WO2021120353A1 - 复合多孔生物陶瓷的金属假体及其制备方法 - Google Patents

复合多孔生物陶瓷的金属假体及其制备方法 Download PDF

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Publication number
WO2021120353A1
WO2021120353A1 PCT/CN2020/071326 CN2020071326W WO2021120353A1 WO 2021120353 A1 WO2021120353 A1 WO 2021120353A1 CN 2020071326 W CN2020071326 W CN 2020071326W WO 2021120353 A1 WO2021120353 A1 WO 2021120353A1
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metal
metal frame
composite
ceramic
pore
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PCT/CN2020/071326
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English (en)
French (fr)
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卢建熙
卢霄
王臻
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上海贝奥路生物材料有限公司
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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
    • A61L27/50—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
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
    • A61L27/427—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of other specific inorganic materials not covered by A61L27/422 or A61L27/425
    • 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
    • A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction

Definitions

  • the invention relates to the field of biomedical materials, in particular to a composite porous bioceramic metal prosthesis and a preparation method thereof.
  • the surgical metal prosthesis has strong mechanical strength and good durability, it will loose and break when implanted in the human body for a long time, which will lead to the failure of the artificial prosthesis.
  • the key to the successful long-term implantation of artificial prostheses in the body is the combination of the prosthesis and the tissue interface and the biomechanical matching, so that it can achieve a stable biological fixation, and this is also a worldwide problem.
  • a large number of researches and technological inventions focused on the surface modification and modification of metal prostheses, that is, through physical and chemical modification of the metal prosthesis surface, ceramic coating, spraying beads, and creating porosity to find solutions, but the results are very effective. micro.
  • Porous bioceramics can induce and guide the regeneration of blood vessels and tissues, form a perfect combination with host tissues, and can be completely degraded and disappeared in the body. It has been widely accepted by clinicians as bone repair materials. There have been studies exploring the use of porous bioceramics for surgical implantation of prostheses. However, due to the serious shortcomings and shortcomings of the mechanical strength and brittleness of porous bioceramics, it cannot meet the long-term high-strength, high-frequency and multi-directional movement in the human body. Requirement, leading to failure of the exploration results.
  • the purpose of the present invention is to provide a metal prosthesis of composite porous bioceramics and a preparation method thereof, so that the composite of porous bioceramics and metal has both the robustness and durability of metal and the excellent tissue repair function of porous bioceramics.
  • the present invention provides a method for preparing a composite porous bioceramic metal prosthesis, including:
  • Step S1 using medical metal materials to prepare a metal frame
  • Step S2 filling the metal frame with a hole-forming agent to obtain a composite body of the hole-making frame and the metal frame;
  • Step S3 pouring the prefabricated ceramic slurry into the composite body of the hole-making structure and the metal frame to obtain a composite body of the ceramic green body and the metal frame;
  • Step S4 removing the pore former in the composite of the ceramic body and the metal frame, and sintering the composite of the ceramic body and the metal frame to obtain a composite of porous bioceramic and metal.
  • the metal frame is prepared by at least one of cutting processing, sand casting, 3D printing, welding and weaving; the material of the metal frame includes magnesium and its alloys, titanium At least one of and its alloys, tantalum and its alloys, zinc and its alloys, copper and its alloys, iron and its alloys, stainless steel, and cobalt-chromium-molybdenum alloy.
  • the metal frame is simulated and designed by finite element modeling and support mechanics calculation in advance to obtain the design parameters of the metal frame, and the design parameters include structure, density, and The shape, size and quantity of the reinforcement columns; according to the design parameters, suitable medical metal materials are selected to make the metal frame.
  • a mold is prefabricated, and the size and shape of the mold are the same as those of the metal frame and/or the porous bioceramic and
  • the metal composite body matches; in step S2, the metal frame is fixed in the prefabricated mold, and the pore former is filled in both the mold and the metal frame; in step S3 , Pour the prefabricated ceramic slurry into the mold, and remove the mold after the ceramic slurry is dried to obtain a composite body of the ceramic green body and the metal frame.
  • the mold is prepared by at least one of mold casting, cutting, 3D printing, welding, stacking, splicing, and weaving; the material of the mold includes plaster, plastic or metal materials.
  • the preparation step of the composite body of the pore-forming structure and the metal frame includes: firstly, filling the pore-forming agent in the metal frame; and then, in the metal frame An organic solvent is injected into the inside to dissolve the surface layer of the pore-forming agent; then, water is injected into the metal frame to terminate the dissolution, and the pore-forming agent is bonded, and after drying, the pore-forming frame and the metal frame are obtained Complex.
  • the pore former is filled into the metal frame by vibrations of different frequencies and different amplitudes.
  • the pore former includes regular particles or irregular particles or a mixture of regular particles and irregular particles; the pore former includes organic microspheres; the pore former includes polystyrene, polyethylene, and polystyrene. At least one of propylene, polyvinyl chloride, polyamide, polyurethane, and polymethyl methacrylate; the diameter of the pore former is 50 ⁇ m to 5000 ⁇ m; the organic solvent includes acetone, diacetone, bromochloromethane, methyl methacrylate At least one of isobutyl ketone and chloroform.
