesium strontium-silicon phosphate material with the following structural formula: Sr 4.99 Mg 0.01 (PO 4 ) 2 SiO 4 (x 0.01), the preparation method is as follows:
  • the gel was dried in an oven at 100°C for 8 hours and heated at 900°C for 2 hours to obtain a magnesium strontium-silica phosphate material.
  • Preparation Example 2 The only difference from Preparation Example 1 is that the molar ratio of Sr source and Mg source is controlled so that x of the final magnesium strontium-silicate phosphate material is 0.03 (Preparation Example 2), 0.05 (Preparation Example 3), and 2.5 (Preparation Example 2). Example 4), 4.99 (Preparation Example 5).
  • strontium-silicon phosphate material with the following structural formula:
  • the preparation method is as follows:
  • a magnesium-silicon phosphate material with the following structural formula:
  • the preparation method is as follows:
  • XRD analysis use X-ray diffractometer to analyze the phase composition of the synthesized material to determine whether the elemental composition of the material is correct;
  • Fig. 1 is the XRD pattern of the magnesium strontium-silicon phosphate material provided in Examples 1-3. It can be seen from the figure that the magnesium strontium-silicon phosphate material was successfully prepared by the present invention.
  • Micro morphology use scanning electron microscope (SEM) to analyze its micro morphology
  • 2A-2C are SEM images of magnesium strontium-silicate phosphate materials provided in Examples 1-3. It can be seen from the figures that magnesium-strontium-silicate phosphate materials with different Mg content have different microscopic morphologies.
  • Element composition Use EDS to detect the element composition of the sample.
  • Figure 3 is an EDS diagram of the magnesium strontium-silicon phosphate material provided in Examples 1-3. It can be seen from the figure that the sample provided by the present invention contains both magnesium and strontium.
  • This embodiment provides a porous bone repair composite scaffold material, which is composed of poly-3-hydroxybutyrate and the magnesium strontium-silicate phosphate material (Sr 5-x Mg x (PO 4 ) 2 provided in Preparation Examples 1-5). SiO 4 ) composition.
  • the preparation method is as follows:
  • step (3) Add the mixed solution in step (2) to the 3D printing equipment to print the three-dimensional stent; among them, the printing parameters are the nozzle diameter of 50 ⁇ m, the nozzle moving speed of 10 mm/s, and the spinning speed of 25 mm 3 /s , Print size 20 ⁇ 20 ⁇ 30 mm;
  • Example 10 The difference from Example 1 is that, in this example, the mass ratio of poly-3-hydroxybutyrate to magnesium strontium-phosphosilicate material is 0.5:1 (embodiment 6), 5:1 (embodiment 7), 3:1 (Example 8), 0.3:1 (Example 9), 7:1 (Example 10).
  • Example 11 poly-3-hydroxybutyrate is replaced with poly-3-hydroxyvalerate (Example 11), 3-hydroxybutyric acid and 3-hydroxyhexanoic acid Copolyester (Example 12), polylactic acid (Example 13).
  • Example 1 The difference from Example 1 is that in this comparative example, the magnesium strontium-phosphosilicate material is replaced with the strontium-phosphosilicate material provided in Comparative Preparation Example 1.
  • Example 2 The difference from Example 1 is that in this comparative example, the magnesium-strontium-phosphosilicate material is replaced with the magnesium-phosphosilicate material provided in Comparative Preparation Example 2.
  • Example 2 The difference from Example 1 is that in this comparative example, the magnesium-strontium-phosphosilicate material is replaced with a combination of strontium-phosphosilicate material and magnesium-phosphosilicate material, wherein the molar ratio of the two is It is 4.99:0.01.
  • Example 1 The difference from Example 1 is that in this comparative example, no magnesium strontium-phosphosilicate material is added.
  • Example 1 The difference from Example 1 is that in this comparative example, no poly-3-hydroxybutyrate is added.
  • Figure 4 is an apparent morphology of the porous bone repair composite scaffold provided in Example 1. It can be seen from the figure that the composite scaffold provided by the present invention is porous.
  • the sterilized 3D composite stent is immersed in simulated body fluid (SBF) at a mass-to-volume ratio of 1:10, sealed and placed in a 37°C incubator for 4 weeks to collect the extract;
  • SBF simulated body fluid
  • Figures 5A and 5B are graphs showing the results of the samples provided in Examples 1-3 and Comparative Example 1 on enhancing the osteogenic differentiation ability of mouse BMSCs.
  • Figure 5A shows the staining activity of ALP expression
  • Figure 5B shows the extracellular calcium nodule alizarin. Red staining shows that as the Mg content increases, the osteogenic ability increases.
