WO2019153794A1 - 一种中空多孔球形颗粒人工骨及其制备方法和应用 - Google Patents

一种中空多孔球形颗粒人工骨及其制备方法和应用 Download PDF

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WO2019153794A1
WO2019153794A1 PCT/CN2018/111612 CN2018111612W WO2019153794A1 WO 2019153794 A1 WO2019153794 A1 WO 2019153794A1 CN 2018111612 W CN2018111612 W CN 2018111612W WO 2019153794 A1 WO2019153794 A1 WO 2019153794A1
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artificial bone
spherical particle
hollow porous
particle artificial
extrusion
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PCT/CN2018/111612
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English (en)
French (fr)
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叶建东
何福坡
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华南理工大学
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Publication of WO2019153794A1 publication Critical patent/WO2019153794A1/zh
Priority to US16/725,861 priority Critical patent/US11077225B2/en

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    • 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
    • A61L27/10—Ceramics or glasses
    • 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
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/3094—Designing or manufacturing processes
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/3094—Designing or manufacturing processes
    • A61F2002/30968—Sintering
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00179—Ceramics or ceramic-like structures
    • A61F2310/00293—Ceramics or ceramic-like structures containing a phosphorus-containing compound, 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the invention relates to the field of artificial bone materials, in particular to a hollow porous spherical particle artificial bone and a preparation method and application thereof.
  • Bone grafts are usually required for critical bone defects caused by trauma, infection, osteonecrosis, bone tumors, and the like.
  • synthetic bone repair materials artificial bone
  • the most commonly used artificial bones in clinical practice are calcium phosphate ceramics, silicate ceramics, calcium carbonate ceramics, calcium sulfate ceramics, calcium phosphate bone cement, phosphate bioglass and silicate bioglass materials.
  • Artificial bone is usually used in the form of lumps or granules for bone defect repair.
  • the block artificial bone has relatively good mechanical properties and can be used for the repair of bone defects in low load-bearing or moderate load-bearing parts after processing according to the shape of the bone defect.
  • the sintered ceramic material is difficult to process, and the shape of the bone defect is different, and the bulk material is difficult to sufficiently fill the defect portion, resulting in a certain limitation of the clinical application of the block artificial bone.
  • Granular artificial bone can be arbitrarily filled in the bone defect site, is not limited by the shape of the bone defect, and is fully filled, which is favored by orthopedic clinicians.
  • the disadvantage is that the mechanical support is poor, mainly used for non-load-bearing or low load-bearing parts. Repair of bone defects.
  • Artificial bone particles mainly include irregular non-spherical particles and spherical particles.
  • the non-spherical particles are mainly obtained by breaking up the bulk material, and the fluidity is poor, and the sharp edges and corners may damage the surrounding tissue after being implanted into the body.
  • the spherical particles have good fluidity, are easy to handle, and are filled in the bone defect site to achieve any accumulation of the sphere.
  • the microspheres can form three-dimensional pores that communicate with each other, which is beneficial to the growth of blood vessels and bone tissue.
  • studies have shown that the inflammatory response of spherical particles after implantation in vivo is significantly smaller than that of non-spherical particles.
  • the methods for preparing spherical particle artificial bone are mainly a droplet condensation method and a microemulsion method.
  • a spherical material having a large size (>1 mm) and a small size distribution range can be obtained by the droplet condensation method, but it is difficult to prepare a spherical material of a small size.
  • the microemulsion method can be used to prepare spherical materials with different particle size ranges, but the process is complicated and it is difficult to control the size distribution of the spherical materials.
  • the spherical materials prepared by these two methods all have the problem of low yield.
  • the spherical particles filled in the bone defect site can obtain a completely three-dimensionally connected pore structure, the porosity is low ( ⁇ 40%).
  • the porous structure is made inside the spherical particles by adding the pore-forming agent method and the gas foaming method, which can accelerate the degradation of the artificial bone and is beneficial to the repair and reconstruction of the bone defect.
  • a large number of studies have shown that artificial bones with large pore-microporous structure have better bone repair effects.
  • the porous spherical particle artificial bone with macroporous-microporous structure has unique advantages in the repair of non-weight bearing bone defects.
  • the current techniques for preparing porous spherical particles have problems such as complicated processes, low yield, and difficulty in controlling ball diameter and ball diameter distribution.
  • an object of the present invention is to provide a method for preparing an empty porous spherical particle artificial bone, which is simple in preparation method, does not require the addition of a pore former, and adjusts the content of the excipient and the sintering system. It can regulate the hollow size in the spherical particles and the pore size of the macropores and micropores in the shell.
  • Another object of the present invention is to provide an empty porous spherical particle artificial bone prepared by the above preparation method, which has a hollow structure, and has a large number of macropores and micropores distributed in the shell of the spherical particles, the pore structure is controllable, the porosity and high strength.
  • a further object of the present invention is to provide an empty porous spherical particle artificial bone prepared by the above preparation method.
  • a method for preparing hollow porous spherical particle artificial bone comprising the following steps:
  • the solid phase mixture, the mass fraction of the excipient is 10% to 85%; the mass ratio of the bioceramic and the glass sintering aid is 0.01 to 100;
  • the mass ratio of the binder solid phase mixture is 0.2 to 3;
  • the strip material obtained in the step (2) is placed in a spheronizing device of an extrusion spheronizer, and after being cut, is rounded into spherical granules;
  • the spherical particles obtained in the step (3) are placed in a furnace, degreased to remove excipients and binders, and then sintered at 750 to 1550 ° C to obtain hollow porous spherical particle artificial bone.
  • the bioceramic powder according to the step (1) is one or more selected from the group consisting of hydroxyapatite powder, calcium phosphate powder, silicate powder, calcium carbonate powder, and calcium sulfate powder.
  • the bioglass powder of the step (1) is a phosphate glass powder or a silicate glass powder.
