WO2017031899A1 - Porous calcium phosphate microsphere material having big surface holes, and preparation method and applications - Google Patents

Porous calcium phosphate microsphere material having big surface holes, and preparation method and applications Download PDF

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WO2017031899A1
WO2017031899A1 PCT/CN2015/099636 CN2015099636W WO2017031899A1 WO 2017031899 A1 WO2017031899 A1 WO 2017031899A1 CN 2015099636 W CN2015099636 W CN 2015099636W WO 2017031899 A1 WO2017031899 A1 WO 2017031899A1
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calcium phosphate
phosphate
bone cement
microspheres
porous
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PCT/CN2015/099636
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French (fr)
Chinese (zh)
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叶建东
李海燕
李继彦
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华南理工大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges

Definitions

  • the present invention relates to the field of bone defect repair medical treatment, and in particular to a porous calcium phosphate microsphere material having a large surface pore, a preparation method and application thereof.
  • the artificial bone material that replaces the bone defect site clinically is mainly calcium phosphate materials, including hydroxyapatite ceramics, ⁇ -tricalcium phosphate ceramics, two-phase calcium phosphate, calcium phosphate bone cement, bioactive glass, and various Calcium phosphate based composite.
  • the application forms of calcium phosphate materials in the field of bone repair are mainly classified into two types, dense and porous. Dense bone repair materials, whose porosity is too low, are not conducive to tissue and cell growth and angiogenesis, affecting the biological properties of materials. The presence of interconnected pores in the material provides access to blood transport, exchange of nutrients and metabolites, and vascular and tissue ingrowth.
  • porous calcium phosphate materials mainly include: soluble particle leaching method, freeze drying method, gas foaming method, rapid prototyping method (also referred to as 3D printing), and addition of pore-forming agent method.
  • soluble particle leaching method freeze drying method
  • gas foaming method rapid prototyping method
  • addition of pore-forming agent method by changing the pore size of the pore-forming agent or soluble particles such as mannitol, degradable polymer microspheres, sodium chloride, etc., although the pore size inside the calcium phosphate material can be adjusted, the connectivity between the pores formed is relatively better. Poor, and mainly closed pores, most of the pores are not connected to the outside.
  • the close packing between the microspheres can form three-dimensional pores that communicate with each other, which is beneficial to the growth of blood vessels and bone tissues.
  • the microspheres have good fluidity and can be realized in irregular bones. Any filling of the defect.
  • Calcium phosphate cement has self-curing properties and can undergo a curing reaction at body temperature or room temperature, which is more conducive to the loading of bioactive substances and drugs than calcium phosphate ceramics which require high temperature sintering.
  • the calcium phosphate cement microsphere itself is rich in micropores but lacks macropores, and the connectivity between the pores is poor, which is not conducive to the growth of blood vessels and bone tissue into the material; in addition, its degradation rate is slow and cannot be Match the growth rate of new bone.
  • Porosity, pore size and distribution in the material, connectivity between the pores for the bone restoration It has important influence on clinical application. Macropores are beneficial to the growth of new bone and the formation of blood vessels. Micropores are beneficial to the adhesion of proteins and the transport of nutrients. Therefore, the calcium phosphate microspheres having a connected porous structure have good practical value as a bone repair material.
  • an object of the present invention is to provide a method for preparing a porous calcium phosphate microsphere material having a large surface pore, which can be obtained with a large surface without a high temperature sintering treatment. Calcium phosphate microspheres with high porosity and good pore connectivity.
  • a method for preparing a porous calcium phosphate microsphere material having a large surface pore comprising the following steps:
  • the thickener is dissolved in deionized water at 25 ⁇ 80 ° C to prepare a thickener solution with a concentration of 0.1 ⁇ 3 ⁇ 4 ⁇ 5 ⁇ 3 ⁇ 4 W / V ;
  • the ultrasonic frequency is 16 ⁇ 40 kHz, and the ultrasonic time is 5 ⁇ 30 min;
  • step (5) using a syringe with an inner diameter of 0.5 to 1.5 mm, the calcium phosphate cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres; Curing and hydration for 1 to 7 days in an environment of 25 to 60 ° C and a relative humidity of 90% to 100 ⁇ 3 ⁇ 4, vacuum drying to obtain porous calcium phosphate microspheres having large pores on the surface; the pore diameter of the macropores is 20 ⁇ 85 ⁇ .
  • the polysaccharide gum of step (1) is at least one of modified starch, gelatin, xanthan gum, soluble chitosan, hydroxyethyl cellulose, dextrin, gum arabic, carrageenan, guar gum.
  • the thickener according to the step (2) is modified starch, oxidized starch, sodium carboxymethyl cellulose, sodium hydroxypropyl cellulose, sodium alginate, polyvinyl alcohol, pectin, hydroxypropyl group At least one of the base celluloses.
  • the calcium phosphate bone cement according to the step (4) is a "tetracalcium phosphate-calcium hydrogen phosphate" system bone cement, a “dihydrogen phosphate-ot-tricalcium phosphate-calcium carbonate” system bone cement, "phosphorus tetra Calcium-ot-tricalcium phosphate "system bone cement, “tetracalcium phosphate- ⁇ -tricalcium phosphate-dicalcium phosphate” system bone cement, "amorphous calcium phosphate-calcium hydrogen phosphate” system bone cement, “partially crystalline phosphoric acid Calcium-calcium hydrogen phosphate "system bone cement or one of the "calcium hydrogen phosphate- ⁇ -tricalcium phosphate-calcium carbonate” system bone cement.
  • porous calcium phosphate microsphere material having a surface macroporous prepared by the method for preparing a porous calcium phosphate microsphere material having a large surface pore, wherein the pores of the porous calcium phosphate microsphere are connected to each other, the internal pore
  • the size is 100 ⁇ 160 ⁇ .
  • the porous calcium phosphate microsphere material having a large surface pore serves as a medical bone defect filling material or as a drug carrier material.
  • the application as the medical bone defect filling material is as follows: According to the size of the bone defect site, the porous calcium phosphate microsphere with the surface large pores of the appropriate particle diameter is selected and filled into the bone defect site, and the wound is sutured. .
  • porous calcium phosphate microspheres having large pores on the surface are drug-loaded microspheres.
  • the drug-loaded microspheres are specifically prepared by: immersing the prepared microspheres in a drug solution, and loading the drug by liquid phase adsorption.
  • the drug-loaded microspheres are specifically prepared by: adding a target drug to the calcium phosphate bone cement liquid phase in the step (3); or adding the target drug to the calcium phosphate bone cement slurry in the step (4) .
  • the microspheres of the present invention not only have a regular spherical shape but also have a uniform size distribution; the microspheres contain a large number of large pores on the surface and inside, in addition to the micropores, and good connectivity between the internal pores.
  • Such a structure not only facilitates the growth of blood vessels and new bone tissue; secondly, the microspheres have a high specific surface area, which increases the contact area between the material and the tissue fluid, and also promotes the degradation rate of the bone cement;
  • the porous structure of calcium phosphate microspheres enables high drug loading and encapsulation efficiency.
  • the present invention utilizes the negative pressure formed by the stirring center and the ultrasonic cavitation to cause a local tensile stress in the liquid to form a negative pressure.
  • the gas dissolved in the liquid is supersaturated. It escapes from the liquid, thereby forming many small bubbles in the liquid.
  • the present invention utilizes the shearing action in the high-speed stirring process to control the amount of bubbles in the slurry by controlling the stirring speed, thereby controlling the number and size of the pores in the calcium phosphate microspheres.
  • the porous calcium phosphate microspheres having large pores prepared by the invention solve the defects that the surface of the existing calcium phosphate microspheres lacks macropores and poor pore connectivity, and the surface of the prepared porous calcium phosphate microspheres is There are a large number of micropores and macropores in the interior, which have high porosity and pore connectivity, and the pore distribution is relatively uniform.
  • the porous calcium phosphate microspheres having large surface pores prepared by the invention have multi-stage pores, and the functions thereof are diversified, and the surface macropores can provide adhesion and cut-in position for the tissue and cells to grow into the interior of the material.
  • the internal macropores provide space for tissue and cells to grow inside the material, and the surface and internal micropores serve as a conduit for the exchange or transport of nutrients and cellular metabolites.
  • the porous calcium phosphate microspheres having large surface pores according to the present invention have a simple preparation method, have better biomedical properties, can achieve better clinical application effects, and have broad application prospects.
  • FIG. 1 is a scanning electron micrograph of the surface topography of porous calcium phosphate microspheres having macropores prepared in Example 1.
  • FIG. 2 is a scanning electron micrograph of the cross-sectional morphology of porous calcium phosphate microspheres having a large surface pore prepared in Example 1.
  • FIG. 2 is a scanning electron micrograph of the cross-sectional morphology of porous calcium phosphate microspheres having a large surface pore prepared in Example 1.
  • the step of preparing porous calcium phosphate microspheres having surface macropores by using gelatin as polysaccharide gum, modified starch as thickener and "calcium dihydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement includes: [0034] (1) The gelatin is dissolved in deionized water at 30 ° C in a ratio of 6 g / 100 mL to prepare a gelatin solution having a concentration of 6% (w / v);
  • the ratio of g/100mL is dissolved in deionized water at 25 ° C to prepare a modified starch solution having a concentration of 2% (w/v); [0036] (3) The gelatin solution obtained in the step (1) and the step (2) The obtained modified starch solution is mixed to obtain a gelatin/modified starch mixed solution, which is a liquid phase of the "dihydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement;
  • step (5) using a syringe having an inner diameter of 1.2 mm, the "calcium dihydrogen phosphate-ot-tricalcium phosphate-calcium carbonate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain a frozen Bone cement microspheres; the frozen bone cement microspheres were hydrated for 2 days in an environment of 37 ° C, a relative humidity of 98% (% of water vapor in the air), and dried under vacuum to obtain porous calcium phosphate having large pores on the surface. Microspheres.
  • the morphology of the microspheres is shown in Figure 1:
  • the particle size of the microspheres is 2.2 mm, a large number of large pores are distributed on the surface of the microspheres, and the large pore size is 30 ⁇ 50 ⁇ , and the internal structure of the microspheres is shown in Fig. 2.
  • the interior contains a large number of pores, and the pores communicate with each other.
  • the internal pore size is 120 ⁇ 160 ⁇ , and the porosity is 74.24%.
  • PBS salt buffer solution
  • Step of preparing porous calcium phosphate microspheres having surface macropores by using modified starch as polysaccharide gum, sodium alginate as thickener, and "tetracalcium phosphate- ⁇ -tricalcium phosphate-dicalcium phosphate" system bone cement includes:
  • the modified starch is dissolved in deionized water at 35 ° C in a ratio of 12 g / 100 mL to a concentration of 12%.
  • the ratio of g/100mL is dissolved in deionized water at 30 ° C to prepare a sodium alginate solution having a concentration of 2% (w/v); [0045] (3) the modified starch solution obtained in step (1) and the step ( 2) The obtained sodium alginate solution is mixed
  • step (5) using a syringe having an inner diameter of 1.5 mm, the "tetracalcium phosphate- ⁇ -tricalcium phosphate-dicalcium phosphate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain Frozen bone cement microspheres; the frozen bone cement microspheres were hydrated for 3 days in an environment of 25 ° C, relative humidity of 96% (% of water vapor in the air), and dried under vacuum to obtain porous phosphoric acid having large pores on the surface. Calcium microspheres.
  • the particle diameter of the microsphere is 2.6 mm, and a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 40 to 70 ⁇ , the inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 110 to 170.
  • the step of preparing porous calcium phosphate microspheres having surface macropores by using xanthan gum as polysaccharide gum, sodium hydroxypropylcellulose as a thickener and "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement comprises:
  • the ratio of g/100mL is dissolved in deionized water at 60 ° C to prepare a hydroxypropyl cellulose sodium solution having a concentration of 4% (w/v); (3) mixing the xanthan gum solution obtained in the step (1) with the sodium hydroxypropylcellulose solution obtained in the step (2) to obtain a mixed solution of xanthan gum/hydroxypropylcellulose sodium as a part Crystalline calcium phosphate-calcium hydrogen phosphate" liquid phase of systemic bone cement;
  • step (5) using a syringe having an inner diameter of 0.8 mm, the "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres;
  • the frozen bone cement microspheres were hydrated for 1 day in an environment of 35 ° C and a relative humidity of 100% (% of water vapor in the air), and dried under vacuum to obtain porous calcium phosphate microspheres having large pores on the surface.