  • the prefabricated ceramic slurry in step S3 is obtained by mixing the ceramic raw material powder and the liquid medium through stirring and/or grinding; the mass ratio of the ceramic raw material powder to the liquid medium
  • the ceramic raw material powder includes pure calcium phosphate, doped calcium phosphate, pure calcium carbonate, doped calcium carbonate, pure alumina, doped alumina, pure zirconia, doped zirconia, At least one of titanium dioxide and aluminum-magnesium spinel;
  • the liquid medium includes at least one of pure water, ethanol, ethylene glycol, isopropanol, and ethyl acetate.
  • a micropore-forming agent and/or a biological activator and/or an antibacterial agent are added to the prefabricated ceramic slurry.
  • the composition of the micropore former is the same as or different from the composition of the pore former, the diameter of the micropore former is 0.1 ⁇ m-10 ⁇ m, and the micropore former accounts for the proportion of the ceramic slurry.
  • the mass percentage is 0.1%-40%;
  • the bioactivator includes at least one of magnesium, zinc, and strontium;
  • the antibacterial agent includes silver and/or copper;
  • the diameter of the bioactivator and the antibacterial agent are both 0.01 ⁇ m-100 ⁇ m, the mass percentages of the biological activator and the antibacterial agent in the ceramic slurry are both 0.1%-40%.
  • the metal frame in the composite of the hole-making structure and the metal frame is subjected to surface treatment and/or surface coating.
  • the surface treatment includes at least one of polishing, grinding, corrosion, electroplating, micro-nano engraving, and anti-oxidation treatment
  • the surface coating includes plasma spraying of hydroxyapatite and/or tricalcium phosphate.
  • the composite of the ceramic body and the metal frame is placed at a temperature of 100°C to 600°C for 6h-30h to vaporize and eliminate the pore former;
  • the sintering temperature is 800° C. to 1600° C., and the sintering time is 1 h to 10 h.
  • the present invention also provides a composite porous bioceramic metal prosthesis, which is prepared by the method for preparing the composite porous bioceramic metal prosthesis provided by the present invention.
  • the preparation method of the composite porous bioceramic metal prosthesis of the present invention is to prepare a metal frame by using medical metal materials; fill the metal frame with a pore former to obtain a composite body of the pore-forming framework and the metal frame;
  • the prefabricated ceramic slurry is poured into the composite body of the pore-forming structure and the metal frame to obtain a composite body of the ceramic body and the metal frame;
  • the pore former in the composite body of the ceramic body and the metal frame is removed, and After sintering the composite of the ceramic body and the metal frame, a composite of porous bioceramics and metal is obtained, so that the composite of porous bioceramics and metal prepared has both the robustness and durability of metal and the excellent properties of porous bioceramics.
  • the tissue repair function is conducive to the repair and reconstruction of large bone defects.
  • the method can tailor the shape, size, mechanical and biological properties of the porous bioceramic and metal composite for the patient, and has high feasibility, good reproducibility and strong practicability, and can achieve the goal of precise treatment.
  • the method can also control the microstructure and components of the composite of porous bioceramics and metal, and realize the tissue repair ability and degradation performance of the ceramic part.
  • the composite of porous bioceramic and metal prepared by the method has the effects of promoting tissue regeneration and/or antibacterial, which expands the scope of clinical application.
  • the metal prosthesis of the composite porous bioceramic of the present invention is prepared by the method for preparing the metal prosthesis of the composite porous bioceramic provided by the present invention, so that the composite of the porous bioceramic and metal has excellent mechanical properties of metal. It also has the excellent tissue repair ability of porous ceramics and can meet the requirements of surgical implant prostheses.
  • the composite body of porous bioceramics and metal not only meets the three-dimensional space of tissue regeneration, but also meets the mechanical requirements of repair parts.
  • the ceramic in the composite of the porous bioceramic and metal has a porous microstructure, such as micropores, macropores, pores, and the shape, size and distribution of internal connections, etc.
  • the pores are completely interconnected, making it more beneficial to blood vessels. And the growth of tissues to achieve permanent biological fixation of the prosthesis.
  • the composite of the porous bioceramic and metal can be used as the loading base of the artificial joint to make it more stable, longer-lasting, and more durable, so that the composite of the porous bioceramic and metal can be widely used in biomedicine. And the veterinary field.
  • Fig. 1 is a flow chart of a method for preparing a composite porous bioceramic metal prosthesis according to an embodiment of the present invention
  • FIG. 2 is a light microscope view of the surface morphology of a titanium alloy prosthesis of the upper femur composite with HA porous bioceramics according to an embodiment of the present invention
  • FIG. 3 is a scanning electron microscope view of the ceramic microstructure in the titanium alloy prosthesis of the upper femur composite with HA porous bioceramics according to an embodiment of the present invention
  • 4a to 4g are pictures of a titanium alloy prosthesis using composite HA porous bioceramics for treating osteosarcoma of the right tibia according to an embodiment of the present invention.