  • the excipient described in the step (1) is microcrystalline cellulose, methyl cellulose, lactose, monosaccharide, cyclodextrin, starch, alginate, chitosan, pectic acid, carrageenan, At least one of polyacrylate, polyvinylidene alcohol, carboxymethyl cellulose, xanthan gum, and polyvinylpyrrolidone.
  • the degreasing described in the step (4) is degreasing at 300 to 750 °C.
  • the extrusion device of the extrusion spheronizer of the step (2) has an orifice diameter of 0.3 to 3 mm.
  • the hollow porous spherical particle artificial bone obtained by the method for preparing the hollow porous spherical particle artificial bone is characterized in that it has a hollow spherical shell structure, and the large pores and the micropores are distributed on the spherical shell.
  • the central cavity of the spherical particles has a size of 50 to 1200 ⁇ m; the large pore diameter of the spherical shell is 10 to 200 ⁇ m, and the pore diameter of the micropores is 0.1 to 10 ⁇ m.
  • the hollow porous spherical particle artificial bone is used for repairing a bone defect site.
  • the present invention has the following advantages and benefits:
  • the invention utilizes the principle that the bioglass forms a liquid phase and the liquid phase encapsulates the gas during the sintering process, and the porous spherical particle artificial bone having the hollow and multi-stage pore structure is prepared, and the preparation method is simple, and no pore-forming agent is needed.
  • the content of the excipients and the sintering system it is possible to regulate the hollow size in the spherical particles and the pore size of the macropores and micropores in the shell.
  • the hollow porous spherical particle artificial bone prepared by the method of the invention has high sphericity, large yield, and narrow size distribution; and can be adjusted by adjusting the pore size of the orifice of the extrusion device, the excipient content, the sintering temperature, etc.
  • the size of the hollow porous spherical particle artificial bone is regulated within the size range (from micron to millimeter).
  • the multi-stage pores and hollow structure of the hollow porous spherical particle artificial bone prepared by the method of the present invention contribute to the promotion of material degradation and the growth of cells and bone tissues, thereby promoting osteogenesis; the hollow porous spherical particles provide higher porosity.
  • the rate and large specific surface area are suitable as carriers for drugs and growth factors.
  • Example 1 is a scanning electron micrograph of a hollow porous spherical particle artificial bone prepared in Example 1.
  • Example 2 is a scanning electron micrograph of a hollow porous spherical particle artificial bone prepared in Example 6.
  • a ⁇ -tricalcium phosphate powder, a phosphate glass (component: 50P 2 O 5 -2ZnO-28CaO-20Na 2 O), and microcrystalline cellulose are uniformly mixed to obtain a solid phase mixture.
  • the mass fraction of microcrystalline cellulose is 50%, and the mass ratio of ⁇ -tricalcium phosphate to phosphate glass is 3:1.
  • a 0.5% methylcellulose solution was placed, and the methylcellulose solution was slowly added to the solid mixture (the mass ratio of the solution to the solid phase mixture was 0.85), and uniformly mixed to obtain a wet material having good plasticity.
  • the strip material obtained in the step (2) is loaded into the spheronizing device of the extrusion spheronizing machine, and the strip material is cut into a short column material in the rolling disc, and then rounded into a sphere having a diameter of about 1.4 mm. Particles.
  • the spherical particles obtained in the step (3) are placed in a high-temperature furnace, heated to 700 ° C at a heating rate of 1 ° C / min, and kept for 2 h to remove the microcrystalline cellulose and methyl cellulose, and then at 2 ° C / min.
  • the heating rate was raised to 1000 ° C and held for 1 hour to obtain hollow porous ⁇ -tricalcium phosphate/phosphate glass spherical particle artificial bone.
  • the hollow porous ⁇ -tricalcium phosphate/phosphate glass spherical particle artificial bone obtained in the present embodiment is as shown in FIG. 1 , the spherical diameter is about 1.2 mm, the spherical cavity central cavity size is about 600 ⁇ m, and the macropore pore size in the shell is about It is 20 to 110 ⁇ m and the pore size is about 0.5 to 8 ⁇ m.
  • Calcium carbonate powder, phosphate bioglass (component: 50P 2 O 5 -3SrO-12CaO-35Na 2 O) and microcrystalline cellulose are uniformly mixed to obtain a solid phase mixture.
  • the mass fraction of microcrystalline cellulose is 30%, and the mass ratio of calcium carbonate to phosphate glass is 1:1.
  • a 0.6% methylcellulose solution was prepared, and the solution was slowly added to the solid mixture (the mass ratio of the solution to the solid phase mixture was 0.65), and uniformly mixed to obtain a wet material having good plasticity.
  • the strip material obtained in the step (2) is loaded into the spheronization device of the extrusion spheronizer, and the strip material is cut into a short column material in the rolling disc, and then spheronized into a sphere having a diameter of about 1.5 mm. Particles.
  • the spherical particles obtained in the step (3) are placed in a high-temperature furnace, heated to 600 ° C at a temperature increase rate of 0.8 ° C / min, and kept for 2 h to remove the microcrystalline cellulose and methyl cellulose, and then at 1 ° C / min.
  • the heating rate was raised to 660 ° C and held for 1 hour to obtain hollow porous calcium carbonate/phosphate glass spherical particle artificial bone.
  • the diameter of the hollow porous calcium carbonate/phosphate glass spherical particle artificial bone obtained in this embodiment is 1.4 mm
  • the central cavity size of the spherical particle is about 150 ⁇ m
  • the macropore pore size in the shell is about 50-100 ⁇ m
  • the pore size is about 1 to 10 ⁇ m.
  • the strip material obtained in the step (2) is loaded into the spheronizing device of the extrusion spheronizing machine, and the strip material is cut into a short column material in the rolling disc, and then spheronized into a sphere having a diameter of about 1.9 mm. Particles.