  • the sterilized 3D composite stent is immersed in simulated body fluid (SBF) at a mass-to-volume ratio of 1:10, sealed and placed in a 37°C incubator for 4 weeks to collect the extract;
  • SBF simulated body fluid
  • Fig. 6 is an analysis diagram of the in vitro 6-h microvascular formation ability of the samples provided in Examples 1-3 and Comparative Example 1. It can be seen from the figure that as the Mg content increases, the blood vessel formation ability increases.
  • the porous bone repair composite scaffold material provided by the present invention has good biocompatibility, can promote osteogenesis and angiogenesis, and has good mechanical strength, which can meet application requirements.
  • Example 1 From the comparison of Example 1 and Comparative Examples 1-2, it can be seen that there is a synergistic effect between magnesium ion and strontium ion, and the two work together to promote the proliferation and differentiation of osteoblasts, which is beneficial to osteogenesis and osteogenesis in the process of bone repair.
  • the angiogenesis function shortens the repair time of bone defect.
  • magnesium ion or strontium ion is used alone, it can only promote bone formation or blood vessel formation, and cannot form a coupling process; from the comparison of Example 1 and Comparative Example 3, it can be seen that there is only magnesium ion Strontium and strontium ions exist in the form of Sr 5-x Mg x (PO 4 ) 2 SiO 4 , which is more conducive to the proliferation and differentiation of osteoblasts, is conducive to the osteogenesis and angiogenesis function in the bone repair process, and shortens bone defects Repair time; from the comparison of Example 1 and Comparative Examples 4-5, it can be seen that the magnesium strontium-phosphosilicate material and polyhydroxy fatty acid ester are indispensable. If the magnesium strontium-phosphosilicate material is lacking, it will be It leads to a decline in the ability of osteogenic differentiation, on the other hand, its elastic modulus is low and its mechanical properties are poor.