  • An embodiment of the present invention provides a method for preparing a metal prosthesis of composite porous bioceramics.
  • FIG. 1 is a flowchart of a method for preparing a composite porous bioceramic metal prosthesis according to an embodiment of the present invention.
  • the preparation method of the composite porous bioceramic metal prosthesis includes:
  • Step S1 Use medical metal materials to prepare a metal frame
  • Step S2 Fill the metal frame with a hole-forming agent to obtain a composite body of the hole-making frame and the metal frame;
  • Step S3 pour the prefabricated ceramic slurry into the composite body of the hole-making frame and the metal frame to obtain a composite body of the ceramic green body and the metal frame;
  • Step S4 removing the pore former in the composite of the ceramic body and the metal frame, and sintering the composite of the ceramic body and the metal frame to obtain a composite of porous bioceramic and metal.
  • a metal frame is prepared using medical metal materials.
  • the metal frame can be simulated and designed through finite element modeling and support mechanics calculation in advance to obtain the design parameters of the metal frame.
  • the design parameters include the structure and density of the metal frame, and the shape, size and number of reinforcement columns.
  • suitable medical metal materials can be selected to make the metal frame.
  • the metal frame may be prepared by at least one of cutting processing, sand casting, 3D printing, welding, and weaving.
  • the material of the metal frame may include at least one of magnesium and its alloys, titanium and its alloys, tantalum and its alloys, zinc and its alloys, copper and its alloys, iron and its alloys, stainless steel, and cobalt-chromium-molybdenum alloys, It should be noted that the material of the metal frame is not limited to the above-mentioned materials, and may also include other medical metal materials that meet the requirements of biocompatibility and corresponding mechanical strength.
  • the metal frame may be in the form and size of a prosthesis, or it may be in the form and size of a non-prosthesis.
  • the required shape and size of the prosthesis can be prepared by loading the metal frame into a mold.
  • a mold can be prefabricated, the size and shape of the mold are the same as the metal frame and/or the porous bioceramic and metal.
  • the composite body is matched with each other so that the metal frame can be loaded into the mold, and then in the subsequent steps, the pore former and the ceramic slurry are filled in a limited manner, so as to ensure that the porous bioceramic and metal formed in step S4
  • the shape and size of the complex can be effectively controlled.
  • the mold can be prepared by at least one of methods such as mold casting, cutting, 3D printing, welding, stacking, splicing, and weaving.
  • the material of the mold may include materials with good water absorption properties or non-absorbent materials, materials with good water absorption properties may include gypsum, and non-absorbent materials may include plastic or metal materials.
  • the material of the mold is a non-water-absorbing material, the mold is used for a ceramic slurry prepared with a volatile liquid (such as alcohol, etc.) for intermittent layered grouting.
  • a pore-forming agent is filled in the metal frame to obtain a composite body of the pore-forming frame and the metal frame.
  • the preparation steps of the composite of the pore-forming structure and the metal frame include: firstly, filling the metal frame with the pore-forming agent; alternatively, the metal frame can also be loaded into a prefabricated mold first, And fix it, and then fill the pore-forming agent in both the mold and the metal frame; the pore-forming agent can be filled into the metal frame and the mold through vibrations of different frequencies and different amplitudes ; Then, inject an organic solvent into the metal frame and the mold to dissolve the surface layer of the pore-forming agent; then, inject water into the metal frame and the mold to terminate the dissolution, and make the The porogen is bonded and further dried to obtain a composite body of the pore-forming structure and the metal frame.
  • the pore former may include regular particles or irregular particles or a mixture of regular particles and irregular particles.
  • the pore former may include organic microspheres; the pore former may include at least one of polystyrene, polyethylene, polypropylene, polyvinyl chloride, polyamide, polyurethane, and polymethyl methacrylate.
  • the material of the pore former is not limited to the above-mentioned materials, but can also include other materials that can be dissolved by organic solvents, do not leave any harmful substances after high-temperature sintering, and do not chemically react with the matrix material.
  • the diameter of the pore former may be 50 ⁇ m to 5000 ⁇ m (for example, 100 ⁇ m, 1000 ⁇ m, 4000 ⁇ m, etc.). It should be noted that the diameter of the pore former is not limited to the above range. The diameter of the pore former can be determined according to the vascularization and tissue regeneration requirements of the repair site. The diameter of the pore former can be directly positive. Affect the porosity of porous ceramics.
  • the organic solvent may include at least one of acetone, diacetone, bromochloromethane, methyl isobutyl ketone, and chloroform. It should be noted that the type of the organic solvent is not limited to the above range, and the dissolution rate of the organic solvent to the surface layer of the pore former can be controlled according to the different types of the selected organic solvent.
  • the volume concentration of the organic solvent may be 1% to 100%.
  • the dissolution time for the surface layer of the pore former can be defined according to the size of the connection between the pore formers, for example, the dissolution time can be 1 min to 30 min.