  • the spherical particles obtained in the step (3) are placed in a high-temperature furnace, heated to 650 ° C at a heating rate of 0.9 ° C / min, and the starch, microcrystalline cellulose and hydroxypropyl cellulose are removed by holding for 2 hours, and then 1 The heating rate of °C/min was raised to 1120 ° C and held for 2 hours to obtain hollow porous calcium silicate/silicate bioglass spherical particle artificial bone.
  • the hollow porous calcium silicate/silicate bioglass spherical particle artificial bone obtained in this embodiment has a diameter of 1.65 mm, the central cavity of the spherical particle has a size of about 250 ⁇ m, and the macropore pore size in the shell is about 20 to 90 ⁇ m, and the micropores.
  • the size is about 0.5 to 10 ⁇ m.
  • the plastic wet material of the step (1) was placed in an extrusion device of an extrusion spheronizer (the extrusion orifice has a pore diameter of 0.5 mm) to obtain a strip material.
  • the strip material obtained in the step (2) is loaded into the spheronization device of the extrusion spheronizer, and the strip material is cut into a short columnar material in the rolling disc, and then spheronized into a sphere having a diameter of about 0.5 mm. Particles.
  • the spherical particles obtained in the step (3) are placed in a high temperature furnace, and the temperature is raised to 650 ° C at a heating rate of 0.5 ° C / min, and the cyclodextrin, microcrystalline cellulose and polyvinyl alcohol are removed for 2 hours, and then 2 The temperature increase rate of ° C / min was raised to 1100 ° C, and the temperature was maintained for 2 hours to obtain a hollow porous calcium silicate / ⁇ -tricalcium phosphate / phosphate bioglass spherical particle artificial bone.
  • the diameter of the hollow porous calcium silicate/ ⁇ -tricalcium phosphate/phosphate bioglass spherical particle artificial bone obtained in the present embodiment is 0.4 mm, the central cavity size of the spherical particle is about 100 ⁇ m, and the macropore diameter in the shell is about 10 ⁇ 50 ⁇ m, the pore size is about 0.3 to 10 ⁇ m.
  • Hydroxyapatite, phosphate bioglass (component: 45P 2 O 5 -2CuO-33CaO-20Na 2 O), lactose and microcrystalline cellulose are uniformly mixed to obtain a solid phase mixture.
  • the total mass fraction of lactose and microcrystalline cellulose is 70%, the mass ratio of lactose to microcrystalline cellulose is 1:1, and the mass ratio of hydroxyapatite to phosphate bioglass is 4:1.
  • a 0.5% sodium alginate solution was prepared, and the solution was slowly added to the solid mixture (the mass ratio of the solution to the solid phase mixture was 0.95), and uniformly mixed to obtain a wet material having good plasticity.
  • the strip material obtained in the step (2) is loaded into the spheronization device of the extrusion spheronizer, and the strip material is cut into a short column material in the rolling disc, and then spheronized into a sphere having a diameter of about 1.5 mm. Particles.
  • the spherical particles obtained in the step (3) are placed in a high-temperature furnace, heated to 400 ° C at a heating rate of 0.7 ° C / min, and kept for 2 h to remove sodium alginate, lactose and microcrystalline cellulose, and then at 2 ° C / The heating rate of min was raised to 1200 ° C and kept for 2 hours to obtain hollow porous hydroxyapatite/phosphate bioglass spherical particle artificial bone.
  • the diameter of the hollow porous hydroxyapatite/phosphate bioglass spherical particle artificial bone obtained in this embodiment is 1.25 mm
  • the central cavity of the spherical particle is about 300 ⁇ m
  • the macropore pore size in the shell is about 20-100 ⁇ m.
  • the size is about 0.1 to 10 ⁇ m.
  • the Mg-doped hydroxyapatite, calcium carbonate, and phosphate bioglass (component: 45P 2 O 5 -35CaO-20Na 2 O), sodium alginate, and microcrystalline cellulose are uniformly mixed to obtain a solid phase mixture.
  • the total mass fraction of sodium alginate and microcrystalline cellulose is 60%
  • the mass ratio of sodium alginate to microcrystalline cellulose is 1:20
  • the mass ratio of magnesium-doped hydroxyapatite, calcium carbonate and phosphate bioglass is 2. :2:2.
  • a 3% gelatin solution was prepared, and the solution was slowly added to the solid mixture (the mass ratio of the solution to the solid phase mixture was 0.9), and the mixture was uniformly stirred to obtain a wet material having good plasticity.
  • the strip material obtained in the step (2) is loaded into the spheronization device of the extrusion spheronizer, and the strip material is cut into a short column material in the rolling disc, and then spheronized into a sphere having a diameter of about 1.5 mm. Particles.
  • the spherical particles obtained in the step (3) are placed in a high-temperature furnace, heated up to 400 ° C at a temperature increase rate of 0.8 ° C / min, and kept for 2 h to remove sodium alginate, microcrystalline cellulose and gelatin, and then at 2 ° C / The heating rate of min was raised to 1250 ° C and kept for 2 hours to obtain hollow porous hydroxyapatite/calcium carbonate/phosphate bioglass spherical particle artificial bone.
  • the hollow porous hydroxyapatite/calcium carbonate/phosphate bioglass spherical particle artificial bone of the present embodiment has a diameter of 1.25 mm as shown in FIG. 2, and the central cavity of the spherical particle has a size of about 300 ⁇ m, and the macropore pore size in the shell is about It is 20 to 100 ⁇ m and the pore size is about 0.1 to 10 ⁇ m.
  • Magnesite, silicate bioglass (component: 44SiO 2 -28CaO-16Na 2 O-4P 2 O 5 -8B 2 O 3 ), polypyrrolidone, and microcrystalline cellulose are uniformly mixed to obtain a solid phase mixture.
  • the total mass fraction of polypyrrolidone and microcrystalline cellulose is 25%
  • the mass ratio of lactose to microcrystalline cellulose is 1:4
  • the mass ratio of magnesium feldspar to silicate bioglass is 2:1.