  • the present invention uses the above-mentioned examples to illustrate the magnesium strontium-silicate phosphate material and preparation method of the present invention, and the porous bone repair composite scaffold material with controllable structure containing the same, but the present invention is not limited to the above process steps This does not mean that the present invention must rely on the above process steps to be implemented.
  • any improvement of the present invention, the equivalent replacement of the raw materials selected in the present invention, the addition of auxiliary components, the selection of specific methods, etc. fall within the scope of protection and disclosure of the present invention.

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Abstract

一种镁锶-磷酸硅盐材料及制备方法、包含镁锶-磷酸硅盐材料的结构可控的多孔骨修复复合支架材料。所述镁锶-磷酸硅盐材料具有如下结构式, Sr 5-xMg x(PO 4) 2SiO 4，0＜x＜5。其中镁离子和锶离子之间具有协同增效作用，二者共同作用，可以促进成骨细胞的增殖、分化，有利于骨修复过程中成骨和成血管功能，缩短了骨缺损修复时间。

Description

镁锶-磷酸硅盐材料及制备方法、包含其的结构可控的多孔骨修复复合支架材料 技术领域
本发明属于生物医学组织工程技术领域，涉及一种镁锶-磷酸硅盐材料及制备方法、包含其的结构可控的多孔骨修复复合支架材料。
 背景技术
创伤、先天性畸形、骨质疏松和骨肿瘤切除等原因造成的各种类型骨缺损十分常见，大范围、大面积骨缺损的修复和功能重建一直是矫形外科、颅面外科和整形外科所共同面临的难题之一。据美国骨科医师协会（AAOS）统计，在美国每年有630万人发生骨折，其中需要接受骨移植物的患者就有50万之多，2005年在骨移植方面的费用支出高达25亿美元（Stevens B, Yang YZ, MohandaS A, Stucker B, Nguyen KT. A review of materials, fabrication to enhance bone regeneration in methods, and strategies used engineered bone tissues. J Biomed Mater Res B 2008;85B:573-82.）。我国每年骨缺损病人超过350万（俞兴. 仿生组织工程骨的研制与开发. 中国科技成果 2011;12:1-2.），每年新增病例达到数十万之多，创伤住院年增长率达7.2%，高居住院人数的第二位，骨缺损的高发生率致使骨移植物成为仅次于输血之后需求量最大的移植物，给社会带来沉重的医疗负担。因此，骨科疾病特别是大段骨缺损方面的修复治疗已经成为世界上最主要的临床医疗需求之一。
自体骨移植一直作为骨缺损治疗的金标准，然而依旧存在着诸如取骨区疼痛、出血、来源有限等问题而受到很大的应用限制。而异体骨取代自体骨移植则存在着感染、免疫排斥反应、传播疾病等风险。因此，研发具备骨诱导活性的生物复合支架材料具有重要的临床研究意义。近年来随着骨组织工程研究的不断深入，为大段骨缺损的修复带来了新的希望，它改变了以往创伤修复的传统模式，能以少量组织细胞修复大范围组织缺损，并可按需塑形达到理想形态，为实现创伤修复及完美的生物学重建提供了理论和方法。
硅酸盐类生物陶瓷材料在物理、化学性质上与天然骨矿物成分非常相似，具有良好的生物相容性和骨传导性，并能促进与骨的直接化学键合而受到了骨组织工程领域研究者们的广泛关注。由于硅酸盐陶瓷可调节化学组成，通过向陶瓷组分中引入不同含量的具有促成骨成血管活性的离子，不仅能够调节和控制材料的力学强度、降解速度，而且可以改善陶瓷材料在骨修复方面的生物学效应，提高骨组织再生能力。锶-磷硅酸盐（SPS，Sr 5(PO 4) 2SiO 4）生物陶瓷化学组成成分中，Sr行使的功能类似于骨中的Ca，在骨质疏松模型和骨质疏松患者中，Sr的药理作用被证明对提高骨量、骨质量和骨抵抗力方面具有有益作用（Bonnelye E, Chabadel A, Saltel F, Jurdic P. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone 2008;42:129-38.）