  • the particle diameter of the microsphere is 2.1 mm, a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 30 to 60 ⁇ , the inner part contains a large number of pores, and the pores are connected to each other, and the inner pore size is 100-160.
  • the step of preparing the porous calcium phosphate microspheres having surface macropores by using dextrin as a polysaccharide gum, a polyvinyl alcohol as a thickener, and a "tetracalcium phosphate-a-tricalcium phosphate" system bone cement comprises:
  • the "tetracalcium phosphate-ot-phosphoric acid trioxide" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres.
  • the frozen bone cement microspheres were hydrated for 4 days in an environment of 60 ° C, a relative humidity of 90% (% of water vapor in the air), and dried under vacuum to obtain porous calcium phosphate microspheres having large pores on the surface.
  • the particle diameter of the microsphere is 1.8 mm, and a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 20 to 60 ⁇ , the inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 100 to 140.
  • the step of preparing porous calcium phosphate microspheres having surface macropores by using soluble chitosan as polysaccharide gum, pectin as thickener and "amorphous calcium phosphate-calcium hydrogen phosphate" system bone cement comprises:
  • the ratio of g/100mL is dissolved in deionized water at 30 ° C to prepare a pectin solution having a concentration of 0.2% (w/v); [3] The soluble chitosan solution and the step obtained in the step (1) (2) The pectin solution obtained is mixed
  • step (5) using a syringe having an inner diameter of 1.0 mm, the "amorphous calcium phosphate-calcium hydrogen phosphate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres;
  • the frozen bone cement microspheres were hydrated for 5 days in an environment of 45 ° C, a relative humidity of 95% (% of water vapor in the air), and vacuum dried to obtain porous calcium phosphate microspheres having large pores on the surface.
  • the particle diameter of the microsphere is 2.3 mm, and a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 40 to 80 ⁇ , the inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 120 to 160.
  • the step of preparing a porous calcium phosphate microsphere having a surface macroporous by using guar gum as a polysaccharide gum, hydroxypropylmethylcellulose as a thickener, and a "tetracalcium phosphate-calcium phosphate" system bone cement includes :
  • guar gum is 2 g/100
  • the ratio of mL is dissolved in deionized water at 30 ° C to prepare a guar gum solution with a concentration of 2% (w/v);
  • step (5) using a syringe with an inner diameter of 0.6 mm, the "tetracalcium phosphate-calcium phosphate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres; Frozen bone cement microspheres placed at 55° C. Relative humidity: 99% (% of water vapor in the air) The environment was hydrated for 7 days in the environment, and vacuum dried to obtain porous calcium phosphate microspheres having large pores on the surface.
  • the particle diameter of the microsphere is 2.2 mm, a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 35 to 80 ⁇ , the inner part contains a large number of pores, and the pores are connected to each other, and the inner pore size is 105 to 150.
  • step (5) using a syringe having an inner diameter of 1.2 mm, the "calcium hydrogen phosphate-ot-tricalcium phosphate-calcium carbonate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone.
  • the porous calcium phosphate microsphere obtained in the step (6) is immersed in the bone injection for 30 min at 20 ° C. , vacuum drying, to obtain porous calcium phosphate drug microspheres loaded with Gu Ning injection.
  • the microspheres have a particle diameter of 3.0 mm, and a large number of large pores are distributed on the surface of the microspheres, and the large pore size is 30 to 75 ⁇ m.
  • the inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 100 to 140.
  • the ratio of g/100mL is dissolved in deionized water at 60 ° C to prepare a oxidized starch solution having a concentration of 3% (w/v); [0101] (3) the hydroxyethyl cellulose solution obtained in the step (1) and The oxidized starch solution obtained in the step (2) is mixed to obtain a hydroxyethyl cellulose/oxidized starch mixed solution, which is used as a liquid phase of the "dihydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement;
  • the porous calcium phosphate microspheres obtained in the step (6) were immersed in the bone peptide for injection for 30 min at 20 ° C, and dried under vacuum to obtain porous calcium phosphate drug microspheres loaded with the bone peptide for injection.
  • the porous calcium phosphate drug microspheres of the bone peptide for injection injection obtained in the step (7) were implanted into the femur defect of the rabbit, and the surgical incision was sutured layer by layer, and the healing of the surgical incision was observed after the operation.
  • the particle diameter of the microsphere is 2.8 mm, and a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 40 to 85 ⁇ m.
  • the inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 110 to 150.
  • the step of preparing carrageenan as a polysaccharide gum, a polyvinyl alcohol as a thickener, and a "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement to prepare porous calcium phosphate microspheres having surface macropores includes:
  • the ratio of mL is dissolved in deionized water at 40 ° C to prepare a carrageenan solution with a concentration of 15% (w/v);
  • the ratio of g/100mL is dissolved in deionized water at 60 ° C to prepare a polyvinyl alcohol solution having a concentration of 2% (w/v); [0312] (3) The carrageenan solution obtained in the step (1) and the step ( 2) The obtained polyvinyl alcohol solution is mixed to obtain a carrageenan/polyvinyl alcohol mixed solution, which is a liquid phase of the "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement;
  • step (5) The vancomycin-"partially crystallized calcium phosphate-calcium hydrogen phosphate" system bone cement slurry in step (5) is added to liquid nitrogen with a syringe having an inner diameter of 0.8 mm to obtain a frozen bone.
  • the drug-loaded microspheres have a particle size of 1.8 mm, and a large number of large pores are distributed on the surface of the microspheres, and the large pore size is 25 to 85 ⁇ m.
  • the inside contains a large number of pores, and the pores are connected to each other, and the inner pore size is 100 to 140 ⁇ .
  • the porosity was 66.48%.
  • the in vitro anti-disintegration experiment showed that the porous calcium phosphate microspheres with large pores in the surface were immersed in phosphate buffer solution (PBS) for 16 days, and the microspheres did not disintegrate. After 3 weeks of in vitro degradation, the weight loss rate of the porous calcium phosphate drug-loaded microspheres was 12.68%. The encapsulation efficiency of the porous calcium phosphate drug-loaded microspheres was 96%.

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Abstract

A porous calcium phosphate microsphere material having big surface holes, and a preparation method thereof and applications thereof. The preparation method comprises the following steps: (1) dissolving polysaccharide gum in deionized water to prepare a polysaccharide gum solution; (2) dissolving a thickener in deionized water to prepare a thickener solution; (3) mixing the polysaccharide gum solution with the thickener solution to obtain a polysaccharide gum/thickener solution; (4) mixing calcium phosphate bone cement powder with the polysaccharide gum/thickener solution to obtain calcium phosphate bone cement slurry; and (5), stirring the calcium phosphate bone cement slurry at a high speed, conducting ultrasonic treatment, dropwise adding the slurry to liquid nitrogen, and conducting curing and vacuum drying on refrigerated microspheres to obtain porous calcium phosphate microspheres having big surface holes.

Description

发明名称：一种具有表面大孔的多孔磷酸钙微球材料、 制备方法及 应用  Inventive name: porous calcium phosphate microsphere material with large surface pores, preparation method and application thereof
技术领域  Technical field
[0001] 本发明涉及属于骨缺损修复医用领域， 特别涉及一种具有表面大孔的多孔磷酸 钙微球材料、 制备方法及应用。  [0001] The present invention relates to the field of bone defect repair medical treatment, and in particular to a porous calcium phosphate microsphere material having a large surface pore, a preparation method and application thereof.
背景技术  Background technique
[0002] 临床上替代骨缺损部位的人工骨材料主要是磷酸钙类材料， 包括羟基磷灰石陶 瓷、 β-磷酸三钙陶瓷、 双相磷酸钙、 磷酸钙骨水泥、 生物活性玻璃以及各种磷酸 钙基复合材料。 一般来说， 磷酸钙类材料在骨修复领域的应用形式按其结构划 分主要有致密和多孔两种类型。 致密型骨修复材料， 其孔隙率过低， 不利于组 织和细胞长入以及血管生成， 影响材料的生物学性能。 而材料中存在连通的孔 隙可为血液输送、 营养物质与代谢物质之间的相互交换、 血管和组织的长入等 提供通道。 有学者认为， 尺寸在 100 μηι以上的大孔有利于组织的长入， 所以幵 发具有较高孔隙率的磷酸钙骨修复材料至关重要。  [0002] The artificial bone material that replaces the bone defect site clinically is mainly calcium phosphate materials, including hydroxyapatite ceramics, β-tricalcium phosphate ceramics, two-phase calcium phosphate, calcium phosphate bone cement, bioactive glass, and various Calcium phosphate based composite. In general, the application forms of calcium phosphate materials in the field of bone repair are mainly classified into two types, dense and porous. Dense bone repair materials, whose porosity is too low, are not conducive to tissue and cell growth and angiogenesis, affecting the biological properties of materials. The presence of interconnected pores in the material provides access to blood transport, exchange of nutrients and metabolites, and vascular and tissue ingrowth. Some scholars believe that large pores with a size above 100 μηι are beneficial for tissue ingrowth, so it is important to develop calcium phosphate bone repair materials with higher porosity.
[0003] 已有研究报道多孔磷酸钙材料的制备方法主要有： 可溶粒子沥滤法、 冷冻干燥 法、 气体发泡法、 快速原型法 （也称 3D打印） 、 添加造孔剂法等。 然而， 通过 改变造孔剂或可溶粒子的尺寸如甘露醇、 可降解高分子微球、 氯化钠等方法虽 然可以调控磷酸钙材料内部的孔径大小， 但所形成的孔隙之间连通性较差， 并 且以闭口孔为主， 多数孔隙与外部不连通。 相比于多孔块状材料， 微球之间的 紧密堆积即可形成相互连通的三维孔隙， 有利于血管和骨组织的长入； 其次， 微球具有良好的流动性， 可实现在不规则骨缺损部位的任意填充。 磷酸钙骨水 泥具有自固化性， 可在体温或室温下发生固化反应， 与需要经高温烧结的磷酸 钙陶瓷相比， 更利于生物活性物质和药物的负载。 但是作为骨修复填充材料， 磷酸钙骨水泥微球本身虽富含微孔但缺乏大孔、 孔隙之间的连通性差， 不利于 血管和骨组织向材料内部生长； 此外， 其降解速度缓慢， 无法匹配新骨的生长 速度。 材料中的孔隙率、 孔隙尺寸及其分布、 孔隙之间的连通性对于骨修复材 料在临床上的应用具有重要影响， 大孔有利于新骨生长以及血管的生成， 微孔 有利于蛋白的粘附和营养物质的传输。 因此， 具有连通多孔结构的磷酸钙微球 作为骨修复材料具有良好的实用价值。 [0003] It has been reported that the preparation methods of porous calcium phosphate materials mainly include: soluble particle leaching method, freeze drying method, gas foaming method, rapid prototyping method (also referred to as 3D printing), and addition of pore-forming agent method. However, by changing the pore size of the pore-forming agent or soluble particles such as mannitol, degradable polymer microspheres, sodium chloride, etc., although the pore size inside the calcium phosphate material can be adjusted, the connectivity between the pores formed is relatively better. Poor, and mainly closed pores, most of the pores are not connected to the outside. Compared with porous block materials, the close packing between the microspheres can form three-dimensional pores that communicate with each other, which is beneficial to the growth of blood vessels and bone tissues. Secondly, the microspheres have good fluidity and can be realized in irregular bones. Any filling of the defect. Calcium phosphate cement has self-curing properties and can undergo a curing reaction at body temperature or room temperature, which is more conducive to the loading of bioactive substances and drugs than calcium phosphate ceramics which require high temperature sintering. However, as a bone repair filling material, the calcium phosphate cement microsphere itself is rich in micropores but lacks macropores, and the connectivity between the pores is poor, which is not conducive to the growth of blood vessels and bone tissue into the material; in addition, its degradation rate is slow and cannot be Match the growth rate of new bone. Porosity, pore size and distribution in the material, connectivity between the pores for the bone restoration It has important influence on clinical application. Macropores are beneficial to the growth of new bone and the formation of blood vessels. Micropores are beneficial to the adhesion of proteins and the transport of nutrients. Therefore, the calcium phosphate microspheres having a connected porous structure have good practical value as a bone repair material.