  • a 0.75% polyvinyl butyral solution was prepared, and the solution was slowly added to the solid mixture (the mass ratio of the solution to the solid phase mixture was 0.65), and uniformly mixed to obtain a wet material having good plasticity.
  • the strip material obtained in the step (2) is loaded into a spheronizing device of an extrusion spheronizer, and the strip material is cut into a short columnar material in the rolling disc, and then spheronized into spherical granules having a diameter of about 1 mm. .
  • the spherical particles obtained in the step (3) are placed in a high-temperature furnace, heated to 600 ° C at a temperature increase rate of 2 ° C / min, and the polypyrrolidone, microcrystalline cellulose and polyvinyl butyral are removed by holding for 2 hours, and then The temperature increase rate of 5 ° C / min was raised to 1200 ° C, and the temperature was maintained for 3 hours to obtain hollow porous magnesite / silicate bioglass spherical particle artificial bone.
  • the diameter of the hollow porous magnesite/silicate bioglass spherical particle artificial bone obtained in this embodiment is 0.85 mm
  • the central cavity size of the spherical particle is about 50 ⁇ m
  • the macropore pore size in the shell is about 20-50 ⁇ m
  • the pore size is It is about 0.2 to 10 ⁇ m.
  • the total mass fraction of polypyrrolidone and pectic acid is 70%, the mass ratio of polypyrrolidone to pectin is 1:1, and the mass ratio of hydroxyapatite, ⁇ -tricalcium phosphate, and phosphate bioglass is 2:3:2.
  • a 0.2% sodium alginate solution was prepared, and the solution was slowly added to the solid mixture (the mass ratio of the solution to the solid phase mixture was 1), and uniformly mixed to obtain a wet material having good plasticity.
  • the plastic wet material of the step (1) was placed in an extrusion device of an extrusion spheronizer (the extrusion orifice has a pore diameter of 0.5 mm) to obtain a strip material.
  • the strip material obtained in the step (2) is loaded into the spheronization device of the extrusion spheronizer, and the strip material is cut into a short columnar material in the rolling disc, and then spheronized into a sphere having a diameter of about 0.5 mm. Particles.
  • the spherical particles obtained in the step (3) are placed in a high-temperature furnace, heated to 700 ° C at a temperature increase rate of 0.75 ° C / min, and kept for 3 h to remove the polypyrrolidone, pectic acid and sodium alginate, and then at 4 ° C
  • the heating rate of /min was raised to 1100 ° C and kept for 2 hours to obtain hollow porous hydroxyapatite/ ⁇ -tricalcium phosphate/phosphate bioglass spherical particle artificial bone.
  • the diameter of the hollow porous hydroxyapatite/ ⁇ -tricalcium phosphate/phosphate bioglass spherical particle artificial bone of the present embodiment is 0.38 mm
  • the central cavity size of the spherical particle is about 100 ⁇ m
  • the macropore pore size in the shell is about 10 ⁇ 60 ⁇ m
  • the pore size is about 0.2 to 10 ⁇ m.
  • the strip material obtained in the step (2) is loaded into the spheronizing device of the extrusion spheronizer, and the strip material is cut into short columnar materials in the rolling disc, and then spheronized into spherical granules having a diameter of about 3 mm. .
  • the spherical particles obtained in the step (3) are placed in a high-temperature furnace, and the temperature is raised to 720 ° C at a heating rate of 1 ° C / min, and the microcrystalline cellulose and xanthan gum are removed for 2 hours, and then at 2 ° C / min.
  • the heating rate was raised to 1120 ° C, and the temperature was maintained for 2 hours to obtain a hollow porous calcium silicate/magnesium silicate/silicate bioglass spherical particle artificial bone.
  • the diameter of the hollow porous calcium silicate/magnesium silicate/silicate bioglass spherical particle artificial bone obtained in this embodiment is 2.2 mm, the central cavity size of the spherical particle is about 1200 ⁇ m, and the macropore diameter in the shell is about 35-200 ⁇ m.
  • the pore size is about 0.25 to 10 ⁇ m.
  • Hydroxyapatite, ⁇ -tricalcium phosphate, phosphate bioglass (component: 45P 2 O 5 -10SrO-32CaO-20Na 2 O) and microcrystalline cellulose are uniformly mixed to obtain a solid phase mixture.
  • the total mass fraction of microcrystalline cellulose is 60%, and the mass ratio of hydroxyapatite, ⁇ -tricalcium phosphate, and phosphate bioglass is 2:1:1.
  • a 0.6% methylcellulose solution was placed, and the solution was slowly added to the solid mixture (the mass ratio of the solution to the solid phase mixture was 0.9), and uniformly mixed to obtain a wet material having good plasticity.
  • the plastic wet material of the step (1) was placed in an extrusion device of an extrusion spheronizer (the extrusion orifice has a pore diameter of 0.5 mm) to obtain a strip material.
  • the strip material obtained in the step (2) is loaded into the spheronization device of the extrusion spheronizer, and the strip material is cut into a short columnar material in the rolling disc, and then spheronized into a sphere having a diameter of about 0.5 mm. Particles.
  • the spherical particles obtained in the step (3) are placed in a high-temperature furnace, heated to 680 ° C at a temperature increase rate of 1 ° C / min, kept for 3 h to remove the microcrystalline cellulose, and then heated to a temperature increase rate of 3 ° C / min to The temperature was maintained at 1120 ° C for 2 hours to obtain a hollow porous hydroxyapatite/ ⁇ -tricalcium phosphate/phosphate bioglass spherical particle artificial bone.
  • the hollow porous hydroxyapatite/ ⁇ -tricalcium phosphate/phosphate bioglass spherical particle artificial bone has a diameter of 0.4 mm, the central cavity of the spherical particle has a size of about 120 ⁇ m, and the large pore diameter of the shell is about 20-65 ⁇ m, and the micropore The size is about 0.1 to 10 ⁇ m.