、（Thormann U, Ray S, Sommer U, Elkhassawna T, Rehling T, Hundgeburth M, et al. Bone formation induced by strontium modified calcium phosphate cement in critical-size metaphyseal fracture defects in ovariectomized rats. Biomaterials 2013;34:8589-98.）。然而，目前对SPS材料在骨组织工程方面的研究非常有限，早期研究者大多关注的只是SPS及其改性之后的物理光学行为（Huang YL, Gan JH, Seo HJ. Luminescence Investigation of Eu -Activated Sr 5(PO 4) 2SiO 4 Phosphor by Combustion Synthesis. J Am Ceram Soc 2011;94:1143-8）、（Gan JH, Huang YL, Shi L, Qiao XB, Seo HJ. Luminescence properties of Eu 2+-activated Sr 5(PO 4) 2SiO 4 for green-emitting phosphor. Mater Lett 2009;63:2160-2.）。镁(Mg 2+)是人体的必需元素，其含量是人体内排在第10位的元素，约65%的镁存在于骨骼和牙齿中。研究表明镁（Mg 2+）不仅能够诱导血管内皮细胞产生一氧化氮，增强内皮细胞迁移和增殖；且能够动员内皮祖细胞（EPCs），增加VEGF的生成，促进新血管的形成，在维持血管功能方面发挥重要的生理功能（Katakawa M, Fukuda N, Tsunemi A, Mori M, Maruyama T, Matsumoto T, et al. Taurine and magnesium supplementation enhances the function of endothelial progenitor cells through antioxidation in healthy men and spontaneously hypertensive rats. Hypertens Res 2016;39:848-56.）、（Cooke JP, Losordo DW. Nitric oxide and angiogenesis. Circulation 2002;105:2133-5.）。此外，镁（Mg 2+）还能够调控成骨细胞增殖、分化和形态发生，促进骨的形成（Zhang Y, Xu J, Ruan YC, Yu MK, O'Laughlin M, Wise H, et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nature medicine 2016;22:1160-9.）；但是目前并没有有关于Sr和Mg二者共同应用于骨修复材料中的报道。
目前生物陶瓷支架材料因其较弱的力学强度、断裂韧性、脆性大等特点限制了它们在临床上的应用。因此具有多功能的复合支架材料开始广泛出现在组织修复的基础研究和临床应用。尤其是聚合物-生物活性陶瓷类复合材料的出现，因其兼具了各组分的优点，使复合支架材料在组织相容性、力学强度、骨传导及骨诱导性方面展现了良好的临床应用前景，成为骨组织工程研究的热点和新的临床治疗手段。
因此，需要开发一种新的骨修复复合支架材料以满足应用要求。
发明内容
本发明的目的在于提供一种镁锶-磷酸硅盐材料及制备方法、包含其的结构可控的多孔骨修复复合支架材料，本发明提供的复合支架材料具有优异的生物相容性和可降解性，移植到体内释放的锶（Sr）、镁（Mg）离子具有促成骨成血管活性，其复合支架降解产物同样可以促进成骨细胞增殖、分化及矿化，同时抑制破骨细胞活性，具有抗骨质疏松的作用，因此本发明提供的复合支架材料在制备骨缺损修复尤其是骨质疏松性骨缺损修复支架方面表现出巨大的应用潜力。
为达到此发明目的，本发明采用以下技术方案：
第一方面，本发明提供了一种镁锶-磷酸硅盐材料，所述镁锶-磷酸硅盐材料具有如下结构式：
Sr 5-xMg x(PO 4) 2SiO 4，0<x<5。
所述0<x<5可以为0.01、0.05、0.1、0.2、0.4、0.5、0.8、1、1.2、1.4、1.5、1.8、2.0、2.2、2.5、2.8、3.0、3.2、3.4、3.5、3.8、4.0、4.2、4.5、4.8、4.9等。
本发明提供的镁锶-磷酸硅盐材料中，镁离子和锶离子之间具有协同增效作用，二者共同作用，可以促进成骨细胞的增殖、分化，有利骨修复过程中成骨和成血管功能，缩短了骨缺损修复时间。
并且，相比于单独使用Sr 5(PO 4) 2SiO 4和Mg 5(PO 4) 2SiO 4，镁离子和锶离子以本申请提供的Sr 5-xMg x(PO 4) 2SiO 4的形式使用，对骨修复具有更好的促进成骨细胞的增殖、分化的效果。