  • the entire mold and its internal structure can be baked in an environment of 40°C ⁇ 60°C for 20h ⁇ 30h, so as to dissolve the surface layer and bond between the pore formers. It is further bonded and solidified to form a composite of the hole-making structure and the metal frame.
  • the surface layer of the pore former can also be melted by a heating method to achieve mutual bonding between the pore formers.
  • the metal frame in the composite of the pore-forming structure and the metal frame may be subjected to surface treatment and/or surface coating, so as to enhance the interface between the metal and the ceramic. Combining power to achieve a more ideal clinical effect.
  • the surface treatment includes at least one of polishing, grinding, corrosion, electroplating, micro-nano engraving, and anti-oxidation treatment, and the surface coating includes plasma spraying of hydroxyapatite and/or tricalcium phosphate and the like.
  • step S3 the prefabricated ceramic slurry is poured into the composite body of the pore-forming frame and the metal frame to obtain a composite body of the ceramic green body and the metal frame.
  • the mold is removed after the drying treatment, and the structure after the mold is removed is continued to be baked in an environment of 40°C to 60°C for 20 hours ⁇ 30h to obtain the composite of the ceramic body and the metal frame.
  • the prefabricated ceramic slurry can be obtained by mixing the ceramic raw material powder and the liquid medium by stirring or grinding, or by successively stirring and grinding and mixing.
  • the mass ratio of the ceramic raw material powder to the liquid medium can be 10% to 90% (for example, 20%, 50%, 80%, etc.), and the prefabricated ceramic slurry needs to have good fluidity in order to The ceramic slurry can penetrate into the gap of the composite body of the pore-forming frame and the metal frame.
  • the ceramic raw material powder may include pure calcium phosphate (hydroxyapatite, tricalcium phosphate), doped calcium phosphate, pure calcium carbonate, doped calcium carbonate, pure alumina, doped alumina, pure zirconia, doped At least one of heterozirconia, titanium dioxide, and aluminum-magnesium spinel; the liquid medium may include at least one of pure water, ethanol, ethylene glycol, isopropanol, and ethyl acetate. It should be noted that the types of the ceramic raw material powder and the liquid medium are not limited to the above range, and the ceramic raw material powder may be any ceramic powder that can meet biological compatibility. Choose a suitable kind of the liquid medium.
  • the prefabricated ceramic slurry may be added with a pore-forming agent and/or a biological activator and/or an antibacterial agent.
  • the micropore former added to the ceramic slurry can form a corresponding amount of micropores after sintering, so as to facilitate the degradation of the material; the composition of the micropore former and the composition of the pore former can be the same or different, As long as the micropore former can be removed after sintering, for example, the micropore former can be organic materials or carbon, etc.; the micropore former can also include regular particles or irregular particles or regular particles and A mixture of irregular particles; the diameter of the microporogen may be 0.1 ⁇ m to 10 ⁇ m (for example, 1 ⁇ m, 5 ⁇ m, 9 ⁇ m, etc.), and the mass percentage of the microporogen in the ceramic slurry is 0.1% to 40 % (For example, 1%, 10%, 30%, etc.).
  • the biological activator added to the ceramic slurry can increase the biological activity of the material, which is conducive to vascularization and tissue regeneration; the biological activator may include at least one of magnesium, zinc and strontium particles.
  • the antibacterial agent added in the ceramic slurry makes the material have an antibacterial effect; the antibacterial agent may include silver and/or copper.
  • the diameter of the bioactivator and the antibacterial agent may both be 0.01 ⁇ m-100 ⁇ m (for example, 1 ⁇ m, 10 ⁇ m, 50 ⁇ m, 90 ⁇ m, etc.), and the mass percentage of the bioactivator and the antibacterial agent in the ceramic slurry may both be 0.1 %-40% (for example, 1%, 10%, 30%, etc.). It should be noted that the material types and ratios of the micropore former, bioactivator and antibacterial agent are not limited to the above range.
  • step S4 the pore former in the composite of the ceramic body and the metal frame is removed, and the composite of the ceramic body and the metal frame is sintered to obtain a composite of porous bioceramic and metal.
  • the composite body of the ceramic body and the metal frame may be placed at a temperature of 100°C to 600°C (for example, 200°C, 500°C, etc.) for 6h to 30h (for example, 10h, 20h, etc.) to vaporize and combine Eliminate the pore-forming agent, so that the ceramic has a porous structure;
  • the sintering temperature can be 800°C to 1600°C (for example, 900°C, 1500°C, etc.), and the sintering time can be 1h to 10h (for example, 2h) , 9h, etc.).
  • the above-mentioned temperature and time are not limited to the above-mentioned range, and can be adjusted as needed.
  • the ceramics in the composite of porous bioceramics and metals can be degradable (such as tricalcium phosphate), partially degradable (such as dual-phase ceramics) and non-degradable (such as hydroxyapatite), which are determined according to clinical use.