  • excipient microcrystalline cellulose in the above examples may also be replaced by microcrystalline cellulose, methyl cellulose, lactose, monosaccharide, cyclodextrin, starch, alginate, chitosan, pectic acid, One or more of carrageenan, polyacrylate, polyvinylidene alcohol, carboxymethyl cellulose, xanthan gum, and polyvinylpyrrolidone.

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Abstract

一种中空多孔球形颗粒人工骨的制备方法：(1)将生物陶瓷粉末、生物玻璃粉末和赋形剂均匀混合，得到固相混合物，然后将粘结剂溶液加入固相混合物中，均匀混合，获得可塑性湿物料；(2)将可塑性湿物料装入挤出滚圆机的挤出装置中，经挤出装置的孔板挤出，形成条形物料；(3)将条形物料放入挤出滚圆机的滚圆装置中，经切割后被滚圆成球形颗粒；(4)将球形颗粒放入炉中，脱脂除去赋形剂和粘结剂，然后在750～1550℃烧结。还公开了上述制备方法得到的中空多孔球形颗粒人工骨及其应用。所获得的人工骨呈中空结构，具有大量的大孔和微孔，孔结构可控，孔隙率高，强度高，在骨缺损修复材料领域中具有很好的应用前景。

Description

一种中空多孔球形颗粒人工骨及其制备方法和应用 技术领域
本发明涉及人工骨材料领域，特别涉及一种中空多孔球形颗粒人工骨及其制备方法和应用。
背景技术
由于外伤、感染、骨坏死、骨肿瘤等引起的临界性骨缺损通常需要进行骨移植。除了来源有限的自体骨、同种异体骨移植物外，人工合成骨修复材料(人工骨)由于来源广泛，价格低廉，方便对材料的成分和结构进行设计和调控，越来越多地被应用于临床。其中，临床上最常用的人工骨是磷酸钙陶瓷、硅酸盐陶瓷、碳酸钙陶瓷、硫酸钙陶瓷、磷酸钙骨水泥、磷酸盐生物玻璃和硅酸盐生物玻璃材料等。人工骨通常以块状或颗粒的形式用于骨缺损修复。块状人工骨具相对较好的力学性能，根据骨缺损的形状进行加工后，可以用于低承重或适度承重部位骨缺损的修复。但是，经过烧结的陶瓷材料难以加工，而且骨缺损的形态各异，块体材料难以对缺损部位进行充分填充，导致块状人工骨的临床应用受到一定的限制。颗粒状人工骨可以任意填充于骨缺损部位，不受骨缺损形状的限制，填充充分，更受骨科临床医生的青睐，其不足之处是力学支撑较差，主要用于非承重或低承重部位骨缺损的修复。人工骨颗粒主要包括不规则的非球形颗粒和球形颗粒两种。非球形颗粒主要通过大块材料破碎后获得，流动性较差，其尖锐的棱角植入体内后可能损伤周围组织。球形颗粒具有良好的流动性，便于操作，填充于骨缺损部位后，实现球体的任意堆积。根据球体任意堆积原理，微球可形成相互连通的三维孔隙，有利于血管和骨组织的长入。此外，研究表明，球形颗粒植入体内后的炎性反应明显比非球形颗粒的小。
目前，用于制备球形颗粒人工骨的方法主要是液滴冷凝法和微乳液法。采用液滴冷凝法可以获得大尺寸(>1mm)且尺寸分布范围小的球形材料，但是难以制备小尺寸的球形材料。采用微乳液法可以制备不同粒径范围的球形材料，但是工艺较为复杂，而且难以控制球形材料的尺寸分布。采用这两种方法制备的球形材料均存在产率较低的问题。虽然填充于骨缺损部位的球形颗粒可以获 得完全三维连通的孔结构，但是孔隙率偏低(<40％)。采用添加造孔剂法、气体发泡法等方法在球形颗粒内部制造出多孔结构，可以加速人工骨的降解，有利于骨缺损的修复和重建。大量的研究表明，具有大孔-微孔结构的人工骨具有更好的骨修复效果。
综上所述，具有大孔-微孔结构的多孔球形颗粒人工骨在非承重骨缺损修复方面具有独特的优势。然而，目前用于制备多孔球形颗粒的技术存在工艺复杂、产量低、难以控制球径及球径分布等问题。
发明内容
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空多孔球形颗粒人工骨的制备方法，制备方法简单，不需要添加造孔剂，通过调整赋形剂的含量和烧结制度，可以调控球形颗粒内中空尺寸以及壳中大孔和微孔的孔径。
本发明的另一目的在于提供上述制备方法制备得到的空多孔球形颗粒人工骨，呈中空结构，同时有大量的大孔和微孔分布于球形颗粒的壳中，孔结构可控，孔隙率和强度高。
本发明的再一目的在于提供上述制备方法制备得到的空多孔球形颗粒人工骨。
本发明的目的通过以下技术方案实现：
一种中空多孔球形颗粒人工骨的制备方法，包括以下步骤：
(1)将生物陶瓷粉末、生物玻璃粉末和赋形剂均匀混合，得到固相混合物，然后将粘结剂溶液加入固相混合物中，均匀混合，获得可塑性湿物料；
所述固相混合物中，赋形剂的质量分数为10％～85％；生物陶瓷和玻璃烧结助剂的质量比为0.01～100；
所述粘结剂固相混合物的质量比为0.2～3；
(2)将步骤(1)获得的可塑性湿物料装入挤出滚圆机的挤出装置中，经挤出装置的孔板挤出，形成条形物料；
(3)将步骤(2)获得的条形物料放入挤出滚圆机的滚圆装置中，经切割后被滚圆成球形颗粒；
(4)将步骤(3)获得的球形颗粒放入炉中，脱脂除去赋形剂和粘结剂，然后在750～1550℃烧结，获得中空多孔球形颗粒人工骨。
步骤(1)所述生物陶瓷粉末为羟基磷灰石粉末、磷酸钙粉末、硅酸盐粉末、 碳酸钙粉末或硫酸钙粉末中的一种以上。
步骤(1)所述生物玻璃粉末为磷酸盐玻璃粉末或硅酸盐玻璃粉末。
步骤(1)所述的赋形剂为微晶纤维素、甲基纤维素、乳糖、单糖、环糊精、淀粉、海藻酸盐、壳聚糖、果胶酯酸、角叉菜胶、聚丙烯酸酯、聚乙二烯醇、羧甲基纤维素、黄原胶、聚乙烯吡咯烷酮的至少一种。
步骤(4)所述脱脂为在300～750℃脱脂。
步骤(2)所述挤出滚圆机的挤出装置的孔板孔径为0.3～3mm。