第二方面，本发明提供了根据第一方面所述的镁锶-磷酸硅盐材料的制备方法，所述制备方法包括如下步骤：
（1）将Sr源和Mg源的混合液与P源和Si源的混合液混合、老化并反应、然后进行缩聚反应得到凝胶；
（2）对凝胶进行干燥，得到所述镁锶-磷酸硅盐材料。
优选地，所述Sr源和Mg源的摩尔比为(5-x):x，0<x<5，例如4.99:0.01、4.5:0.5、4:1、3:2、2:3、1:4、0.5:4.5、0.01:4.99。
优选地，所述Sr源和Mg源的混合液的溶剂为双蒸水。
优选地，所述Sr源选自硝酸锶；所述Mg源选自六水合硝酸镁。
优选地，所述P源和Si源的摩尔比为2:1。
优选地，所述P源选自磷酸三乙酯，所述Si源选自正硅酸乙酯。
优选地，所述混合的时间为1-3 h，例如1.5 h、1.8 h、2.0 h、2.5 h等。
优选地，所述老化的温度为室温，时间为24-30 h，例如25 h、28 h、29 h等。
优选地，所述反应的温度为80-90℃，例如82℃、85℃、88℃等，时间为16-20 h，例如17 h、18 h、19 h等。
优选地，所述缩聚的温度为75-85℃，例如78℃、80℃、82℃等，时间为5-10 h，例如6 h、7 h、8 h、9 h等。
优选地，所述干燥为先在100-120℃（例如105℃、110℃、115℃）下干燥5-8 h（例如6 h、7 h等），然后在850-900℃（例如860℃、870℃、880℃、890℃等）下干燥2-3 h（例如2.2 h、2.5 h、2.8 h等）。
本发明利用溶胶-凝胶法合成了含有镁离子和锶离子的生物陶瓷材料。
第三方面，本发明提供了一种根据第一方面所述的镁锶-磷酸硅盐材料在制备骨修复复合支架材料中的应用。
第四方面，本发明提供了一种结构可控的多孔骨修复复合支架材料，所述结构可控的多孔骨修复复合支架材料包括聚羟基脂肪酸酯和第一方面所述的镁锶-磷酸硅盐材料。
本发明所使用的聚羟基脂肪酸酯具有良好的生物相容性和降解性，其降解产物3-羟基丁酸（3HB）是哺乳动物体内构成酮体的主要组成之一，不仅对机体无任何的毒性作用，而且可以促进成骨细胞增殖、分化及矿化，同时能够抑制破骨细胞活性，具有抗骨质疏松的作用。
本发明通过使聚羟基脂肪酸酯和镁锶-磷酸硅盐材料复合，在保证了生物陶瓷支架材料的优点的同时，通过聚羟基脂肪酸酯来弥补其力学性能方面的不足，使本发明提供的复合支架材料具有良好的生物相容性的同时，可促进成骨成血管活性，并且，具有较好的机械强度，可满足应用要求。
优选地，所述聚羟基脂肪酸酯和镁锶-磷酸硅盐材料的质量比为(0.5-5):1，例如1:1、1.5:1、2:1、2.5:1、3:1、3.5:1、4:1、4.5:1等，优选(1-3):1。
优选地，所述聚羟基脂肪酸酯选自聚-3-羟基丁酸酯、聚-3-羟基戊酸酯、聚-3-羟基己酸酯、3-羟基丁酸-3-羟基戊酸共聚酯或3-羟基丁酸-3-羟基己酸共聚酯中的任意一种或至少两种的组合。
本发明选择的聚羟基脂肪酸酯具有较好的机械强度，当其应用于骨修复复合支架材料中时，其力学强度较优，具有较好的应用效果。
优选地，所述结构可控的多孔骨修复复合支架材料的孔隙率为60-80%，例如62%、64%、66%、68%、70%、72%、75%、78%等。
优选地，所述结构可控的多孔骨修复复合支架材料的孔连通率为60-90%，例如62%、64%、66%、68%、70%、72%、75%、78%、80%、82%、85%、88%等。
优选地，所述结构可控的多孔骨修复复合支架材料的孔径为200-400 μm，例如220 μm、250 μm、280 μm、300 μm、320 μm、350 μm、380 μm等。
第五方面，本发明提供了一种根据第四方面所述的结构可控的多孔骨修复复合支架材料的制备方法，所述制备方法包括如下步骤：
（1）将聚羟基脂肪酸酯溶液与镁锶-磷酸硅盐材料混合，得到待打印溶液；
（2）利用低温3D打印机进行打印，然后进行冷冻干燥，得到所述结构可控的多孔骨修复复合支架材料。
优选地，所述聚羟基脂肪酸酯溶液的溶剂为1,4-二氧六烷和/或三氯甲烷。
优选地，在所述聚羟基脂肪酸酯溶液中，所述聚羟基脂肪酸酯的浓度为1-2 g/mL，例如1.1 g/mL、1.2 g/mL、1.4 g/mL、1.6 g/mL、1.8 g/mL等。
优选地，所述打印的参数为：喷嘴直径50 μm，喷嘴移动速度10 mm/s，喷丝速度25 mm 3/s，打印尺寸20×20×30 mm。
本发明可以通过控制低温打印机的打印参数可实现多孔骨修复复合支架材料的结构可控。
因为骨修复复合支架的宏观结构可以通过3D打印控制，因此，本发明的“结构可控”指的是其孔隙率、孔径大小以及其孔连通率可控。
优选地，在所述冷冻干燥前，先在低于-20℃（可以是-25℃、-30℃、-40℃、-50℃等）的温度下冷冻至少6 h（可以是6.5 h、7 h、8 h、10 h等）。
第六方面，本发明提供了根据第四方面所述的结构可控的多孔骨修复复合支架材料在制备骨缺损填充材料或骨缺损修复材料中的应用。