技术问题  technical problem
[0004] 为了克服现有技术的上述缺点与不足， 本发明的目的在于提供一种具有表面大 孔的多孔磷酸钙微球材料的制备方法， 无需经过高温烧结处理， 可得到具有表 面大孔、 孔隙率高、 孔隙连通性好的磷酸钙微球。  [0004] In order to overcome the above disadvantages and disadvantages of the prior art, an object of the present invention is to provide a method for preparing a porous calcium phosphate microsphere material having a large surface pore, which can be obtained with a large surface without a high temperature sintering treatment. Calcium phosphate microspheres with high porosity and good pore connectivity.
问题的解决方案  Problem solution
技术解决方案  Technical solution
[0005] 本发明的目的通过以下技术方案实现： [0005] The object of the invention is achieved by the following technical solutions:
[0006] 一种具有表面大孔的多孔磷酸钙微球材料的制备方法， 包括以下步骤：  [0006] A method for preparing a porous calcium phosphate microsphere material having a large surface pore, comprising the following steps:
[0007] ( 1) 将多糖胶溶于 25~80°C去离子水中， 制成浓度为 2<¾~20<¾w/V的多糖胶溶 液； [0007] (1) Dissolving the polysaccharide gum in deionized water at 25-80 ° C to prepare a polysaccharide gum solution having a concentration of 2<3⁄4~20<3⁄4w/ V ;
[0008] (2) 将增稠剂溶于 25~80°C去离子水中， 制成浓度为 0.1<¾~5<¾W/V的增稠剂溶 液； [0008] (2) The thickener is dissolved in deionized water at 25 ~ 80 ° C to prepare a thickener solution with a concentration of 0.1 < 3⁄4 ~ 5 < 3⁄4 W / V ;
[0009] (3) 将步骤 （1) 得到的多糖胶溶液和步骤 （2) 得到的增稠剂溶液混合， 得 到多糖胶 /增稠剂混合溶液， 作为磷酸钙骨水泥的液相；  [0009] (3) mixing the polysaccharide gum solution obtained in the step (1) and the thickener solution obtained in the step (2) to obtain a polysaccharide gum/thickener mixed solution as a liquid phase of the calcium phosphate bone cement;
[0010] (4) 将步骤 （3) 得到的多糖胶 /增稠剂混合溶液与磷酸钙骨水泥粉料按液固 比 2~5 mL/g充分混合、 以速度为 400~1200r/min搅拌， 搅拌吋间为 20~40 min， 制 得富含气泡的磷酸钙骨水泥浆体； [0010] (4) The polysaccharide gum/thickener mixture solution obtained in the step (3) and the calcium phosphate bone cement powder are thoroughly mixed at a liquid to solid ratio of 2 to 5 mL/g, and stirred at a speed of 400 to 1200 r/min. , stirring the crucible for 20~40 min, to obtain a bubble-rich calcium phosphate cement slurry;
[0011] (5) 将步骤 （4) 中得到的富含气泡的磷酸钙骨水泥浆体置于超声波振荡器中[0011] (5) placing the bubble-rich calcium phosphate cement slurry obtained in the step (4) in an ultrasonic oscillator
， 超声频率为 16~40 kHz， 超声吋间为 5~30 min; , the ultrasonic frequency is 16~40 kHz, and the ultrasonic time is 5~30 min;
[0012] (6) 用针头内径为 0.5~1.5 mm的注射器将步骤 （5) 中的磷酸钙骨水泥浆体滴 加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥微球置于 25~60°C、 相对湿度 为 90%~100<¾的环境中养护水化 1~7天， 真空干燥， 得到具有表面大孔的多孔磷 酸钙微球； 所述大孔的孔径为 20~85 μηι。 [0012] (6) using a syringe with an inner diameter of 0.5 to 1.5 mm, the calcium phosphate cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres; Curing and hydration for 1 to 7 days in an environment of 25 to 60 ° C and a relative humidity of 90% to 100 < 3⁄4, vacuum drying to obtain porous calcium phosphate microspheres having large pores on the surface; the pore diameter of the macropores is 20 ~85 μηι.
[0013] 步骤 （1) 所述的多糖胶为变性淀粉、 明胶、 黄原胶、 可溶性壳聚糖、 羟乙基 纤维素、 糊精、 ***胶、 卡拉胶、 瓜尔豆胶中的至少一种。 [0014] 步骤 （2) 所述的增稠剂为改性淀粉、 氧化淀粉、 羧甲基纤维素钠、 羟丙基纤 维素钠、 海藻酸钠、 聚乙烯醇、 果胶、 羟丙基甲基纤维素中的至少一种。 [0013] The polysaccharide gum of step (1) is at least one of modified starch, gelatin, xanthan gum, soluble chitosan, hydroxyethyl cellulose, dextrin, gum arabic, carrageenan, guar gum. Kind. [0014] The thickener according to the step (2) is modified starch, oxidized starch, sodium carboxymethyl cellulose, sodium hydroxypropyl cellulose, sodium alginate, polyvinyl alcohol, pectin, hydroxypropyl group At least one of the base celluloses.
[0015] 步骤 （4) 所述的磷酸钙骨水泥为"磷酸四钙 -磷酸氢钙"***骨水泥、 "磷酸二 氢钙 -ot-磷酸三钙-碳酸钙"***骨水泥、 "磷酸四钙 -ot-磷酸三钙"***骨水泥、 "磷 酸四钙 -β-磷酸三钙-磷酸二氢钙"***骨水泥、 "无定形磷酸钙 -磷酸氢钙"***骨 水泥、 "部分结晶磷酸钙 -磷酸氢钙"***骨水泥或 "磷酸氢钙 -α-磷酸三钙-碳酸钙" ***骨水泥中的一种。  [0015] The calcium phosphate bone cement according to the step (4) is a "tetracalcium phosphate-calcium hydrogen phosphate" system bone cement, a "dihydrogen phosphate-ot-tricalcium phosphate-calcium carbonate" system bone cement, "phosphorus tetra Calcium-ot-tricalcium phosphate "system bone cement, "tetracalcium phosphate-β-tricalcium phosphate-dicalcium phosphate" system bone cement, "amorphous calcium phosphate-calcium hydrogen phosphate" system bone cement, "partially crystalline phosphoric acid Calcium-calcium hydrogen phosphate "system bone cement or one of the "calcium hydrogen phosphate-α-tricalcium phosphate-calcium carbonate" system bone cement.
[0016] 所述的具有表面大孔的多孔磷酸钙微球材料的制备方法制备得到的具有表面大 孔的多孔磷酸钙微球材料， 所述多孔磷酸钙微球孔隙之间相互连通， 内部孔尺 寸为 100〜160 μηι。  [0016] The porous calcium phosphate microsphere material having a surface macroporous prepared by the method for preparing a porous calcium phosphate microsphere material having a large surface pore, wherein the pores of the porous calcium phosphate microsphere are connected to each other, the internal pore The size is 100~160 μηι.
[0017] 所述具有表面大孔的多孔磷酸钙微球材料作为医用骨缺损填充材料或作为药物 载体材料。  [0017] The porous calcium phosphate microsphere material having a large surface pore serves as a medical bone defect filling material or as a drug carrier material.
[0018] 所述作为医用骨缺损填充材料应用吋， 具体为： 根据骨缺损部位的大小， 选择 适当粒径的具有表面大孔的多孔磷酸钙微球填充到骨缺损部位， 对伤口进行缝 合处理。  [0018] The application as the medical bone defect filling material is as follows: According to the size of the bone defect site, the porous calcium phosphate microsphere with the surface large pores of the appropriate particle diameter is selected and filled into the bone defect site, and the wound is sutured. .
[0019] 所述具有表面大孔的多孔磷酸钙微球为载药微球。  [0019] The porous calcium phosphate microspheres having large pores on the surface are drug-loaded microspheres.
[0020] 所述载药微球， 具体制备方法为： 将制好的微球浸泡于药物溶液中， 通过液相 吸附的形式载入药物。  [0020] The drug-loaded microspheres are specifically prepared by: immersing the prepared microspheres in a drug solution, and loading the drug by liquid phase adsorption.
[0021] 所述载药微球， 具体制备方法为： 在步骤 （3) 中的磷酸钙骨水泥液相中加入 目标药物； 或者步骤 （4) 中的磷酸钙骨水泥浆体中加入目标药物。  [0021] The drug-loaded microspheres are specifically prepared by: adding a target drug to the calcium phosphate bone cement liquid phase in the step (3); or adding the target drug to the calcium phosphate bone cement slurry in the step (4) .
发明的有益效果  Advantageous effects of the invention
有益效果  Beneficial effect
[0022] 与现有技术相比， 本发明具有以下优点和有益效果：  [0022] Compared with the prior art, the present invention has the following advantages and benefits:
[0023] ( 1 ) 本发明的微球不仅具有规则的球形， 且尺寸分布均匀； 微球除富含微孔 以外， 其表面和内部均含有大量大孔， 内部孔隙之间有良好的连通性， 这样的 结构不仅有利于血管和新生骨组织的长入； 其次， 微球具有较高的比表面积， 增加了材料与组织液之间的接触面积， 还可促进骨水泥的降解速度； 再次， 具 有多孔结构的磷酸钙微球可实现高载药量和包封率。 [0024] (2) 本发明首次利用搅拌中心所形成的负压以及超声空化作用， 使液体内局 部出现拉应力形成负压， 在较低的压强下， 溶于液体中的气体由于过饱和而从 液体中逸出， 从而在液体中形成许多小气泡。 [0023] (1) The microspheres of the present invention not only have a regular spherical shape but also have a uniform size distribution; the microspheres contain a large number of large pores on the surface and inside, in addition to the micropores, and good connectivity between the internal pores. Such a structure not only facilitates the growth of blood vessels and new bone tissue; secondly, the microspheres have a high specific surface area, which increases the contact area between the material and the tissue fluid, and also promotes the degradation rate of the bone cement; The porous structure of calcium phosphate microspheres enables high drug loading and encapsulation efficiency. [0024] (2) For the first time, the present invention utilizes the negative pressure formed by the stirring center and the ultrasonic cavitation to cause a local tensile stress in the liquid to form a negative pressure. At a lower pressure, the gas dissolved in the liquid is supersaturated. It escapes from the liquid, thereby forming many small bubbles in the liquid.
[0025] (3) 本发明利用高速搅拌过程中的剪切作用， 通过控制搅拌速度调控浆体中 的气泡大小， 从而控制磷酸钙微球中孔隙的数量和大小。 [0025] (3) The present invention utilizes the shearing action in the high-speed stirring process to control the amount of bubbles in the slurry by controlling the stirring speed, thereby controlling the number and size of the pores in the calcium phosphate microspheres.
[0026] (4) 本发明制备的具有表面大孔的多孔磷酸钙微球解决了现有磷酸钙微球的 表面缺乏大孔、 孔隙连通性差的缺点， 所制备的多孔磷酸钙微球表面和内部均 分布着大量微孔和大孔， 具有较高的孔隙率和孔隙连通性， 并且孔隙分布较均 匀。 [0026] (4) The porous calcium phosphate microspheres having large pores prepared by the invention solve the defects that the surface of the existing calcium phosphate microspheres lacks macropores and poor pore connectivity, and the surface of the prepared porous calcium phosphate microspheres is There are a large number of micropores and macropores in the interior, which have high porosity and pore connectivity, and the pore distribution is relatively uniform.
[0027] (5) 本发明制备的具有表面大孔的多孔磷酸钙微球具有多级孔， 其功能多样 化， 表面大孔可为组织和细胞向材料的内部长入提供粘附和切入位点， 内部大 孔可为组织和细胞在材料内部生长提供空间， 表面和内部微孔可作为营养物质 和细胞代谢产物的交换或运输的通道。  [0027] (5) The porous calcium phosphate microspheres having large surface pores prepared by the invention have multi-stage pores, and the functions thereof are diversified, and the surface macropores can provide adhesion and cut-in position for the tissue and cells to grow into the interior of the material. Point, the internal macropores provide space for tissue and cells to grow inside the material, and the surface and internal micropores serve as a conduit for the exchange or transport of nutrients and cellular metabolites.