  • degradable such as tricalcium phosphate
  • partially degradable such as dual-phase ceramics
  • non-degradable such as hydroxyapatite
  • the ceramic raw material powder is pure HA
  • the metal frame is a superimposed mesh structure, and the mesh size is 1mm-6mm
  • the porous microstructure of the product requires a porosity of 70% ⁇ 5%, a pore diameter of 500 ⁇ m ⁇ 50 ⁇ m, and a connection diameter of 120 ⁇ m ⁇ 20 ⁇ m.
  • Step S1 Establish a finite element defect model based on the patient's CT image data, and design the metal frame of the corresponding prosthesis using the topological calculation method, prepare the titanium alloy frame of the prosthesis by 3D printing, and clean and dry the titanium alloy frame ;
  • Step S2 using 3D printing technology to prepare a plaster mold with an inner cavity matching the titanium alloy frame according to the above design parameters, and fix the titanium alloy frame in the plaster mold; fill the plaster mold with a particle size of 500 ⁇ m to 600 ⁇ m by vibration It is known by weighing that 20.1g of organic microspheres are filled in to achieve the filling goal; inject acetone with a volume concentration of 85% into the plaster mold to dissolve the surface layer of the organic microspheres. The dissolution time is 7 minutes. Pure water is injected into the mold to stop the dissolution, so that the organic microspheres that dissolve the surface layer are bonded to each other; the plaster mold is placed in an environment of 50°C for 24 hours;
  • Step S3 prepare the ceramic slurry with the pure HA powder and pure water in a mass ratio of 65:35; pour the ceramic slurry into the gypsum mold, and after the ceramic slurry is completely absorbed, remove the gypsum mold and remove it.
  • the structure after the plaster mold is continuously baked in an environment of 50°C for 24 hours to obtain a composite of ceramic green body and metal frame;
  • step S4 the composite of the ceramic body and the metal frame is placed at a temperature of 300° C. for 12 hours to vaporize and remove the organic microspheres, so that the HA ceramic has a porous structure.
  • the structure after removing the organic microspheres was continued to be sintered at a temperature of 1250°C for 4 hours to form a titanium alloy prosthesis of composite HA porous bioceramics.
  • ⁇ -TCP composite ⁇ -tricalcium phosphate
  • the ceramic raw material powder is pure ⁇ -TCP
  • the metal frame is a superimposed mesh structure with a mesh size of 1mm ⁇ 3mm
  • the porous microstructure of the obtained titanium alloy lumbar fusion cage requires a porosity of 60% ⁇ 5%, a pore diameter of 250 ⁇ m ⁇ 50 ⁇ m, and a connecting diameter of 100 ⁇ m ⁇ 20 ⁇ m in the hole.
  • Step S1 Design the metal frame of the corresponding lumbar fusion cage through finite element model building, and prepare the titanium alloy frame of the lumbar fusion cage by 3D printing, and wash and dry the titanium alloy frame;
  • Step S2 use 3D printing technology to prepare a plastic mold with an inner cavity matching the titanium alloy frame; fix the titanium alloy frame in the plastic mold; vibrate and fill the plastic mold with a particle size of 200 ⁇ m ⁇ 300 ⁇ m
  • the whole plastic mold is filled with organic microspheres by weighing; Inject 90% acetone into the plastic mold to dissolve the surface layer of the organic microspheres, and the dissolution time is 5min. Inject pure water into the plastic mold. To stop the dissolution, so that the dissolved organic microspheres adhere to each other; place the plastic mold in an environment of 50°C for 24 hours;
  • Step S3 Prepare ceramic slurry with pure ⁇ -TCP powder and absolute alcohol at a mass ratio of 65:35; pour the ceramic slurry into the plastic mold at a rate of 0.1 mL/min, and remove the ceramic slurry after it is dried and formed Plastic mold, and put the structure after removing the plastic mold in an environment of 50°C and bake for 24h to obtain a composite of ceramic green body and metal frame;
  • Step S4 the composite of the ceramic body and the metal frame is placed at a temperature of 300°C for 12 hours to vaporize and remove the organic microspheres, so that the ⁇ -TCP ceramic has a porous structure; continue the structure after removing the organic microspheres Sintered at a temperature of 1180°C for 4 hours to form a titanium alloy lumbar fusion cage of composite ⁇ -TCP porous bioceramics.
  • the prepared composite of porous bioceramic and metal not only has excellent mechanical properties of metal, but also has excellent tissue repair ability of porous ceramic, and can meet the requirements of surgical spinal fusion.
  • the metal frame structure prepared by using the methods and materials in the above steps, and then adding interoperable porous bioceramics in it, so that the prepared fusion cage not only meets the three-dimensional space of tissue regeneration, but also meets the mechanical requirements of the fusion site;
  • the microstructure of the above porous ceramics is precisely and controllably manufactured by using degradable and/or non-degradable ceramic materials, which have morphologies such as micropores, macropores, pores and internal connections.