优选地，所述骨缺损为骨质疏松性骨缺损。
相对于现有技术，本发明具有以下有益效果：
（1）本发明提供的镁锶-磷酸硅盐材料中，镁离子和锶离子之间具有协同增效作用，二者共同作用，可以促进成骨细胞的增殖、分化，有利骨修复过程中成骨和成血管功能，缩短了骨缺损修复时间。
（2）本发明通过使聚羟基脂肪酸酯和镁锶-磷酸硅盐材料复合，在保证了生物陶瓷支架材料的优点的同时，通过聚羟基脂肪酸酯来弥补其力学性能方面的不足，使本发明提供的复合支架材料具有良好的生物相容性的同时，可促进成骨成血管活性，并且，具有较好的机械强度，可满足应用要求。
 附图说明
图1是实施例1-3提供的镁锶-磷酸硅盐材料的XRD图。
图2A是实施例1提供的镁锶-磷酸硅盐材料的SEM图。
图2B是实施例2提供的镁锶-磷酸硅盐材料的SEM图。
图2C是实施例3提供的镁锶-磷酸硅盐材料的SEM图。
图3A是实施例1提供的镁锶-磷酸硅盐材料的EDS图。
图3B是实施例2提供的镁锶-磷酸硅盐材料的EDS图。
图3C是实施例3提供的镁锶-磷酸硅盐材料的EDS图。
图4是实施例1提供的多孔骨修复复合支架的表观形貌图
图5A是实施例1-3和对比例1提供的样品对于增强小鼠BMSCs成骨分化能力结果图（ALP表达染色活性）。
图5B是实施例1-3和对比例1提供的样品对于增强小鼠BMSCs成骨分化能力结果图（胞外钙结节茜素红染色）。
图6是实施例1-3和对比例1提供的样品体外诱导HUVEC 6 h微血管形成能力分析图。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。
制备例1
一种镁锶-磷酸硅盐材料，具有如下结构式：Sr 4.99Mg 0.01(PO 4) 2SiO 4（x=0.01）,制备方法如下：
（1）将Sr源（Sr(NO 3) 2）与Mg源（Mg(NO 3) 2·6H 2O）按照4.99:0.01比例混合均匀溶于ddH 2O中；
（2）将P源（C 6H 15O 4P）与Si源（TEOS，Si(OC 2H 5) 4）按照2:1的比例均匀溶于ddH 2O中；
（3）将Sr/Mg源的混合液缓慢加入搅拌的P/Si源溶液中，持续搅拌1 h后，室温下老化24 h；
（4）老化后的溶液在85℃条件下回流16 h以促使离子基团之间相互键合形成溶胶，将溶胶在80℃条件下蒸发8 h，缩聚使凝胶形成；
（5）凝胶置于100℃烘箱中干燥8 h，在900℃加热2 h之后得到镁锶-磷酸硅盐材料。
制备例2-5
与制备例1的区别仅在于，控制Sr源和Mg源的摩尔比，使最后得到的镁锶-磷酸硅盐材料的x为0.03（制备例2）、0.05（制备例3）、2.5（制备例4）、4.99（制备例5）。
对比制备例1
一种锶-磷酸硅盐材料，具有如下结构式：
Sr 5(PO 4) 2SiO 4
制备方法如下：
（1）将0.5 M Sr源（Sr(NO 3) 2）、0.2 M P源（C 6H 15O 4P）和0.1 M Si源（Si(OC 2H 5) 4）分别溶解于ddH 2O；将0.2 M阳离子表面活性剂十六烷基三甲基溴化铵（CTAB）溶解于ddH 2O中，并用超声波处理10 min，形成均匀溶液；
（2）在制备过程中，将最初配置的0.2 M P源添加到0.2 M的CTAB溶液中，磁力搅拌30min；随后向溶液中缓慢滴加0.1 M Si源溶液；将0.5 M Sr源溶液滴加到上述的P和Si-CTAB溶液中，连续搅拌，形成粘稠的凝胶状溶液；随后向上述凝胶溶液中滴加氨水，调整溶液的pH=10，并在室温搅拌4 h；
（3）上述白色凝胶沉淀在室温放在24 h，然后置于烘箱于110℃烘烤12 h；
（4）将上述干的混合物反复用ddH 2O冲洗，去取残存的氨水，并在100℃干燥2 h；将上述干粉在900℃、1000℃分别干燥3 h和5 h，最后得到纯的SPS粉末。
对比制备例2
一种镁-磷酸硅盐材料，具有如下结构式：
Mg 5(PO 4) 2SiO 4
制备方法如下：
（1）将0.5 M Mg源（Mg(NO 3) 2）、0.2 M P源（C 6H 15O 4P）和0.1 M Si源（Si(OC 2H 5) 4）分别溶解于ddH 2O；将0.2 M阳离子表面活性剂十六烷基三甲基溴化铵（CTAB）溶解于ddH 2O中，并用超声波处理10 min，形成均匀溶液；
（2）在制备过程中，将最初配置的0.2 M P源添加到0.2 M的CTAB溶液中，磁力搅拌30 min；随后向溶液中缓慢滴加0.1 M Si源溶液；将0.5 M Mg源溶液滴加到上述的P和Si-CTAB溶液中，连续搅拌，形成粘稠的凝胶状溶液；随后向上述凝胶溶液中滴加氨水，调整溶液的pH=10，并在室温搅拌4 h；
（3）上述白色凝胶沉淀在室温放在24 h，然后置于烘箱于110℃烘烤12 h；
（4）将上述干的混合物反复用ddH 2O冲洗，去取残存的氨水，并在100℃干燥2 h；将上述干粉在900℃、1000℃分别干燥3 h和5 h，最后得到纯的Mg 5(PO 4) 2SiO 4粉末。
性能测试1
对制备例1-5和对比制备例1-2提供的样品进行性能测试，方法如下：