[0028] (6) 本发明所述的具有表面大孔的多孔磷酸钙微球制备方法简单， 具有更优 良的生物医学性能， 可取得更好的临床应用效果， 应用前景广阔。  [0028] (6) The porous calcium phosphate microspheres having large surface pores according to the present invention have a simple preparation method, have better biomedical properties, can achieve better clinical application effects, and have broad application prospects.
对附图的简要说明  Brief description of the drawing
附图说明  DRAWINGS
[0029] 图 1是实施例 1制备的具有表面大孔的多孔磷酸钙微球表面形貌的扫描电子显微 镜照片。  1 is a scanning electron micrograph of the surface topography of porous calcium phosphate microspheres having macropores prepared in Example 1. [0029] FIG.
[0030] 图 2是实施例 1制备的具有表面大孔的多孔磷酸钙微球断面形貌的扫描电子显微 镜照片。  2 is a scanning electron micrograph of the cross-sectional morphology of porous calcium phosphate microspheres having a large surface pore prepared in Example 1. FIG.
实施该发明的最佳实施例  BEST MODE FOR CARRYING OUT THE INVENTION
本发明的最佳实施方式  BEST MODE FOR CARRYING OUT THE INVENTION
[0031] 下面结合实施例， 对本发明作进一步地详细说明， 但本发明的实施方式不限于 此。 The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the present invention are not limited thereto.
[0032] 实施例 1  Embodiment 1
[0033] 应用明胶为多糖胶、 改性淀粉为增稠剂、 "磷酸二氢钙 -a-磷酸三钙-碳酸钙"系 统骨水泥制备具有表面大孔的多孔磷酸钙微球的步骤包括： [0034] ( 1 ) 将明胶以 6 g/100 mL的比例溶于 30°C去离子水中， 制成浓度为 6% (w/v) 的明胶溶液； [0033] The step of preparing porous calcium phosphate microspheres having surface macropores by using gelatin as polysaccharide gum, modified starch as thickener and "calcium dihydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement includes: [0034] (1) The gelatin is dissolved in deionized water at 30 ° C in a ratio of 6 g / 100 mL to prepare a gelatin solution having a concentration of 6% (w / v);
[0035] (2) 将改性淀粉以 2 (2) the modified starch is 2
g/100mL的比例溶于 25°C去离子水中， 制成浓度为 2% (w/v) 的改性淀粉溶液； [0036] (3) 将步骤 （1 ) 得到的明胶溶液和步骤 （2) 得到的改性淀粉溶液混合， 得 到明胶 /改性淀粉混合溶液， 作为"磷酸二氢钙 -a-磷酸三钙-碳酸钙"***骨水泥的 液相；  The ratio of g/100mL is dissolved in deionized water at 25 ° C to prepare a modified starch solution having a concentration of 2% (w/v); [0036] (3) The gelatin solution obtained in the step (1) and the step (2) The obtained modified starch solution is mixed to obtain a gelatin/modified starch mixed solution, which is a liquid phase of the "dihydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement;
[0037] (4) 将步骤 （3) 得到的明胶 /改性淀粉混合溶液与 "磷酸二氢钙 -a-磷酸三钙- 碳酸钙 "***骨水泥粉料按液固比 4 m!Jg充分混合、 高速搅拌， 搅拌速度为 400 r/min , 搅拌吋间为 20min， 制得富含气泡的"磷酸二氢钙 -ot-磷酸三 -碳酸 "系 统骨水浆体；  [0037] (4) The gelatin/modified starch mixed solution obtained in the step (3) and the "dicalcium phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement powder are fully liquid-solid ratio 4 m! Jg Mixing, high-speed stirring, stirring speed is 400 r/min, stirring for 20 minutes, to obtain a bubble-rich "dihydrogen phosphate-ot-phosphate tri-carbonate" system bone water slurry;
[0038] (5) 将步骤 （4) 中得到的富含气泡的 "磷酸二氢钙 -ot-磷酸三钙-碳酸 "*** 骨水泥浆体置于超声波振荡器中， 超声频率为 30kHz， 超声吋间为 5 min ;  [0038] (5) The bubble-rich "calcium dihydrogen phosphate-ot-tricalcium phosphate-carbonic acid" system bone cement slurry obtained in the step (4) is placed in an ultrasonic oscillator, the ultrasonic frequency is 30 kHz, ultrasonic 5 minutes in the daytime;
[0039] (6) 用针头内径为 1.2 mm的注射器将步骤 （5) 中的"磷酸二氢钙 -ot-磷酸三钙- 碳酸钙 "***骨水泥浆体滴加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥微 球置于 37°C、 相对湿度为 98% (空气中水蒸气的百分比） 环境中养护水化 2天， 真空干燥， 得到具有表面大孔的多孔磷酸钙微球。  [0039] (6) using a syringe having an inner diameter of 1.2 mm, the "calcium dihydrogen phosphate-ot-tricalcium phosphate-calcium carbonate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain a frozen Bone cement microspheres; the frozen bone cement microspheres were hydrated for 2 days in an environment of 37 ° C, a relative humidity of 98% (% of water vapor in the air), and dried under vacuum to obtain porous calcium phosphate having large pores on the surface. Microspheres.
[0040] 微球的形貌如图 1所示： 微球粒径为 2.2 mm， 微球表面分布有大量大孔， 且大 孔尺寸为 30〜50 μηι， 微球内部结构形貌如图 2所示， 内部含有大量孔隙， 孔隙 之间相互连通， 内部孔尺寸为 120〜160 μηι， 孔隙率为 74.24% ; 体外抗崩解实验 表明， 将具有表面大孔的多孔磷酸钙微球放入磷酸盐缓冲溶液 （PBS) 中浸泡 15 天后观察， 微球未发生崩解。 体外降解 3周以后， 多孔磷酸钙微球的失重率为 16. 24%。  [0040] The morphology of the microspheres is shown in Figure 1: The particle size of the microspheres is 2.2 mm, a large number of large pores are distributed on the surface of the microspheres, and the large pore size is 30~50 μηι, and the internal structure of the microspheres is shown in Fig. 2. As shown, the interior contains a large number of pores, and the pores communicate with each other. The internal pore size is 120~160 μηι, and the porosity is 74.24%. In vitro anti-disintegration experiments show that porous calcium phosphate microspheres with large pores are placed in phosphoric acid. After soaking for 15 days in salt buffer solution (PBS), the microspheres did not disintegrate. After 3 weeks of in vitro degradation, the weight loss rate of the porous calcium phosphate microspheres was 16.24%.
[0041] 实施例 2  Embodiment 2
[0042] 应用变性淀粉为多糖胶、 海藻酸钠为增稠剂、 "磷酸四钙 -β-磷酸三钙-磷酸二氢 钙"***骨水泥制备具有表面大孔的多孔磷酸钙微球的步骤包括：  [0042] Step of preparing porous calcium phosphate microspheres having surface macropores by using modified starch as polysaccharide gum, sodium alginate as thickener, and "tetracalcium phosphate-β-tricalcium phosphate-dicalcium phosphate" system bone cement Includes:
[0043] ( 1 ) 将变性淀粉以 12 g/100 mL的比例溶于 35°C去离子水中， 制成浓度为 12% [0043] (1) The modified starch is dissolved in deionized water at 35 ° C in a ratio of 12 g / 100 mL to a concentration of 12%.
(w/v) 的变性淀粉溶液； [0044] (2) 将海藻酸钠以 2 (w/v) modified starch solution; (2) Sodium alginate at 2
g/100mL的比例溶于 30°C去离子水中， 制成浓度为 2% (w/v) 的海藻酸钠溶液； [0045] (3) 将步骤 （1) 得到的变性淀粉溶液和步骤 （2) 得到的海藻酸钠溶液混合 The ratio of g/100mL is dissolved in deionized water at 30 ° C to prepare a sodium alginate solution having a concentration of 2% (w/v); [0045] (3) the modified starch solution obtained in step (1) and the step ( 2) The obtained sodium alginate solution is mixed
， 得到变性淀粉 /海藻酸钠混合溶液， 作为"磷酸四钙 -β-磷酸三钙-磷酸二氢钙"系 统骨水泥的液相； , obtaining a mixed solution of modified starch/alginate, as a liquid phase of "tetracalcium phosphate-β-tricalcium phosphate-dicalcium phosphate" system bone cement;
[0046] (4) 将步骤 （3) 得到的变性淀粉 /海藻酸钠混合溶液与 "磷酸四钙 -β-磷酸三钙- 磷酸二氢钙"***骨水泥粉料按液固比 5  [0046] (4) The modified starch/alginate mixed solution obtained in the step (3) and the "tetracalcium phosphate-β-tricalcium phosphate-dicalcium phosphate" system bone cement powder according to the liquid-solid ratio 5
m!Jg充分混合、 高速搅拌， 搅拌速度为 600 r/min， 搅拌吋间为 28 min， 制得富含 气泡的 "磷酸四钙 -β-磷酸三钙-磷酸二氢钙"***骨水泥浆体； ! m Jg sufficiently mixed, high-speed stirring, the stirring speed was 600 r / mi n, between inches stirred 28 min, to obtain enriched "-β- tetracalcium phosphate, tricalcium phosphate - calcium dihydrogen phosphate" bubble system cement Slurry
[0047] (5) 将步骤 （4) 中得到的富含气泡的 "磷酸四钙 -β-磷酸三钙-磷酸二氢 ^'系 统骨水泥浆体置于超声波振荡器中， 超声频率为 16kHz， 超声吋间为 lO min;  [0047] (5) The bubble-rich "tetracalcium phosphate-β-tricalcium phosphate-dihydrogen phosphate system" bone cement slurry obtained in the step (4) is placed in an ultrasonic oscillator, and the ultrasonic frequency is 16 kHz. , ultrasound daytime is lO min;
[0048] (6) 用针头内径为 1.5 mm的注射器将步骤 （5) 中的"磷酸四钙 -β-磷酸三钙-磷 酸二氢钙"***骨水泥浆体滴加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥 微球置于 25°C、 相对湿度为 96% (空气中水蒸气的百分比） 环境中养护水化 3天 ， 真空干燥， 得到具有表面大孔的多孔磷酸钙微球。  [0048] (6) using a syringe having an inner diameter of 1.5 mm, the "tetracalcium phosphate-β-tricalcium phosphate-dicalcium phosphate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain Frozen bone cement microspheres; the frozen bone cement microspheres were hydrated for 3 days in an environment of 25 ° C, relative humidity of 96% (% of water vapor in the air), and dried under vacuum to obtain porous phosphoric acid having large pores on the surface. Calcium microspheres.
[0049] 微球粒径为 2.6 mm， 微球表面分布有大量大孔， 且大孔尺寸为 40〜70 μηι， 内 部含有大量孔隙， 孔隙之间相互连通， 内部孔尺寸为 110〜170  [0049] The particle diameter of the microsphere is 2.6 mm, and a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 40 to 70 μηι, the inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 110 to 170.
μηι, 孔隙率为 76.16% ; 体外抗崩解实验表明， 将具有表面大孔的多孔磷酸钙微 球放入磷酸盐缓冲溶液 （PBS) 中浸泡 18天后观察， 微球未发生崩解。 体外降解 3周以后， 多孔磷酸钙微球的失重率为 18.08%。  Μηι, porosity was 76.16%; in vitro anti-disintegration experiments showed that the porous calcium phosphate microspheres with large pores in the surface were immersed in phosphate buffer solution (PBS) for 18 days, and the microspheres did not disintegrate. After 3 weeks of in vitro degradation, the weight loss rate of the porous calcium phosphate microspheres was 18.08%.