  • the pores are completely interconnected, which is more conducive to the growth of blood vessels and tissues, and can achieve permanent biological fixation of the prosthesis. Therefore, the composite of the porous bioceramic and metal can be widely used in the fields of biomedicine and veterinary medicine.
  • Example 1 Taking the method of the above-mentioned Example 1 to prepare a 17 cm long titanium alloy prosthesis of the upper and middle section of the right tibia composited with HA porous bioceramics as an example, the prosthesis was used to treat a 17-year-old man with osteosarcoma of the proximal right tibia. Before the operation, the X-ray film shown in Figure 4a and the CT shown in Figure 4b showed that the tumor had penetrated the cortical bone.
  • the MRI (magnetic resonance imaging) shown in Figure 4c clarified the scope of the tumor; 3 days after the operation, the figure 4d showed that they were able to move on the ground; continued follow-up for 3, 9 and 12 months, the corresponding X-ray film showed that the prosthesis position was intact (as shown in Figure 4e-4g), and there was no loosening, infection, prosthesis rupture and other complications.
  • the patient's MSTS score showed a satisfactory clinical effect with a limb function score of 80%.
  • the preparation method of the composite porous bioceramic metal prosthesis of the present invention includes: step S1, using medical metal materials to prepare a metal frame; step S2, filling the metal frame with a pore former to obtain The composite body of the hole frame and the metal frame; step S3, pour the prefabricated ceramic slurry into the composite body of the hole-making frame and the metal frame to obtain a composite body of the ceramic body and the metal frame; step S4, remove the The pore-forming agent in the composite body of the ceramic body and the metal frame is sintered to obtain the composite body of porous bioceramics and metal after sintering the composite body of the ceramic body and the metal frame.
  • the composite of porous bioceramic and metal prepared by the preparation method of the composite porous bioceramic metal prosthesis of the present invention not only has the robustness and durability of metal, but also has the excellent tissue repair function of porous bioceramics, which is beneficial to large bones. Repair and reconstruction of defects.
  • the technical scheme of the present invention can tailor the shape, size, mechanical and biological properties of the porous bioceramic and metal composite body for patients, has high feasibility, good repeatability and strong practicability, and can achieve the goal of precise treatment.
  • the technical scheme of the present invention can regulate the microstructure and components of the composite of porous bioceramics and metal, and realize the tissue repair ability and degradation performance of the ceramic part.
  • the porous bioceramic and metal composite prepared by the technical scheme of the present invention has the effect of promoting tissue regeneration and/or antibacterial, which expands the scope of clinical application.
  • An embodiment of the present invention provides a composite porous bioceramic metal prosthesis, which is prepared by the method for preparing the composite porous bioceramic metal prosthesis provided by the present invention.
  • the method for preparing the metal prosthesis of the composite porous bioceramic provided by the present invention is used to prepare the metal prosthesis of the composite porous bioceramic, that is, the composite of the porous bioceramic and the metal is prepared, so that the porous bioceramic and the metal
  • the composite body not only has excellent mechanical properties of metal, but also has good tissue repair ability of porous ceramics, which can meet the requirements of surgical implants.
  • the composite body of porous bioceramics and metal not only meets the three-dimensional space of tissue regeneration, but also meets the mechanical requirements of repair parts.
  • the ceramic in the composite of the porous bioceramic and metal has a porous microstructure, such as micropores, macropores, pores, and the shape, size and distribution of internal connections, etc.
  • the pores are completely interconnected, making it more beneficial to blood vessels. And the growth of tissues to achieve permanent biological fixation of the prosthesis.
  • the composite of porous bioceramics and metal can be used as a loading base of an artificial joint, making the loading base more stable, durable, and durable. The above effects enable the composite of porous bioceramic and metal to be widely used in the fields of biomedicine and veterinary medicine.