（1）XRD分析：利用X射线衍射仪分析合成的材料的相组成，确定材料元素组成是否正确；
图1为实施例1-3提供的镁锶-磷酸硅盐材料的XRD图，由图可知，本发明成功制备得到了镁锶-磷酸硅盐材料。
（2）微观形貌：利用扫描电子显微镜（SEM）分析其微观形貌；
图2A-2C为实施例1-3提供的镁锶-磷酸硅盐材料的SEM图，由图可知，Mg含量不同的镁锶-磷酸硅盐材料具有不同的微观形貌。
（3）元素组成：利用EDS检测样品的元素组成。
图3为实施例1-3提供的镁锶-磷酸硅盐材料的EDS图，由图可知，本发明提供的样品中既具有镁，又具有锶。
实施例1-5
本实施例提供了一种多孔骨修复复合支架材料，由聚-3-羟基丁酸酯和制备例1-5提供的镁锶-磷酸硅盐材料（Sr 5-xMg x(PO 4) 2SiO 4）组成。
制备方法如下：
（1）聚-3-羟基丁酸酯与1,4-二氧六烷在55℃条件下磁力搅拌回流4 h溶解，形成均匀透明的溶液；其中，聚-3-羟基丁酸酯与1,4-二氧六烷的质量体积(w/v)比为1:6；
（2）将镁锶-磷硅酸盐材料粉末加入到（1）所形成的溶液中，37℃条件下磁力搅拌2 h形成均匀的溶液；其中，聚-3-羟基丁酸酯与镁锶-磷硅酸盐材料的质量比为1:1；
（3）将步骤（2）中的混合溶液加入3D打印设备中，进行三维支架的打印；其中，打印参数为喷嘴直径50 μm，喷嘴移动速度10 mm/s，喷丝速度25 mm 3/s，打印尺寸20×20×30 mm；
（4）将3D打印的复合支架放入-40℃低温冰箱8 h，进行一周的真空干燥，得到多孔骨修复复合支架材料。
实施例6-10
与实施例1的区别在于，在本实施例中，聚-3-羟基丁酸酯与镁锶-磷硅酸盐材料的质量比为0.5:1（实施例6）、5:1（实施例7）、3:1（实施例8）、0.3:1（实施例9）、7:1（实施例10）。
实施例11-13
与实施例1的区别在于，在本实施例中，将聚-3-羟基丁酸酯替换为聚-3-羟基戊酸酯（实施例11）、3-羟基丁酸-3-羟基己酸共聚酯（实施例12）、聚乳酸（实施例13）。
对比例1
与实施例1的区别在于，在本对比例中，将镁锶-磷硅酸盐材料替换为对比制备例1提供的锶-磷硅酸盐材料。
对比例2
与实施例1的区别在于，在本对比例中，将镁锶-磷硅酸盐材料替换为对比制备例2提供的镁-磷硅酸盐材料。
对比例3
与实施例1的区别在于，在本对比例中，将镁锶-磷硅酸盐材料替换为锶-磷硅酸盐材料和镁-磷硅酸盐材料的组合，其中，二者的摩尔比为4.99:0.01。
对比例4
与实施例1的区别在于，在本对比例中，不添加镁锶-磷硅酸盐材料。
对比例5
与实施例1的区别在于，在本对比例中，不添加聚-3-羟基丁酸酯。
性能测试2
对实施例1-13和对比例1-5提供的样品进行性能测试，方法如下：
（1）表观形貌：观察其表观形貌。
图4为实施例1提供的多孔骨修复复合支架的表观形貌图，由图可知，本发明提供的复合支架呈多孔状。
（2）成骨分化能力：
A：将灭菌的3D复合支架，按照质量体积比为1:10的比例浸泡于模拟体液中（SBF），密封后静置在37℃培养箱中，浸泡时间4周收集浸提液；
B：将上述浸提液与成骨诱导液按照体积比1:3比例混合均匀；
C：将上述诱导液滴加到每孔含有1×10 5骨髓间充质干细胞（BMSCs）中，每隔三天换液一次，共诱导培养14天；
D：移除上述诱导液，用PBS漂洗三次，随后用4%的多聚甲醛固定15 min；
E：移除上述多聚甲醛，并用PBS漂洗三次，然后加入1 mL的茜素红溶液进行染色15 min；
F：移除上述茜素红溶液，用PBS漂洗三次，并向其中加入0.5 mL 10%的十六烷基氯化吡啶溶液进行萃取；
G：在562 nm波长条件下，利用酶标仪测上述溶液的吸光度，定量成骨分化能力
图5A和图5B为实施例1-3和对比例1提供的样品对于增强小鼠BMSCs成骨分化能力结果图，其中，图5A为ALP表达染色活性，图5B为胞外钙结节茜素红染色，由图可知，随着Mg含量的增加，成骨能力增强。
（3）微血管形成能力：
A：将灭菌的3D复合支架，按照质量体积比为1:10的比例浸泡于模拟体液中（SBF），密封后静置在37℃培养箱中，浸泡时间4周收集浸提液；
B：将上述浸提液与成血管培养基按照体积比1:3比例混合均匀；
C：将上述培养基滴加到每孔含有1×10 4人脐静脉血管内皮细胞（HUVEC）中，37℃培养8 h；
D：用光学显微镜（放大10倍）观察并拍照微血管形成数量。
图6为实施例1-3和对比例1提供的样品体外诱导HUVEC 6 h微血管形成能力分析图，由图可知表明随着Mg含量的增加，血管形成能力增强。
（4）弹性模量：利用力学测试机以10 mm/min的速率压缩支架材料的中心，记录负荷为5 mm直径区域的弹性模量值。
对实施例和对比例的测试结果见表1：
[援引加入(细则20.6) 22.12.2020]　
Figure WO-DOC-TABLE-1
表1
Figure dest_path_image001a
由实施例和性能测试可知，本发明提供的多孔骨修复复合支架材料具有良好的生物相容性的同时，可促进成骨成血管活性，并且，具有较好的机械强度，可满足应用要求。