所述的中空多孔球形颗粒人工骨的制备方法得到的中空多孔球形颗粒人工骨，其特征在于，呈中空的球形壳体结构，大孔和微孔分布于球形壳体上。
所述球形颗粒的中心空腔大小为50～1200μm；球形壳体上大孔孔径为10～200μm，微孔孔径为0.1～10μm。
所述的中空多孔球形颗粒人工骨的用于对骨缺损部位进行修复。
与现有技术相比，本发明具有以下优点和有益效果：
(1)本发明利用烧结过程中生物玻璃形成液相，液相包裹气体的原理，制备了同时具备中空和多级孔结构的多孔球形颗粒人工骨，制备方法简单，不需要添加造孔剂，通过调整赋形剂的含量和烧结制度，可以调控球形颗粒内中空尺寸以及壳中大孔和微孔的孔径。
(2)本发明方式制备的中空多孔球形颗粒人工骨的球形度高，产量大，尺寸分布范围窄；可以通过调整挤出装置的孔板孔径，赋形剂含量，烧结温度等可在较大的尺寸范围内(从微米级到毫米级)调控中空多孔球形颗粒人工骨的尺寸。
(3)本发明方式制备的中空多孔球形颗粒人工骨的多级孔和中空结构有助于促进材料降解以及细胞和骨组织的长入，从而促进成骨；中空多孔球形颗粒提供较高的孔隙率和较大的比表面积，适合作为药物和生长因子的载体。
附图说明
图1是实施例1制备的中空多孔球形颗粒人工骨的扫描电镜照片。
图2是实施例6制备的中空多孔球形颗粒人工骨的扫描电镜照片。
具体实施方式
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。
实施例1
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将β-磷酸三钙粉末、磷酸盐玻璃(成分为50P 2O 5-2ZnO-28CaO-20Na 2O)和微晶纤维素均匀混合，得到固相混合物。微晶纤维素的质量分数为50％，β-磷酸三钙和磷酸盐玻璃质量比为3:1。配置0.5％的甲基纤维素溶液，将甲基纤维素溶液缓慢加入固体混合物中(溶液和固相混合物的质量比为0.85)，均匀混合，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为1.5mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为1.4mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以1℃/min的升温速度升温至700℃，保温2h除去微晶纤维素和甲基纤维素，然后以2℃/min的升温速度升温至1000℃，保温1小时，得到中空多孔β-磷酸三钙/磷酸盐玻璃球形颗粒人工骨。
本实施例得到的中空多孔β-磷酸三钙/磷酸盐玻璃球形颗粒人工骨如图1所示，球径约为1.2mm，球形颗粒中心空腔大小约为600μm，壳中的大孔孔径约为20～110μm，微孔尺寸约为0.5～8μm。
实施例2
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将碳酸钙粉末、磷酸盐生物玻璃(成分为50P 2O 5-3SrO-12CaO-35Na 2O)和微晶纤维素均匀混合，得到固相混合物。微晶纤维素的质量分数为30％，碳酸钙和磷酸盐玻璃的质量比为1:1。配制0.6％的甲基纤维素溶液，将溶液缓慢加入固体混合物中(溶液和固相混合物的质量比为0.65)，均匀混合，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为1.5mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为1.5mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以0.8℃/min的升温速度升温至600℃，保温2h除去微晶纤维素和甲基纤维素，然后以1℃/min的升温速度升温至660℃，保温1小时，得到中空多孔碳酸钙/磷酸盐玻璃球形颗粒人工骨。
本实施例得到的中空多孔碳酸钙/磷酸盐玻璃球形颗粒人工骨的直径为1.4mm，球形颗粒中心空腔大小约为150μm，壳中的大孔孔径约为50～100μm，微孔尺寸约为1～10μm。
实施例3
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将含Cu的硅酸钙粉末、硅酸盐生物玻璃(成分为45SiO 2-26CaO-17Na 2O-5P 2O 5-7B 2O 3)、淀粉和微晶纤维素均匀混合，得到固相混合物。淀粉和微晶纤维素的质量分数为45％，淀粉和微晶纤维素的质量比为1:3，硅酸三钙和硅酸盐生物玻璃质量比为2:1。配制0.6％的羟丙基纤维素溶液，将溶液缓慢加入固体混合物中(溶液和固相混合物的质量比为0.8)，均匀混合，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为2mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为1.9mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以0.9℃/min的升温速度升温至650℃，保温2h除去淀粉、微晶纤维素和羟丙基纤维素，然后以1℃/min的升温速度升温至1120℃，保温2小时，得到中空多孔硅酸钙/硅酸盐生物玻璃球形颗粒人工骨。
本实施例得到的中空多孔硅酸钙/硅酸盐生物玻璃球形颗粒人工骨的直径为1.65mm，球形颗粒中心空腔大小约为250μm，壳中的大孔孔径约为20～90μm，微孔尺寸约为0.5～10μm。
实施例4