Abstract

一种复合多孔生物陶瓷(12)的金属假体及其制备方法，通过采用医用金属材料制备金属框架(11)；在金属框架(11)内填充造孔剂，以获得造孔构架与金属框架(11)的复合体；将预制的陶瓷浆液灌入造孔构架与金属框架(11)的复合体中，以获得陶瓷坯体与金属框架(11)的复合体；去除陶瓷坯体与金属框架(11)的复合体中的造孔剂，并经烧结之后获得多孔生物陶瓷(12)和金属的复合体。所述金属假体同时具备金属的坚固性和耐用性和多孔生物陶瓷(12)优良的组织修复功能，能够达到外科植入假体的要求，且能够为患者量身定制多孔生物陶瓷(12)和金属的复合体的形态、尺寸、机械和生物性能，可行性高、重复性好以及实用性强，能够广泛应用于生物医学和兽医领域。

Description

复合多孔生物陶瓷的金属假体及其制备方法 技术领域
本发明涉及生物医用材料领域，特别涉及一种复合多孔生物陶瓷的金属假体及其制备方法。
背景技术
外科金属假体虽有坚固的力学强度和很好的耐用性，但长期植入人体会出现松动和断裂，进而导致人工假体失败。人工假体是否能够成功长期植入体内的关键是假体与组织界面的结合和生物力学匹配，以使其达到稳固的生物学固定，并且，这也是世界性难题。为此，大量研究和技术发明就聚焦于金属假体表面的改变和修饰，即通过金属假体表面的理化改性、陶瓷涂层、喷结球珠、造成多孔来寻找解决方案，但是收效甚微。近年来由于蓬勃发展的3D打印技术，使得金属假体的可加工性进一步提高，并引发研究目光转向金属假体的框架化和多孔化制造，可是，仍未从本质上解决材料内由血管化和组织化而形成的生物学固定瓶颈。
多孔生物陶瓷有很好的诱导和引导血管和组织再生作用，与宿主组织形成完美的结合，并在体内可被完全降解消失，作为骨修复材料已被临床医生广泛接受。曾有研究探索使用多孔生物陶瓷外科植入假体，但是，由于多孔生物陶瓷的力学强度和脆性存在着严重不足和缺陷，其无法满足人体内长时间的高强度、高频率和多方向的运动需要，导致该探索结果均以失败告终。
根据上述结果来看，金属假体材料和多孔生物陶瓷材料的结合是有可能达到外科植入假体的要求，但是两种材料之间的理化性能和制造工艺完全不同使得二者的一体化制造很难实现。因此，如何制备金属假体材料和多孔生物陶瓷材料的复合体，以使其符合外科植入假体的要求成为本领域亟需解决的问题。
发明内容
本发明的目的在于提供一种复合多孔生物陶瓷的金属假体及其制备方 法，使得多孔生物陶瓷和金属的复合体同时具备金属的坚固性和耐用性和多孔生物陶瓷优良的组织修复功能，能够达到外科植入假体的要求，且能够为患者量身定制多孔生物陶瓷和金属的复合体的形态、尺寸、机械和生物性能，可行性高、重复性好以及实用性强，能够广泛应用于生物医学和兽医领域。
为实现上述目的，本发明提供了一种复合多孔生物陶瓷的金属假体的制备方法，包括：
步骤S1，采用医用金属材料制备金属框架；
步骤S2，在所述金属框架内填充造孔剂，以获得造孔构架与金属框架的复合体；
步骤S3，将预制的陶瓷浆液灌入所述造孔构架与金属框架的复合体中，以获得陶瓷坯体与金属框架的复合体；
步骤S4，去除所述陶瓷坯体与金属框架的复合体中的造孔剂，并烧结所述陶瓷坯体与金属框架的复合体后获得多孔生物陶瓷和金属的复合体。
可选的，在所述步骤S1中，通过切削加工、翻砂铸模、3D打印、焊接和编织的方法中的至少一种制备所述金属框架；所述金属框架的材质包括镁及其合金、钛及其合金、钽及其合金、锌及其合金、铜及其合金、铁及其合金、不锈钢和钴铬钼合金中的至少一种。
可选的，在所述步骤S1中，预先通过有限元建模和托布力学计算对所述金属框架进行模拟设计，以获得所述金属框架的设计参数，所述设计参数包括结构、密度以及增强柱的形态、尺寸和数量；根据所述设计参数，选用合适的医用金属材料来制作所述金属框架。
可选的，在所述步骤S1之前或在所述步骤S1之后且在所述步骤S2之前，预制一模具，所述模具的尺寸和形态与所述金属框架和/或所述多孔生物陶瓷和金属的复合体相匹配；在步骤S2中，将所述金属框架固定在预制的所述模具内，并在所述模具和所述金属框架内均填满所述造孔剂；在步骤S3中，将预制的陶瓷浆液灌入所述模具内，待所述陶瓷浆液干燥后脱去所述模具，以获得所述陶瓷坯体与金属框架的复合体。
可选的，通过模具铸形、切削加工、3D打印、焊接、堆积、拼接和编织 的方法中的至少一种制备所述模具；所述模具的材质包括石膏、塑料或金属材料。
可选的，在所述步骤S2中，所述造孔构架与金属框架的复合体的制备步骤包括：首先，在所述金属框架内填满所述造孔剂；然后，在所述金属框架内注入有机溶剂，以溶解所述造孔剂的表层；接着，在所述金属框架内注入水以终止溶解，并使所述造孔剂粘结，烘干后获得造孔构架与金属框架的复合体。