由实施例1和对比例1-2的对比可知，镁离子和锶离子之间具有协同增效作用，二者共同作用，可以促进成骨细胞的增殖、分化，有利骨修复过程中成骨和成血管功能，缩短了骨缺损修复时间，若单独使用镁离子或者锶离子时，只能促成骨或者促成血管，无法形成偶联过程；由实施例1和对比例3的对比可知，只有镁离子和锶离子以Sr 5-xMg x(PO 4) 2SiO 4的形式存在，才会更有利于成骨细胞的增殖、分化，有利骨修复过程中成骨和成血管功能，缩短了骨缺损修复时间；由实施例1和对比例4-5的对比可知，镁锶-磷硅酸盐材料和聚羟基脂肪酸酯缺一不可，若缺少镁锶-磷硅酸盐材料，则一方面会导致成骨分化能力下降，另一方面其弹性模量较低，机械性能较差。
申请人声明，本发明通过上述实施例来说明本发明的镁锶-磷酸硅盐材料及制备方法、包含其的结构可控的多孔骨修复复合支架材料，但本发明并不局限于上述工艺步骤，即不意味着本发明必须依赖上述工艺步骤才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明所选用原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。

Claims (10)

  1. 一种镁锶-磷酸硅盐材料，其特征在于，所述镁锶-磷酸硅盐材料具有如下结构式：
    Sr 5-xMg x(PO 4) 2SiO 4，0<x<5。
  2. 根据权利要求1所述的镁锶-磷酸硅盐材料的制备方法，其特征在于，所述制备方法包括如下步骤：
    （1）将Sr源和Mg源的混合液与P源和Si源的混合液混合、老化并反应、然后进行缩聚反应得到凝胶；
    （2）对凝胶进行干燥，得到所述镁锶-磷酸硅盐材料。
  3. 根据权利要求2所述的制备方法，其特征在于，所述Sr源和Mg源的摩尔比为(5-x):x，0<x<5；
    优选地，所述Sr源和Mg源的混合液的溶剂为双蒸水；
    优选地，所述Sr源选自硝酸锶，所述Mg源选自六水合硝酸镁；
    优选地，所述P源和Si源的摩尔比为2:1；
    优选地，所述P源选自磷酸三乙酯，所述Si源选自正硅酸乙酯；
    优选地，所述混合的时间为1-3 h；
    优选地，所述老化的温度为室温，时间为24-30 h；
    优选地，所述反应的温度为80-90℃，时间为16-20 h；
    优选地，所述缩聚的温度为75-85℃，时间为5-10 h；
    优选地，所述干燥为先在100-120℃下干燥5-8 h，然后在850-900℃下干燥2-3 h。
  4. 根据权利要求1所述的镁锶-磷酸硅盐材料在制备骨修复复合支架材料中的应用。
  5. 一种结构可控的多孔骨修复复合支架材料，其特征在于，所述结构可控的多孔骨修复复合支架材料包括聚羟基脂肪酸酯和权利要求1所述的镁锶-磷酸硅盐材料。
  6. 根据权利要求5所述的结构可控的多孔骨修复复合支架材料，其特征在于，所述聚羟基脂肪酸酯和镁锶-磷酸硅盐材料的质量比为(0.5-5):1，优选(1-3):1；
    优选地，所述聚羟基脂肪酸酯选自聚-3-羟基丁酸酯、聚-3-羟基戊酸酯、聚-3-羟基己酸酯、3-羟基丁酸-3-羟基戊酸共聚酯或3-羟基丁酸-3-羟基己酸共聚酯中的任意一种或至少两种的组合。
  7. 根据权利要求5或6所述的结构可控的多孔骨修复复合支架材料，其特征在于，所述结构可控的多孔骨修复复合支架材料的孔隙率为60-80%；
    优选地，所述结构可控的多孔骨修复复合支架材料的孔连通率为60-90%；
    优选地，所述结构可控的多孔骨修复复合支架材料的孔径为200-400 μm。
  8. 根据权利要求5-7中的任一项所述的结构可控的多孔骨修复复合支架材料的制备方法，其特征在于，所述制备方法包括如下步骤：
    （1）将聚羟基脂肪酸酯溶液与镁锶-磷酸硅盐材料混合，得到待打印溶液；
    （2）利用低温3D打印机进行打印，然后进行冷冻干燥，得到所述结构可控的多孔骨修复复合支架材料。
  9. 根据权利要求8所述的制备方法，其特征在于，所述聚羟基脂肪酸酯溶液的溶剂为1,4-二氧六烷和/或三氯甲烷；
    优选地，在所述聚羟基脂肪酸酯溶液中，所述聚羟基脂肪酸酯的浓度为1-2 g/mL；
    优选地，所述打印的参数为：喷嘴直径50 μm，喷嘴移动速度10 mm/s，喷丝速度25 mm 3/s，打印尺寸20×20×30 mm；
    优选地，在所述冷冻干燥前，先在低于-20℃的温度下冷冻至少6 h。
  10. 根据权利要求5-7中的任一项所述的结构可控的多孔骨修复复合支架材料在制备骨缺损填充材料或骨缺损修复材料中的应用；
    优选地，所述骨缺损为骨质疏松性骨缺损。
PCT/CN2020/125505 2019-11-01 2020-10-30 镁锶 - 磷酸硅盐材料及制备方法、包含其的结构可控的多孔骨修复复合支架材料 WO2021083369A1 (zh)

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