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将含Sr硅酸钙粉末、β-磷酸三钙、磷酸盐生物玻璃(成分为 48P 2O 5-25CaO-27Na 2O)、环糊精和微晶纤维素均匀混合，得到固相混合物。环糊精和微晶纤维素的总质量分数为55％，淀粉和微晶纤维素的质量比为1:2，含Sr硅酸钙、β-磷酸三钙和硅酸盐生物玻璃质量比为1:1:1。配制0.6％的聚乙烯醇溶液，将溶液缓慢加入固体混合物中(溶液和固相混合物的质量比为0.9)，均匀混合，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为0.5mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为0.5mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以0.5℃/min的升温速度升温至650℃，保温2h除去环糊精、微晶纤维素和聚乙烯醇，然后以2℃/min的升温速度升温至1100℃，保温2小时，得到中空多孔硅酸钙/β-磷酸三钙/磷酸盐生物玻璃球形颗粒人工骨。
本实施例得到的中空多孔硅酸钙/β-磷酸三钙/磷酸盐生物玻璃球形颗粒人工骨的直径为0.4mm，球形颗粒中心空腔大小约为100μm，壳中的大孔孔径约为10～50μm，微孔尺寸约为0.3～10μm。
实施例5
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将羟基磷灰石、磷酸盐生物玻璃(成分为45P 2O 5-2CuO-33CaO-20Na 2O)、乳糖和微晶纤维素均匀混合，得到固相混合物。乳糖和微晶纤维素的总质量分数为70％，乳糖和微晶纤维素的质量比为1:1，羟基磷灰石和磷酸盐生物玻璃质量比为4：1。配制0.5％的海藻酸钠溶液，将溶液缓慢加入固体混合物中(溶液和固相混合物的质量比为0.95)，均匀混合，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为1.5mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为1.5mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以0.7℃/min的升温速度 升温至400℃，保温2h除去海藻酸钠、乳糖和微晶纤维素，然后以2℃/min的升温速度升温至1200℃，保温2小时，得到中空多孔羟基磷灰石/磷酸盐生物玻璃球形颗粒人工骨。
本实施例得到的中空多孔羟基磷灰石/磷酸盐生物玻璃球形颗粒人工骨的直径为1.25mm，球形颗粒中心空腔大小约为300μm，壳中的大孔孔径约为20～100μm，微孔尺寸约为0.1～10μm。
实施例6
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将掺Mg羟基磷灰石、碳酸钙、磷酸盐生物玻璃(成分为45P 2O 5-35CaO-20Na 2O)、海藻酸钠和微晶纤维素均匀混合，得到固相混合物。海藻酸钠和微晶纤维素的总质量分数为60％，海藻酸钠和微晶纤维素的质量比为1:20，掺镁羟基磷灰石、碳酸钙和磷酸盐生物玻璃质量比为2：2：2。配制3％的明胶溶液，将溶液缓慢加入固体混合物中(溶液和固相混合物的质量比为0.9)，均匀搅拌，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为1.5mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为1.5mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以0.8℃/min的升温速度升温至400℃，保温2h除去海藻酸钠、微晶纤维素和明胶，然后以2℃/min的升温速度升温至1250℃，保温2小时，得到中空多孔羟基磷灰石/碳酸钙/磷酸盐生物玻璃球形颗粒人工骨。
本实施例的中空多孔羟基磷灰石/碳酸钙/磷酸盐生物玻璃球形颗粒人工骨如图2所示，直径为1.25mm，球形颗粒中心空腔大小约为300μm，壳中的大孔孔径约为20～100μm，微孔尺寸约为0.1～10μm。
实施例7
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将镁黄长石、硅酸盐生物玻璃(成分为44SiO 2-28CaO-16Na 2O-4P 2O 5-8B 2O 3)、聚吡咯烷酮和微晶纤维素均匀混合，得到 固相混合物。聚吡咯烷酮和微晶纤维素的总质量分数为25％，乳糖和微晶纤维素的质量比为1:4，镁黄长石和硅酸盐生物玻璃质量比为2：1。配制0.75％的聚乙烯缩丁醛溶液，将溶液缓慢加入固体混合物中(溶液和固相混合物的质量比为0.65)，均匀混合，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为1mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为1mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以2℃/min的升温速度升温至600℃，保温2h除去聚吡咯烷酮、微晶纤维素和聚乙烯缩丁醛，然后以5℃/min的升温速度升温至1200℃，保温3小时，得到中空多孔镁黄长石/硅酸盐生物玻璃球形颗粒人工骨。
本实施例得到的中空多孔镁黄长石/硅酸盐生物玻璃球形颗粒人工骨的直径为0.85mm，球形颗粒中心空腔大小约为50μm，壳中的大孔孔径约为20～50μm，微孔尺寸约为0.2～10μm。
实施例8
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将镁羟基磷灰石、β-磷酸三钙、磷酸盐生物玻璃(成分为46P 2O 5-8MgO-26CaO-20Na 2O)、聚吡咯烷酮和果胶酯酸均匀混合，得到固相混合物。聚吡咯烷酮和果胶酯酸的总质量分数为70％，聚吡咯烷酮和果胶酯酸的的质量比为1:1，羟基磷灰石、β-磷酸三钙、磷酸盐生物玻璃的质量比为2：3：2。配制0.2％的海藻酸钠溶液，将溶液缓慢加入固体混合物中(溶液和固相混合物的质量比为1)，均匀混合，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为0.5mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为0.5mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以0.75℃/min的升温速度升温至700℃，保温3h除去聚吡咯烷酮、果胶酯酸和海藻酸钠，然后以4℃/min 的升温速度升温至1100℃，保温2小时，得到中空多孔羟基磷灰石/β-磷酸三钙/磷酸盐生物玻璃球形颗粒人工骨。