[0050] 实施例 3  Embodiment 3
[0051] 应用黄原胶为多糖胶、 羟丙基纤维素钠为增稠剂、 "部分结晶磷酸钙 -磷酸氢钙" ***骨水泥制备具有表面大孔的多孔磷酸钙微球的步骤包括：  [0051] The step of preparing porous calcium phosphate microspheres having surface macropores by using xanthan gum as polysaccharide gum, sodium hydroxypropylcellulose as a thickener and "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement comprises:
[0052] ( 1) 将黄原胶以 8 g/100 mL的比例溶于 40°C去离子水中， 制成浓度为 8% (w/v[0052] (1) Dissolving xanthan gum in deionized water at 40 ° C in a ratio of 8 g / 100 mL to a concentration of 8% (w / v)
) 的黄原胶溶液； a xanthan gum solution;
[0053] (2) 将羟丙基纤维素钠以 4 (2) sodium hydroxypropylcellulose as 4
g/100mL的比例溶于 60°C去离子水中， 制成浓度为 4% (w/v) 的羟丙基纤维素钠 溶液； [0054] (3) 将步骤 （1) 得到的黄原胶溶液和步骤 （2) 得到的羟丙基纤维素钠溶液 混合， 得到黄原胶 /羟丙基纤维素钠混合溶液， 作为"部分结晶磷酸钙 -磷酸氢钙" ***骨水泥的液相； The ratio of g/100mL is dissolved in deionized water at 60 ° C to prepare a hydroxypropyl cellulose sodium solution having a concentration of 4% (w/v); (3) mixing the xanthan gum solution obtained in the step (1) with the sodium hydroxypropylcellulose solution obtained in the step (2) to obtain a mixed solution of xanthan gum/hydroxypropylcellulose sodium as a part Crystalline calcium phosphate-calcium hydrogen phosphate" liquid phase of systemic bone cement;
[0055] (4) 将步骤 （3) 得到的黄原胶 /羟丙基纤维素钠混合溶液与"部分结晶磷酸钙- 磷酸氢钙"***骨水泥粉料按液固比 2  [0055] (4) The xanthan gum / hydroxypropyl cellulose sodium mixed solution obtained in the step (3) and the "partially crystalline calcium phosphate - calcium hydrogen phosphate" system bone cement powder according to liquid to solid ratio 2
m!Jg充分混合、 高速搅拌， 搅拌速度为 1200 r/min， 搅拌吋间为 36 min， 制得富 含气泡的"部分结晶磷酸钙-磷酸氢钙 "***骨水泥浆体； ! m Jg sufficiently mixed, high-speed stirring, the stirring speed is 1200 r / mi n, between inches stirred 36 min, to obtain a bubble-rich "partially crystalline calcium phosphate - dicalcium phosphate" System bone cement paste;
[0056] (5) 将步骤 （4) 中得到的富含气泡的 "部分结晶磷酸钙 -磷酸氢钙"***骨水泥 浆体置于超声波振荡器中， 超声频率为 40kHz， 超声吋间为 12 min; [0056] (5) The bubble-rich "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement slurry obtained in the step (4) is placed in an ultrasonic oscillator, the ultrasonic frequency is 40 kHz, and the ultrasonic time is 12 Min;
[0057] (6) 用针头内径为 0.8 mm的注射器将步骤 （5) 中的"部分结晶磷酸钙-磷酸氢 钙"***骨水泥浆体滴加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥微球置 于 35°C、 相对湿度为 100% (空气中水蒸气的百分比） 环境中养护水化 1天， 真空 干燥， 得到具有表面大孔的多孔磷酸钙微球。 [0057] (6) using a syringe having an inner diameter of 0.8 mm, the "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres; The frozen bone cement microspheres were hydrated for 1 day in an environment of 35 ° C and a relative humidity of 100% (% of water vapor in the air), and dried under vacuum to obtain porous calcium phosphate microspheres having large pores on the surface.
[0058] 微球粒径为 2.1 mm， 微球表面分布有大量大孔， 且大孔尺寸为 30〜60 μηι， 内 部含有大量孔隙， 孔隙之间相互连通， 内部孔尺寸为 100〜160 [0058] The particle diameter of the microsphere is 2.1 mm, a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 30 to 60 μηι, the inner part contains a large number of pores, and the pores are connected to each other, and the inner pore size is 100-160.
μηι, 孔隙率为 68.16% ; 体外抗崩解实验表明， 将具有表面大孔的多孔磷酸钙微 球放入磷酸盐缓冲溶液 （PBS) 中浸泡 21天后观察， 微球未发生崩解。 体外降解 Μηι, porosity was 68.16%; in vitro anti-disintegration experiments showed that the porous calcium phosphate microspheres with large pores in the surface were immersed in phosphate buffer solution (PBS) for 21 days, and the microspheres did not disintegrate. In vitro degradation
3周以后， 多孔磷酸钙微球的失重率为 14.52%。 After 3 weeks, the weight loss rate of the porous calcium phosphate microspheres was 14.52%.
[0059] 实施例 4 Embodiment 4
[0060] 应用糊精为多糖胶、 聚乙烯醇为增稠剂、 "磷酸四钙 -a-磷酸三钙"***骨水泥制 备具有表面大孔的多孔磷酸钙微球的步骤包括：  [0060] The step of preparing the porous calcium phosphate microspheres having surface macropores by using dextrin as a polysaccharide gum, a polyvinyl alcohol as a thickener, and a "tetracalcium phosphate-a-tricalcium phosphate" system bone cement comprises:
[0061] ( 1) 将糊精以 20 g/100 mL的比例溶于 25°C去离子水中， 制成浓度为 20% (w/v[0061] (1) The dextrin is dissolved in deionized water at 25 ° C in a ratio of 20 g / 100 mL to a concentration of 20% (w / v)
) 的糊精溶液； Dextrin solution;
[0062] (2) 将聚乙烯醇以 O.l g/lOOmL的比例溶于 45°C去离子水中， 制成浓度为 0.1%  [0062] (2) Dissolving polyvinyl alcohol in deionized water at 45 ° C in a ratio of 0.1 g / 100 mL to a concentration of 0.1%
(w/v) 的聚乙烯醇溶液；  (w/v) polyvinyl alcohol solution;
[0063] (3) 将步骤 （1) 得到的糊精溶液和步骤 （2) 得到的聚乙烯醇溶液混合， 得 到糊精 /聚乙烯醇混合溶液， 作为"磷酸四钙 -a-磷酸三 "***骨水泥的液相； [0064] (4) 将步骤 （3) 得到的糊精 /聚乙烯醇混合溶液与 "磷酸四钙 -a-磷酸三 ^'系 统骨水泥料按液固比 3 m!Jg充分混合、 高速搅拌， 搅拌速度为 1000 r/min， 搅拌 吋间为 40 min， 制得富含气泡的"磷酸四钙 -ot-磷酸三钙"***骨水泥浆体； [0063] (3) mixing the dextrin solution obtained in the step (1) and the polyvinyl alcohol solution obtained in the step (2) to obtain a dextrin/polyvinyl alcohol mixed solution as "tetracalcium phosphate-a-phosphate three" Liquid phase of systemic cement; [0064] (4) The dextrin/polyvinyl alcohol mixed solution obtained in the step (3) and the "tetracalcium phosphate-a-phosphate tri" system The cement material is fully mixed and stirred at a high liquid-solid ratio of 3 m! Jg. The stirring speed is 1000 r/min, and the stirring time is 40 min. The bubble-rich "tetracalcium phosphate-ot-tricalcium phosphate" is obtained. Systemic cement slurry;
[0065] (5) 将步骤 （4) 中得到的富含气泡的 "磷酸四钙 -ot-磷酸三 ^'***骨水泥浆体 置于超声波振荡器中， 超声频率为 28kHz， 超声吋间为 18 min ;  [0065] (5) The bubble-rich "tetracalcium phosphate-ot-phosphate tri" system bone cement slurry obtained in the step (4) is placed in an ultrasonic oscillator, the ultrasonic frequency is 28 kHz, and the ultrasonic time is 18 min ;
[0066] (6) 用针头内径为 0.5 mm的注射器将步骤 （5) 中的"磷酸四钙 -ot-磷酸三 ^'系 统骨水泥浆体滴加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥微球置于 60° C、 相对湿度为 90% (空气中水蒸气的百分比） 环境中养护水化 4天， 真空干燥 ， 得到具有表面大孔的多孔磷酸钙微球。  [0066] (6) using a syringe having an inner diameter of 0.5 mm, the "tetracalcium phosphate-ot-phosphoric acid trioxide" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres. The frozen bone cement microspheres were hydrated for 4 days in an environment of 60 ° C, a relative humidity of 90% (% of water vapor in the air), and dried under vacuum to obtain porous calcium phosphate microspheres having large pores on the surface.
[0067] 微球粒径为 1.8 mm， 微球表面分布有大量大孔， 且大孔尺寸为 20〜60 μηι， 内 部含有大量孔隙， 孔隙之间相互连通， 内部孔尺寸为 100〜140  [0067] The particle diameter of the microsphere is 1.8 mm, and a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 20 to 60 μηι, the inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 100 to 140.
μηι , 孔隙率为 67.46% ; 体外抗崩解实验表明， 将具有表面大孔的多孔磷酸钙微 球放入磷酸盐缓冲溶液 （PBS) 中浸泡 17天后观察， 微球未发生崩解。 体外降解 3周以后， 多孔磷酸钙微球的失重率为 12.36%。  Μηι , porosity was 67.46%; in vitro anti-disintegration experiments showed that the porous calcium phosphate microspheres with large pores in the surface were immersed in phosphate buffer solution (PBS) for 17 days, and the microspheres did not disintegrate. After 3 weeks of in vitro degradation, the weight loss rate of the porous calcium phosphate microspheres was 12.36%.
[0068] 实施例 5  Example 5
[0069] 应用可溶性壳聚糖为多糖胶、 果胶为增稠剂、 "无定形磷酸钙 -磷酸氢钙"***骨 水泥制备具有表面大孔的多孔磷酸钙微球的步骤包括：  [0069] The step of preparing porous calcium phosphate microspheres having surface macropores by using soluble chitosan as polysaccharide gum, pectin as thickener and "amorphous calcium phosphate-calcium hydrogen phosphate" system bone cement comprises:
[0070] ( 1 ) 将可溶性壳聚糖以 16 g/100 (1) dissolving soluble chitosan at 16 g/100
mL的比例溶于 80°C去离子水中， 制成浓度为 16% (w/v) 的可溶性壳聚糖溶液； [0071] (2) 将果胶以 0.2  The ratio of mL is dissolved in deionized water at 80 ° C to prepare a soluble chitosan solution with a concentration of 16% (w/v); [0071] (2) Pectin is 0.2
g/100mL的比例溶于 30°C去离子水中， 制成浓度为 0.2% (w/v) 的果胶溶液； [0072] (3) 将步骤 （1 ) 得到的可溶性壳聚糖溶液和步骤 （2) 得到的果胶溶液混合 The ratio of g/100mL is dissolved in deionized water at 30 ° C to prepare a pectin solution having a concentration of 0.2% (w/v); [3] The soluble chitosan solution and the step obtained in the step (1) (2) The pectin solution obtained is mixed
， 得到可溶性壳聚糖 /果胶混合溶液， 作为"无定形磷酸钙 -磷酸氢钙"***骨水泥 的液相； , obtaining a soluble chitosan / pectin mixed solution, as a liquid phase of "amorphous calcium phosphate - calcium hydrogen phosphate" system bone cement;
[0073] (4) 将步骤 （3) 得到的可溶性壳聚糖 /果胶混合溶液与"无定形磷酸钙-磷酸氢 钙"***骨水泥粉料按液固比 4 m!Jg充分混合、 高速搅拌， 搅拌速度为 1200 r/min ， 搅拌吋间为 36 min， 制得富含气泡的"无定形磷酸钙 -磷酸氢钙"***骨水泥浆 体；  [0073] (4) The soluble chitosan/pectin mixed solution obtained in the step (3) and the "amorphous calcium phosphate-calcium hydrogen phosphate" system bone cement powder are thoroughly mixed at a liquid-solid ratio of 4 m! Jg, and high speed. Stirring, stirring speed is 1200 r / min, stirring for 36 min, to obtain a bubble-rich "amorphous calcium phosphate - calcium hydrogen phosphate" system bone cement slurry;
[0074] (5) 将步骤 （4) 中得到的富含气泡的"无定形磷酸钙 -磷酸氢钙"***骨水泥浆 体置于超声波振荡器中， 超声频率为 40kHz， 超声吋间为 30 min; [0074] (5) The bubble-rich "amorphous calcium phosphate-calcium hydrogen phosphate" system bone cement slurry obtained in the step (4) The body is placed in an ultrasonic oscillator with an ultrasonic frequency of 40 kHz and an ultrasound time of 30 min;
[0075] (6) 用针头内径为 1.0 mm的注射器将步骤 （5) 中的"无定形磷酸钙-磷酸氢钙 "***骨水泥浆体滴加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥微球置于 4 5°C、 相对湿度为 95% (空气中水蒸气的百分比） 环境中养护水化 5天， 真空干燥 ， 得到具有表面大孔的多孔磷酸钙微球。  [0075] (6) using a syringe having an inner diameter of 1.0 mm, the "amorphous calcium phosphate-calcium hydrogen phosphate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres; The frozen bone cement microspheres were hydrated for 5 days in an environment of 45 ° C, a relative humidity of 95% (% of water vapor in the air), and vacuum dried to obtain porous calcium phosphate microspheres having large pores on the surface.
[0076] 微球粒径为 2.3 mm， 微球表面分布有大量大孔， 且大孔尺寸为 40〜80 μηι， 内 部含有大量孔隙， 孔隙之间相互连通， 内部孔尺寸为 120〜160  [0076] The particle diameter of the microsphere is 2.3 mm, and a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 40 to 80 μηι, the inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 120 to 160.
μηι, 孔隙率为 72.52% ; 体外抗崩解实验表明， 将具有表面大孔的多孔磷酸钙微 球放入磷酸盐缓冲溶液 （PBS) 中浸泡 20天后观察， 微球未发生崩解。 体外降解 3周以后， 多孔磷酸钙微球的失重率为 15.42%。  Μηι, porosity was 72.52%; in vitro anti-disintegration experiments showed that the porous calcium phosphate microspheres with large pores in the surface were immersed in phosphate buffer solution (PBS) for 20 days, and the microspheres did not disintegrate. After 3 weeks of in vitro degradation, the weight loss rate of the porous calcium phosphate microspheres was 15.42%.
[0077] 实施例 6  Example 6
[0078] 应用瓜尔豆胶为多糖胶、 羟丙基甲基纤维素为增稠剂、 "磷酸四钙 -磷酸氢钙"系 统骨水泥制备具有表面大孔的多孔磷酸钙微球的步骤包括：  [0078] The step of preparing a porous calcium phosphate microsphere having a surface macroporous by using guar gum as a polysaccharide gum, hydroxypropylmethylcellulose as a thickener, and a "tetracalcium phosphate-calcium phosphate" system bone cement includes :
[0079] ( 1) 将瓜尔豆胶以 2 g/100 [0079] (1) guar gum is 2 g/100
mL的比例溶于 30°C去离子水中， 制成浓度为 2% (w/v) 的瓜尔豆胶溶液；  The ratio of mL is dissolved in deionized water at 30 ° C to prepare a guar gum solution with a concentration of 2% (w/v);
[0080] (2) 将羟丙基甲基纤维素以 5 g/100mL的比例溶于 80°C去离子水中， 制成浓度 为 5% (w/v) 的羟丙基甲基纤维素溶液； [0080] (2) Dissolving hydroxypropyl methylcellulose in deionized water at 80 ° C in a ratio of 5 g / 100 mL to prepare a hydroxypropyl methylcellulose solution having a concentration of 5% (w/v) ;
[0081] (3) 将步骤 （1) 得到的瓜尔豆胶溶液和步骤 （2) 得到的羟丙基甲基纤维素 溶液混合， 得到瓜尔豆胶 /羟丙基甲基纤维素混合溶液， 作为"磷酸四钙-磷酸氢 钙"***骨水泥的液相； (3) mixing the guar gum solution obtained in the step (1) with the hydroxypropyl methylcellulose solution obtained in the step (2) to obtain a guar gum/hydroxypropyl methylcellulose mixed solution. , as the liquid phase of the "tetracalcium phosphate-calcium hydrogen phosphate" system bone cement;
[0082] (4) 将步骤 （3) 得到的瓜尔豆胶 /羟丙基甲基纤维素混合溶液与"磷酸四钙-磷 酸氢钙 "***骨水泥粉料按液固比 5 m!Jg充分混合、 高速搅拌， 搅拌速度为 600 r/min, 搅拌吋间为 20 min， 制得富含气泡的"磷酸四钙 -磷酸氢钙"***骨水泥浆 体； [0082] (4) The guar gum/hydroxypropyl methylcellulose mixed solution obtained in the step (3) and the "tetracalcium phosphate-calcium phosphate" system bone cement powder are liquid-solid ratio 5 m! Jg Fully mixed, high-speed stirring, stirring speed is 600 r / min, stirring for 20 min, to produce a bubble-rich "tetracalcium phosphate - calcium hydrogen phosphate" system bone cement slurry;
[0083] (5) 将步骤 （4) 中得到的富含气泡的 "磷酸四钙 -磷酸氢钙"***骨水泥浆体置 于超声波振荡器中， 超声频率为 24kHz， 超声吋间为 16 min;  [0083] (5) The bubble-rich "tetracalcium phosphate-calcium hydrogen phosphate" system bone cement slurry obtained in the step (4) is placed in an ultrasonic oscillator, the ultrasonic frequency is 24 kHz, and the ultrasonic time is 16 min. ;
[0084] (6) 用针头内径为 0.6 mm的注射器将步骤 （5) 中的"磷酸四钙-磷酸氢钙 "系 统骨水泥浆体滴加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥微球置于 55° C、 相对湿度为 99% (空气中水蒸气的百分比） 环境中养护水化 7天， 真空干燥 ， 得到具有表面大孔的多孔磷酸钙微球。 [0084] (6) using a syringe with an inner diameter of 0.6 mm, the "tetracalcium phosphate-calcium phosphate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone cement microspheres; Frozen bone cement microspheres placed at 55° C. Relative humidity: 99% (% of water vapor in the air) The environment was hydrated for 7 days in the environment, and vacuum dried to obtain porous calcium phosphate microspheres having large pores on the surface.
[0085] 微球粒径为 2.2 mm， 微球表面分布有大量大孔， 且大孔尺寸为 35〜80 μηι， 内 部含有大量孔隙， 孔隙之间相互连通， 内部孔尺寸为 105〜150  [0085] The particle diameter of the microsphere is 2.2 mm, a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 35 to 80 μηι, the inner part contains a large number of pores, and the pores are connected to each other, and the inner pore size is 105 to 150.
μηι , 孔隙率为 71.18% ; 体外抗崩解实验表明， 将具有表面大孔的多孔磷酸钙微 球放入磷酸盐缓冲溶液 （PBS) 中浸泡 18天后观察， 微球未发生崩解。 体外降解 3周以后， 多孔磷酸钙微球的失重率为 14.37%。  Μηι , porosity was 71.18%; in vitro anti-disintegration experiments showed that the porous calcium phosphate microspheres with large pores in the surface were immersed in phosphate buffer solution (PBS) for 18 days, and the microspheres did not disintegrate. After 3 weeks of in vitro degradation, the weight loss rate of the porous calcium phosphate microspheres was 14.37%.
[0086] 实施例 7  Example 7
[0087] 应用***胶为多糖胶、 羧甲基纤维素钠为增稠剂、 "磷酸氢钙 -a-磷酸三钙-碳 酸钙"***骨水泥制备具有表面大孔的多孔磷酸钙微球的步骤包括：  [0087] The use of gum arabic as polysaccharide gum, sodium carboxymethyl cellulose as a thickener, "calcium hydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement to prepare porous calcium phosphate microspheres with surface macropores The steps include:
[0088] ( 1 ) 将***胶以 18 g/100 mL的比例溶于 65°C去离子水中， 制成浓度为 18% [0088] (1) The gum arabic is dissolved in deionized water at 65 ° C in a ratio of 18 g / 100 mL to a concentration of 18%.
(w/v) 的***胶溶液；  (w/v) gum arabic solution;
[0089] (2) 将羧甲基纤维素钠以 0.4 g/100mL的比例溶于 55°C去离子水中， 制成浓度 为 0.4% (w/v) 的羧甲基纤维素钠溶液； [0089] (2) sodium carboxymethylcellulose was dissolved in deionized water at 55 ° C in a ratio of 0.4 g / 100 mL to prepare a sodium carboxymethyl cellulose solution having a concentration of 0.4% (w / v);
[0090] (3) 将步骤 （1 ) 得到的***胶溶液和步骤 （2) 得到的羧甲基纤维素钠溶 液混合， 得到***胶 /羧甲基纤维素钠混合溶液， 作为"磷酸氢钙 -a-磷酸三钙- 碳酸钙"***骨水泥的液相； [0090] (3) The gum arabic solution obtained in the step (1) and the sodium carboxymethyl cellulose solution obtained in the step (2) are mixed to obtain a gum arabic / sodium carboxymethyl cellulose mixed solution, as "calcium hydrogen phosphate" -a-tricalcium phosphate-calcium carbonate" liquid phase of systemic bone cement;
[0091] (4) 将步骤 （3) 得到的***胶 /羧甲基纤维素钠混合溶液与 "磷酸氢钙 -a-磷 酸三钙-碳酸钙"***骨水泥粉料按液固比 4.5 m!Jg充分混合、 高速搅拌， 搅拌速 度为 1 100 r/min， 搅拌吋间为 35 min， 制得富含气泡的"磷酸氢钙 -ot-磷酸三 -碳 酸钙"***骨水泥浆体； [0091] (4) The gum arabic / sodium carboxymethyl cellulose mixed solution obtained in the step (3) and the "calcium hydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement powder according to a liquid-solid ratio of 4.5 m Jg is fully mixed, high-speed stirring, stirring speed is 1 100 r / min, stirring for 35 min, to obtain a bubble-rich "calcium hydrogen phosphate-ot-phosphate tri-calcium carbonate" system bone cement slurry;
[0092] (5) 将步骤 （4) 中得到的富含气泡的 "磷酸氢钙 -ot-磷酸三钙-碳酸 "***骨 水泥浆体置于超声波振荡器中， 超声频率为 20kHz， 超声吋间为 24 min ; [0092] (5) The bubble-rich "calcium hydrogen phosphate-ot-tricalcium phosphate-carbonic acid" system bone cement slurry obtained in the step (4) is placed in an ultrasonic oscillator at an ultrasonic frequency of 20 kHz, ultrasonic 吋The interval is 24 min ;
[0093] (6) 用针头内径为 1.2 mm的注射器将步骤 （5) 中的"磷酸氢钙 -ot-磷酸三钙-碳 酸钙"***骨水泥浆体滴加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥微球 置于 35°C、 相对湿度为 94% (空气中水蒸气的百分比） 环境中养护水化 6天， 真 空干燥， 得到具有表面大孔的多孔磷酸钙微球。 [0093] (6) using a syringe having an inner diameter of 1.2 mm, the "calcium hydrogen phosphate-ot-tricalcium phosphate-calcium carbonate" system bone cement slurry in step (5) is added dropwise to liquid nitrogen to obtain frozen bone. Cement microspheres; the frozen bone cement microspheres were placed in a 35 ° C, relative humidity of 94% (% of water vapor in the air) environment for 6 days of hydration, vacuum drying, to obtain porous calcium phosphate microporous with surface macropores ball.
[0094] (7) 将步骤 （6) 中得到的多孔磷酸钙微球于 20°C在骨宁注射液中浸泡 30 min ， 真空干燥， 得到负载骨宁注射液的多孔磷酸钙药物微球。 (7) The porous calcium phosphate microsphere obtained in the step (6) is immersed in the bone injection for 30 min at 20 ° C. , vacuum drying, to obtain porous calcium phosphate drug microspheres loaded with Gu Ning injection.
[0095] (8) 将步骤 （7) 中得到的负载骨宁注射液的多孔磷酸钙药物微球植入到兔子 的股骨缺损处， 逐层缝合手术切口， 术后观察手术切口的愈合情况。  [0095] (8) The porous calcium phosphate drug microsphere loaded with the bone cement injection obtained in the step (7) was implanted into the femur defect of the rabbit, and the surgical incision was sutured layer by layer, and the healing of the surgical incision was observed after operation.