本实施例的中空多孔羟基磷灰石/β-磷酸三钙/磷酸盐生物玻璃球形颗粒人工骨的直径为0.38mm，球形颗粒中心空腔大小约为100μm，壳中的大孔孔径约为10～60μm，微孔尺寸约为0.2～10μm。
实施例9
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将硅酸钙、硅酸镁、硅酸盐生物玻璃(成分为45SiO 2-2SrO-27CaO-14Na 2O-5P 2O 5-7B 2O 3)和微晶纤维素均匀混合，微晶纤维素的总质量分数为48％，硅酸钙、硅酸镁、硅酸盐生物玻璃质量比为2：1：2。配制0.1％的黄原胶溶液，将溶液缓慢加入固体混合物中(溶液和固相混合物的质量比为0.8)，均匀混合，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为3mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为3mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以1℃/min的升温速度升温至720℃，保温2h除去微晶纤维素和黄原胶，然后以2℃/min的升温速度升温至1120℃，保温2小时，得到中空多孔硅酸钙/硅酸镁/硅酸盐生物玻璃球形颗粒人工骨。
本实施例得到的中空多孔硅酸钙/硅酸镁/硅酸盐生物玻璃球形颗粒人工骨的直径为2.2mm，球形颗粒中心空腔大小约为1200μm，壳中大孔孔径约为35～200μm，微孔尺寸约为0.25～10μm。
实施例10
本实施例的中空多孔球形颗粒人工骨的制备方法包括以下步骤：
(1)将羟基磷灰石、α-磷酸三钙、磷酸盐生物玻璃(成分为45P 2O 5-10SrO-32CaO-20Na 2O)和微晶纤维素均匀混合，得到固相混合物。微晶纤维素的总质量分数为60％，羟基磷灰石、α-磷酸三钙、磷酸盐生物玻璃的质量比为2：1：1。配置0.6％的甲基纤维素溶液，将溶液缓慢加入固体混合物中 (溶液和固相混合物的质量比为0.9)，均匀混合，得到可塑性良好的湿物料。
(2)将步骤(1)的可塑性湿物料装入挤出滚圆机的挤出装置(挤出孔板孔径为0.5mm)中，获得条状物料。
(3)将步骤(2)得到的条状物料装入挤出滚圆机的滚圆装置中，条状物料在滚圆盘中被切割成短柱状物料，然后被滚圆成直径为0.5mm左右的球形颗粒。
(4)将步骤(3)获得的球形颗粒放入高温炉中，以1℃/min的升温速度升温至680℃，保温3h除去微晶纤维素，然后以3℃/min的升温速度升温至1120℃，保温2小时，得到中空多孔羟基磷灰石/α-磷酸三钙/磷酸盐生物玻璃球形颗粒人工骨。
中空多孔羟基磷灰石/α-磷酸三钙/磷酸盐生物玻璃球形颗粒人工骨的直径为0.4mm，球形颗粒中心空腔大小约为120μm，壳中大孔孔径约为20～65μm，微孔尺寸约为0.1～10μm。
上述实施例中的赋形剂微晶纤维素还可替换为微晶纤维素、甲基纤维素、乳糖、单糖、环糊精、淀粉、海藻酸盐、壳聚糖、果胶酯酸、角叉菜胶、聚丙烯酸酯、聚乙二烯醇、羧甲基纤维素、黄原胶、聚乙烯吡咯烷酮中的一种以上。
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。

Claims (9)

  1. 一种中空多孔球形颗粒人工骨的制备方法，其特征在于，包括以下步骤：
    (1)将生物陶瓷粉末、生物玻璃粉末和赋形剂均匀混合，得到固相混合物，然后将粘结剂溶液加入固相混合物中，均匀混合，获得可塑性湿物料；
    所述固相混合物中，赋形剂的质量分数为10％～85％；生物陶瓷和玻璃烧结助剂的质量比为0.01～100；
    所述粘结剂固相混合物的质量比为0.2～3；
    (2)将步骤(1)获得的可塑性湿物料装入挤出滚圆机的挤出装置中，经挤出装置的孔板挤出，形成条形物料；
    (3)将步骤(2)获得的条形物料放入挤出滚圆机的滚圆装置中，经切割后被滚圆成球形颗粒；
    (4)将步骤(3)获得的球形颗粒放入炉中，脱脂除去赋形剂和粘结剂，然后在750～1550℃烧结，获得中空多孔球形颗粒人工骨。
  2. 根据权利要求1所述的中空多孔球形颗粒人工骨的制备方法，其特征在于，步骤(1)所述生物陶瓷粉末为羟基磷灰石粉末、磷酸钙粉末、硅酸盐粉末、碳酸钙粉末或硫酸钙粉末中的一种以上。
  3. 根据权利要求1所述的中空多孔球形颗粒人工骨的制备方法，其特征在于，步骤(1)所述生物玻璃粉末为磷酸盐玻璃粉末或硅酸盐玻璃粉末。
  4. 根据权利要求1所述的中空多孔球形颗粒人工骨的制备方法，其特征在于，步骤(1)所述的赋形剂为微晶纤维素、甲基纤维素、乳糖、单糖、环糊精、淀粉、海藻酸盐、壳聚糖、果胶酯酸、角叉菜胶、聚丙烯酸酯、聚乙二烯醇、羧甲基纤维素、黄原胶、聚乙烯吡咯烷酮的至少一种。
  5. 根据权利要求1所述的中空多孔球形颗粒人工骨的制备方法，其特征在于，步骤(4)所述脱脂为在300～750℃脱脂。
  6. 根据权利要求1所述的中空多孔球形颗粒人工骨的制备方法，其特征在于，步骤(2)所述挤出滚圆机的挤出装置的孔板孔径为0.3～3mm。
  7. 权利要求1～6任一项所述的中空多孔球形颗粒人工骨的制备方法得到的中空多孔球形颗粒人工骨，其特征在于，呈中空的球形壳体结构，大孔和微孔分布于球形壳体上。
  8. 根据权利要求7所述的中空多孔球形颗粒人工骨，其特征在于，所述球形颗粒的中心空腔大小为50～1200μm；球形壳体上大孔孔径为10～200μm，微 孔孔径为0.1～10μm。
  9. 权利要求7～8任一项所述的中空多孔球形颗粒人工骨的用于对骨缺损部位进行修复。
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