[0096] 微球粒径为 3.0 mm， 微球表面分布有大量大孔， 且大孔尺寸为 30〜75μηι， 内 部含有大量孔隙， 孔隙之间相互连通， 内部孔尺寸为 100〜140  [0096] The microspheres have a particle diameter of 3.0 mm, and a large number of large pores are distributed on the surface of the microspheres, and the large pore size is 30 to 75 μm. The inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 100 to 140.
μηι , 孔隙率为 73.56% ; 体外抗崩解实验表明， 将具有表面大孔的多孔磷酸钙微 球放入磷酸盐缓冲溶液 （PBS) 中浸泡 16天后观察， 微球未发生崩解。 体外降解 3周以后， 多孔磷酸钙微球的失重率为 13.24%。 多孔磷酸钙载药微球中药物的包 封率为 92% ; 术后 6周组织学观察结果显示， 新生的骨组织能够长入到微球堆积 所形成的间隙以及多孔微球内部， 骨修复效果良好。  Μηι , porosity was 73.56%; in vitro anti-disintegration experiments showed that the porous calcium phosphate microspheres with large pores in the surface were immersed in phosphate buffer solution (PBS) for 16 days, and the microspheres did not disintegrate. After 3 weeks of in vitro degradation, the weight loss rate of the porous calcium phosphate microspheres was 13.24%. The encapsulation efficiency of the drug in the porous calcium phosphate drug-loaded microspheres was 92%. The histological observation at 6 weeks after surgery showed that the new bone tissue could grow into the gap formed by the accumulation of microspheres and the inside of the porous microspheres. The effect is good.
[0097] 实施例 8  Example 8
[0098] 应用羟乙基纤维素为多糖胶、 氧化淀粉为增稠剂、 "磷酸二氢钙 -a-磷酸三钙-碳 酸钙"***骨水泥制备具有表面大孔的多孔磷酸钙微球的步骤包括：  [0098] using hydroxyethyl cellulose as a polysaccharide gum, oxidized starch as a thickener, "calcium dihydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement to prepare porous calcium phosphate microspheres with surface macropores The steps include:
[0099] ( 1 ) 将羟乙基纤维素以 lO g/100 [0099] (1) hydroxyethyl cellulose at 10 g / 100
mL的比例溶于 25°C去离子水中， 制成浓度为 10% (w/v) 的羟乙基纤维素溶液； [0100] (2) 将氧化淀粉以 3  The ratio of mL is dissolved in deionized water at 25 ° C to prepare a hydroxyethyl cellulose solution having a concentration of 10% (w/v); [0100] (2) Oxidized starch is 3
g/100mL的比例溶于 60°C去离子水中， 制成浓度为 3% (w/v) 的氧化淀粉溶液； [0101] (3) 将步骤 （1 ) 得到的羟乙基纤维素溶液和步骤 （2) 得到的氧化淀粉溶液 混合， 得到羟乙基纤维素 /氧化淀粉混合溶液， 作为"磷酸二氢钙 -a-磷酸三钙-碳 酸钙"***骨水泥的液相；  The ratio of g/100mL is dissolved in deionized water at 60 ° C to prepare a oxidized starch solution having a concentration of 3% (w/v); [0101] (3) the hydroxyethyl cellulose solution obtained in the step (1) and The oxidized starch solution obtained in the step (2) is mixed to obtain a hydroxyethyl cellulose/oxidized starch mixed solution, which is used as a liquid phase of the "dihydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement;
[0102] (4) 将步骤 （3) 得到的羟乙基纤维素 /氧化淀粉混合溶液与 "磷酸二氢钙 -a-磷 酸三钙-碳酸钙"***骨水泥粉料按液固比 5 m!Jg充分混合、 高速搅拌， 搅拌速度 为 900 r/min， 搅拌吋间为 25 min， 制得富含气泡的"磷酸二氢钙 -ot-磷酸三钙 -碳酸 钙"***骨水泥浆体； [0102] (4) The hydroxyethyl cellulose/oxidized starch mixed solution obtained in the step (3) and the "dicalcium phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement powder are liquid-solid to a ratio of 5 m. Jg is fully mixed, high-speed stirring, stirring speed is 900 r / min, stirring for 25 min, to obtain a bubble-rich "calcium dihydrogen phosphate-ot-tricalcium phosphate-calcium carbonate" system bone cement slurry;
[0103] (5) 将步骤 （4) 中得到的富含气泡的 "磷酸二氢钙 -ot-磷酸三钙-碳酸 "*** 骨水泥浆体置于超声波振荡器中， 超声频率为 18kHz， 超声吋间为 12 min ;  [0103] (5) The bubble-rich "calcium dihydrogen phosphate-ot-tricalcium phosphate-carbonic acid" system bone cement slurry obtained in the step (4) is placed in an ultrasonic oscillator, the ultrasonic frequency is 18 kHz, and the ultrasonic wave 12 minutes in the daytime;
[0104] (6) 用针头内径为 1.0 mm的注射器将步骤 （5) 中的"磷酸二氢钙 -ot-磷酸三钙- 碳酸钙 "***骨水泥浆体滴加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥微 球置于 37°C、 相对湿度为 96% (空气中水蒸气的百分比） 环境中养护水化 3天， 真空干燥， 得到具有表面大孔的多孔磷酸钙微球。 [0104] (6) The "calcium dihydrogen phosphate-ot-tricalcium phosphate-calcium carbonate" system bone cement slurry in step (5) is added to liquid nitrogen with a syringe having an inner diameter of 1.0 mm to obtain a frozen Bone cement microspheres; will freeze bone cement micro The ball was hydrated for 3 days at 37 ° C, a relative humidity of 96% (% of water vapor in the air), and vacuum dried to obtain porous calcium phosphate microspheres having large pores on the surface.
[0105] (7) 将步骤 （6) 中得到的多孔磷酸钙微球于 20°C在注射用骨肽中浸泡 30 min ， 真空干燥， 得到负载注射用骨肽的多孔磷酸钙药物微球。  (7) The porous calcium phosphate microspheres obtained in the step (6) were immersed in the bone peptide for injection for 30 min at 20 ° C, and dried under vacuum to obtain porous calcium phosphate drug microspheres loaded with the bone peptide for injection.
[0106] (8) 将步骤 （7) 中得到的负载注射用骨肽的多孔磷酸钙药物微球植入到兔子 的股骨缺损处， 逐层缝合手术切口， 术后观察手术切口的愈合情况。  (8) The porous calcium phosphate drug microspheres of the bone peptide for injection injection obtained in the step (7) were implanted into the femur defect of the rabbit, and the surgical incision was sutured layer by layer, and the healing of the surgical incision was observed after the operation.
[0107] 微球粒径为 2.8 mm， 微球表面分布有大量大孔， 且大孔尺寸为 40〜85μηι， 内 部含有大量孔隙， 孔隙之间相互连通， 内部孔尺寸为 110〜150  [0107] The particle diameter of the microsphere is 2.8 mm, and a large number of large pores are distributed on the surface of the microsphere, and the large pore size is 40 to 85 μm. The inner portion contains a large number of pores, and the pores are connected to each other, and the inner pore size is 110 to 150.
μηι, 孔隙率为 68.34% ; 体外抗崩解实验表明， 将具有表面大孔的多孔磷酸钙微 球放入磷酸盐缓冲溶液 （PBS) 中浸泡 15天后观察， 微球未发生崩解。 体外降解 3周以后， 多孔磷酸钙微球的失重率为 11.26%。 多孔磷酸钙载药微球中药物的包 封率为 87% ; 术后 4周组织学观察结果显示， 新生的骨组织能够长入到微球堆积 所形成的间隙以及多孔微球内部， 骨修复效果良好。  Μηι, porosity was 68.34%; in vitro anti-disintegration experiments showed that the porous calcium phosphate microspheres with large pores in the surface were immersed in phosphate buffer solution (PBS) for 15 days, and the microspheres did not disintegrate. After 3 weeks of in vitro degradation, the weight loss rate of the porous calcium phosphate microspheres was 11.26%. The encapsulation efficiency of the drug in the porous calcium phosphate drug-loaded microspheres was 87%. The histological observation at 4 weeks after surgery showed that the new bone tissue could grow into the gap formed by the accumulation of microspheres and the inside of the porous microspheres. The effect is good.
[0108] 实施例 9  Example 9
[0109] 应用卡拉胶为多糖胶、 聚乙烯醇为增稠剂、 "部分结晶磷酸钙 -磷酸氢钙"***骨 水泥制备具有表面大孔的多孔磷酸钙微球的步骤包括：  [0109] The step of preparing carrageenan as a polysaccharide gum, a polyvinyl alcohol as a thickener, and a "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement to prepare porous calcium phosphate microspheres having surface macropores includes:
[0110] ( 1) 将卡拉胶以 15 g/100 [0110] (1) Carrageenan at 15 g/100
mL的比例溶于 40°C去离子水中， 制成浓度为 15% (w/v) 的卡拉胶溶液；  The ratio of mL is dissolved in deionized water at 40 ° C to prepare a carrageenan solution with a concentration of 15% (w/v);
[0111] (2) 将聚乙烯醇以 2 (2) Polyvinyl alcohol as 2
g/100mL的比例溶于 60°C去离子水中， 制成浓度为 2% (w/v) 的聚乙烯醇溶液； [0112] (3) 将步骤 （1) 得到的卡拉胶溶液和步骤 （2) 得到的聚乙烯醇溶液混合， 得到卡拉胶 /聚乙烯醇混合溶液， 作为"部分结晶磷酸钙 -磷酸氢钙"***骨水泥的 液相；  The ratio of g/100mL is dissolved in deionized water at 60 ° C to prepare a polyvinyl alcohol solution having a concentration of 2% (w/v); [0312] (3) The carrageenan solution obtained in the step (1) and the step ( 2) The obtained polyvinyl alcohol solution is mixed to obtain a carrageenan/polyvinyl alcohol mixed solution, which is a liquid phase of the "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement;
[0113] (4) 将万古霉素以 10 mg/mL比例添加到步骤 （3) 得到的卡拉胶 /聚乙烯醇混 合溶液中， 得到万古霉素-卡拉胶 /聚乙烯醇混合溶液；  (4) adding vancomycin to the carrageenan/polyvinyl alcohol mixed solution obtained in the step (3) at a ratio of 10 mg/mL to obtain a vancomycin-carrageenan/polyvinyl alcohol mixed solution;
[0114] (5) 将步骤 （4) 中得到的万古霉素-卡拉胶 /聚乙烯醇混合溶液与步骤 （4) 的 "部分结晶磷酸钙 -磷酸氢钙"***骨水泥粉料按液固比 3.5 m!Jg充分混合、 高速搅 拌， 搅拌速度为 1100 r/min， 搅拌吋间为 36 min， 制得富含气泡的万古霉素- "部 分结晶磷酸钙 -磷酸氢钙"***骨水泥浆体； [0114] (5) The vancomycin-carrageenan/polyvinyl alcohol mixed solution obtained in the step (4) and the "partially crystalline calcium phosphate-calcium hydrogen phosphate" system bone cement powder in the step (4) are liquid-solidified. More than 3.5 m! Jg, mixing at high speed, stirring at 1100 r/min, stirring for 36 min, to produce vanamycin rich in bubbles - "Ministry Separation of crystalline calcium phosphate-calcium hydrogen phosphate "systemic cement slurry;
[0115] (6) 将步骤 （5) 中得到的富含气泡的万古霉素-"部分结晶磷酸钙 -磷酸氢钙" ***骨水泥浆体置于超声波振荡器中， 超声频率为 32kHz， 超声吋间为 26 min;  [0115] (6) The bubble-rich vancomycin-"partially crystallized calcium phosphate-calcium hydrogen phosphate" system bone cement slurry obtained in the step (5) is placed in an ultrasonic oscillator, the ultrasonic frequency is 32 kHz, and the ultrasonic wave is used. The time is 26 min;
[0116] (7) 用针头内径为 0.8 mm的注射器将步骤 （5) 中的万古霉素-"部分结晶磷酸 钙-磷酸氢钙 "***骨水泥浆体滴加到液氮中， 得到冷冻骨水泥载药微球； 将冷冻 骨水泥载药微球置于 50°C、 相对湿度为 90% (空气中水蒸气的百分比） 环境中养 护水化 2天， 真空干燥， 得到具有表面大孔的多孔磷酸钙载药微球。  [0116] (7) The vancomycin-"partially crystallized calcium phosphate-calcium hydrogen phosphate" system bone cement slurry in step (5) is added to liquid nitrogen with a syringe having an inner diameter of 0.8 mm to obtain a frozen bone. Cement-loaded microspheres; the frozen bone cement-loaded microspheres were hydrated for 2 days in an environment of 50 ° C, relative humidity of 90% (% of water vapor in the air), and dried under vacuum to obtain macropores with surface Porous calcium phosphate drug-loaded microspheres.
[0117] 载药微球粒径为 1.8 mm， 微球表面分布有大量大孔， 且大孔尺寸为 25〜85μηι ， 内部含有大量孔隙， 孔隙之间相互连通， 内部孔尺寸为 100〜140 μηι， 孔隙率 为 66.48% ; 体外抗崩解实验表明， 将具有表面大孔的多孔磷酸钙微球放入磷酸 盐缓冲溶液 （PBS) 中浸泡 16天后观察， 微球未发生崩解。 体外降解 3周以后， 多孔磷酸钙载药微球的失重率为 12.68%。 多孔磷酸钙载药微球的包封率为 96%。  [0117] The drug-loaded microspheres have a particle size of 1.8 mm, and a large number of large pores are distributed on the surface of the microspheres, and the large pore size is 25 to 85 μm. The inside contains a large number of pores, and the pores are connected to each other, and the inner pore size is 100 to 140 μηι. The porosity was 66.48%. The in vitro anti-disintegration experiment showed that the porous calcium phosphate microspheres with large pores in the surface were immersed in phosphate buffer solution (PBS) for 16 days, and the microspheres did not disintegrate. After 3 weeks of in vitro degradation, the weight loss rate of the porous calcium phosphate drug-loaded microspheres was 12.68%. The encapsulation efficiency of the porous calcium phosphate drug-loaded microspheres was 96%.
[0118] 上述实施例为本发明较佳的实施方式， 但本发明的实施方式并不受所述实施例 的限制， 其他的任何未背离本发明的精神实质与原理下所作的改变、 修饰、 替 代、 组合、 简化， 均应为等效的置换方式， 都包含在本发明的保护范围之内。  The above-described embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the embodiments, and any other changes, modifications, and modifications made without departing from the spirit and principles of the present invention. Alternatives, combinations, simplifications, and equivalent substitutions are all included in the scope of the present invention.

Claims

权利要求书 Claim
[权利要求 1] 一种具有表面大孔的多孔磷酸钙微球材料的制备方法， 其特征在于， 包括以下步骤：  [Claim 1] A method for preparing a porous calcium phosphate microsphere material having a large surface pore, comprising the steps of:
( 1) 将多糖胶溶于 25~80°C去离子水中， 制成浓度为 2<¾~20<¾w/V的 多糖胶溶液； (1) Dissolving the polysaccharide gum in deionized water at 25-80 ° C to prepare a polysaccharide gum solution having a concentration of 2<3⁄4~20<3⁄4w/ V ;
(2) 将增稠剂溶于 25~80°C去离子水中， 制成浓度为 0.1<¾~5<¾W/V的 增稠剂溶液； (2) dissolving the thickener in deionized water at 25-80 ° C to prepare a thickener solution having a concentration of 0.1<3⁄4~5<3⁄4 W / V ;
(3) 将步骤 （1) 得到的多糖胶溶液和步骤 （2) 得到的增稠剂溶液 混合， 得到多糖胶 /增稠剂混合溶液， 作为磷酸钙骨水泥的液相； (3) mixing the polysaccharide gum solution obtained in the step (1) and the thickener solution obtained in the step (2) to obtain a polysaccharide gum/thickener mixed solution as a liquid phase of the calcium phosphate bone cement;
(4) 将步骤 （3) 得到的多糖胶 /增稠剂混合溶液与磷酸钙骨水泥粉 料按液固比 2~5 mIJg充分混合、 以速度为 400~1200r/min搅拌， 搅拌 吋间为 20~40 min, 制得富含气泡的磷酸钙骨水泥浆体； (4) Mix the polysaccharide gum/thickener mixture solution obtained in step (3) with the calcium phosphate bone cement powder at a liquid-solid ratio of 2~5 mIJg, stir at a speed of 400~1200r/min, and stir the crucible. 20~40 min, a bubble-rich calcium phosphate cement slurry is prepared;
(5) 将步骤 （4) 中得到的富含气泡的磷酸钙骨水泥浆体置于超声波 振荡器中， 超声频率为 16~40 kHz， 超声吋间为 5~30 min;  (5) placing the bubble-rich calcium phosphate cement slurry obtained in the step (4) in an ultrasonic oscillator, the ultrasonic frequency is 16 to 40 kHz, and the ultrasonic time is 5 to 30 minutes;
(6) 用针头内径为 0.5~1.5 mm的注射器将步骤 （5) 中的磷酸钙骨水 泥浆体滴加到液氮中， 得到冷冻骨水泥微球； 将冷冻骨水泥微球置于 25~60°C、 相对湿度为 QOy^lOO^的环境中养护水化 1~7天， 真空干 燥， 得到具有表面大孔的多孔磷酸钙微球； 所述大孔的孔径为 20~85 μηι。  (6) The calcium phosphate cement slurry in step (5) is added to liquid nitrogen with a syringe having an inner diameter of 0.5 to 1.5 mm to obtain a frozen bone cement microsphere; the frozen bone cement microsphere is placed at 25~ Curing and hydration in an environment of 60 ° C and relative humidity of QOy ^ lOO ^ for 1 to 7 days, vacuum drying, to obtain porous calcium phosphate microspheres having large pores on the surface; the pore size of the macropores is 20 to 85 μηι.
[权利要求 2] 根据权利要求 1所述的具有表面大孔的多孔磷酸钙微球材料的制备方 法， 其特征在于， 步骤 （1) 所述的多糖胶为变性淀粉、 明胶、 黄原 胶、 可溶性壳聚糖、 羟乙基纤维素、 糊精、 ***胶、 卡拉胶、 瓜尔 豆胶中的至少一种。  [Claim 2] The method for preparing a porous calcium phosphate microsphere material having a large surface pore according to claim 1, wherein the polysaccharide gum of step (1) is modified starch, gelatin, xanthan gum, At least one of soluble chitosan, hydroxyethyl cellulose, dextrin, gum arabic, carrageenan, guar gum.
[权利要求 3] 根据权利要求 1所述的具有表面大孔的多孔磷酸钙微球材料的制备方 法， 其特征在于， 步骤 （2) 所述的增稠剂为改性淀粉、 氧化淀粉、 羧甲基纤维素钠、 羟丙基纤维素钠、 海藻酸钠、 聚乙烯醇、 果胶、 羟 丙基甲基纤维素中的至少一种。  [Claim 3] The method for preparing a porous calcium phosphate microsphere material having a large surface pore according to claim 1, wherein the thickener according to the step (2) is a modified starch, an oxidized starch, or a carboxy group. At least one of sodium methylcellulose, sodium hydroxypropylcellulose, sodium alginate, polyvinyl alcohol, pectin, and hydroxypropylmethylcellulose.
[权利要求 4] 根据权利要求 1所述的具有表面大孔的多孔磷酸钙微球材料的制备方 法， 其特征在于， 步骤 （4 ) 所述的磷酸钙骨水泥为"磷酸四钙 -磷酸 氢钙"***骨水泥、 "磷酸二氢钙 -a-磷酸三钙-碳酸钙"***骨水泥、 " 磷酸四钙 磷酸三钙"***骨水泥、 "磷酸四钙 -β-磷酸三钙-磷酸二氢 钙"***骨水泥、 "无定形磷酸钙 -磷酸氢钙"***骨水泥、 "部分结晶 磷酸钙 -磷酸氢钙"骨水泥或"磷酸氢钙 磷酸三钙-碳酸钙"***骨水 泥中的一种。 [Claim 4] The preparation method of the porous calcium phosphate microsphere material having a large surface pore according to claim 1. The method is characterized in that: the calcium phosphate bone cement according to the step (4) is a "calcium phosphate-calcium hydrogen phosphate" system bone cement, a "dihydrogen phosphate-a-tricalcium phosphate-calcium carbonate" system bone cement, "Calcium tetracalcium phosphate tricalcium" system bone cement, "tetracalcium phosphate-β-tricalcium phosphate-dicalcium phosphate" system bone cement, "amorphous calcium phosphate-calcium hydrogen phosphate" system bone cement, "partially crystalline phosphoric acid" Calcium-calcium hydrogen phosphate "bone cement or one of the "calcium phosphate dicalcium phosphate-calcium carbonate" system bone cement.
[权利要求 5] 权利要求 1~4所述的具有表面大孔的多孔磷酸钙微球材料的制备方法 制备得到的具有表面大孔的多孔磷酸钙微球材料， 其特征在于， 所述 多孔磷酸钙微球孔隙之间相互连通， 内部孔尺寸为 100〜160 μηι。  [Claim 5] The porous calcium phosphate microsphere material having a surface macropores prepared by the method for preparing a porous calcium phosphate microsphere material having a large surface pore according to any one of claims 1 to 4, wherein the porous phosphoric acid The pores of the calcium microspheres are connected to each other, and the inner pore size is 100 to 160 μη.
[权利要求 6] 权利要求 5的具有表面大孔的多孔磷酸钙微球材料的应用， 其特征在 于， 所述具有表面大孔的多孔磷酸钙微球材料作为医用骨缺损填充材 料或作为药物载体材料。 [Claim 6] The use of the porous calcium phosphate microsphere material having a large surface pore according to claim 5, wherein the porous calcium phosphate microsphere material having a large surface pore is used as a medical bone defect filling material or as a drug carrier material.
[权利要求 7] 根据权利要求 6的具有表面大孔的多孔磷酸钙微球材料的应用， 其特 征在于， 所述作为医用骨缺损填充材料应用吋， 具体为： 根据骨缺损 部位的大小， 选择适当粒径的具有表面大孔的多孔磷酸钙微球填充到 骨缺损部位， 对伤口进行缝合处理。 [Claim 7] The porous calcium phosphate microsphere material having a large surface pore according to claim 6, wherein the medical bone defect filling material is applied, specifically: according to the size of the bone defect portion, A porous calcium phosphate microsphere having a large pore size of a suitable particle diameter is filled in a bone defect site, and the wound is sutured.
[权利要求 8] 根据权利要求 7的具有表面大孔的多孔磷酸钙微球材料的应用， 其特 征在于， 所述具有表面大孔的多孔磷酸钙微球为载药微球。 [Claim 8] The use of a porous calcium phosphate microsphere material having a large surface pore according to claim 7, wherein the porous calcium phosphate microsphere having a large surface pore is a drug-loaded microsphere.
[权利要求 9] 根据权利要求 8的具有表面大孔的多孔磷酸钙微球材料的应用， 其特 征在于， 所述载药微球， 具体制备方法为： 将制好的微球浸泡于药物 溶液中， 通过液相吸附的形式载入药物。 [Claim 9] The use of the porous calcium phosphate microsphere material having a large surface pore according to claim 8, wherein the drug-loaded microspheres are specifically prepared by: immersing the prepared microspheres in a drug solution Medium, the drug is loaded by liquid phase adsorption.
[权利要求 10] 根据权利要求 8的具有表面大孔的多孔磷酸钙微球材料的应用， 其特 征在于， 所述载药微球， 具体制备方法为： 在权利要求 1的步骤 （3) 中的磷酸钙骨水泥液相中加入目标药物； 或者 [Claim 10] The use of a porous calcium phosphate microsphere material having a macroporous surface according to claim 8, wherein the drug-loaded microspheres are specifically prepared in the step (3) of claim 1. Adding the target drug to the calcium phosphate bone cement liquid phase; or
在权利要求 1的步骤 （4) 中的磷酸钙骨水泥粉料中加入目标药物。  The target drug is added to the calcium phosphate bone cement powder in the step (4) of claim 1.
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