可选的，在所述步骤S2中，通过不同频率和不同振幅的震动将所述造孔剂填入所述金属框架内。
可选的，所述造孔剂包括规则颗粒或非规则颗粒或规则颗粒与非规则颗粒的混合物；所述造孔剂包括有机微球；所述造孔剂包括聚苯乙烯、聚乙烯、聚丙烯、聚氯乙烯、聚酰胺、聚氨酯和聚甲基丙烯酸甲酯中的至少一种；所述造孔剂的直径为50μm～5000μm；所述有机溶剂包括丙酮、双丙酮、溴氯甲烷、甲基异丁基甲酮和氯仿中的至少一种。
可选的，通过将陶瓷原料粉体和液体介质经搅拌和/或研磨混合，来获得所述步骤S3中的预制的所述陶瓷浆液；所述陶瓷原料粉体与所述液体介质的质量比为10％～90％；所述陶瓷原料粉体包括纯磷酸钙、掺杂磷酸钙、纯碳酸钙、掺杂碳酸钙、纯氧化铝、掺杂氧化铝、纯氧化锆、掺杂氧化锆、二氧化钛和铝镁尖晶石中的至少一种；所述液体介质包括纯水、乙醇、乙二醇、异丙醇和乙酸乙酯中的至少一种。
可选的，在所述步骤S3中，预制的所述陶瓷浆液中添加有造微孔剂和/或生物活化剂和/或抗菌剂。
可选的，所述造微孔剂的成分和所述造孔剂的成分相同或不同，所述造微孔剂的直径为0.1μm～10μm，所述造微孔剂占所述陶瓷浆液的质量百分比为0.1％～40％；所述生物活化剂包括镁、锌和锶中的至少一种；所述抗菌剂包括银和/或铜；所述生物活化剂和抗菌剂的直径均为0.01μm～100μm，所述生物活化剂和抗菌剂占所述陶瓷浆液的质量百分比均为0.1％～40％。
可选的，在所述步骤S2之后且在所述步骤S3之前，对所述造孔构架与 金属框架的复合体中的金属框架进行表面处理和/或表面涂层。
可选的，所述表面处理包括抛光、打磨、腐蚀、电镀、微纳雕刻和抗氧化处理中的至少一种，所述表面涂层包括羟基磷灰石和/或磷酸三钙的等离子喷涂。
可选的，在所述步骤S4中，通过将所述陶瓷坯体与金属框架的复合体置于100℃～600℃的温度下6h～30h，以气化并消除所述造孔剂；在所述步骤S4中，所述烧结的温度为800℃～1600℃，所述烧结的时间为1h～10h。
本发明还提供了一种复合多孔生物陶瓷的金属假体，采用本发明提供的所述复合多孔生物陶瓷的金属假体的制备方法制备。
与现有技术相比，本发明的技术方案具有以下有益效果：
1、本发明的复合多孔生物陶瓷的金属假体的制备方法，通过采用医用金属材料制备金属框架；在所述金属框架内填充造孔剂，以获得造孔构架与金属框架的复合体；将预制的陶瓷浆液灌入所述造孔构架与金属框架的复合体中，以获得陶瓷坯体与金属框架的复合体；去除所述陶瓷坯体与金属框架的复合体中的造孔剂，并烧结所述陶瓷坯体与金属框架的复合体后获得多孔生物陶瓷和金属的复合体，使得制备的多孔生物陶瓷和金属的复合体既具备金属的坚固性和耐用性又具备多孔生物陶瓷优良的组织修复功能，有利于大段骨缺损的修复和重建。该方法能够为患者量身定制多孔生物陶瓷和金属的复合体的形态、尺寸、机械和生物性能，可行性高、重复性好以及实用性强，能够达到精准治疗的目标。该方法还能够调控多孔生物陶瓷和金属的复合体的微结构和组分，实现陶瓷部分的组织修复能力和降解性能。同时，该方法制备的多孔生物陶瓷和金属的复合体具有促进组织再生和/或抗菌作用，拓展了临床应用范围。
2、本发明的复合多孔生物陶瓷的金属假体，由于采用本发明提供的所述复合多孔生物陶瓷的金属假体的制备方法制备，使得多孔生物陶瓷和金属的复合体既具有金属优良的力学性能，又具有多孔陶瓷很好的组织修复能力，能够达到外科植入假体的要求。所述多孔生物陶瓷和金属的复合体既有符合组织再生的三维立体空间，又能达到修复部位的力学要求。同时，所述多孔 生物陶瓷和金属的复合体中的陶瓷具有多孔的微结构，如微孔、宏孔、孔隙以及内连接的形态、尺寸和分布等，其孔隙完全互通，使得更有利于血管和组织的长入，达到假体的永久性生物学固定。并且，所述多孔生物陶瓷和金属的复合体能够作为人工关节的装载基座，使其更稳定、更持久、更耐用，进而使得所述多孔生物陶瓷和金属的复合体能够广泛应用于生物医学和兽医领域。
附图说明
图1是本发明一实施例的复合多孔生物陶瓷的金属假体的制备方法的流程图；
图2是本发明一实施例的股骨上段复合HA多孔生物陶瓷的钛合金假体的表面形貌的光镜图；
图3是本发明一实施例的股骨上段复合HA多孔生物陶瓷的钛合金假体中的陶瓷微结构的扫描电子显微镜图；
图4a～4g是本发明一实施例的采用复合HA多孔生物陶瓷的钛合金假体治疗右胫骨近端骨肉瘤的图片。
具体实施方式
为使本发明的目的、优点和特征更加清楚，以下结合附图1～4g对本发明提出的复合多孔生物陶瓷的金属假体及其制备方法作进一步详细说明。需说明的是，附图均采用非常简化的形式且均使用非精准的比例，仅用以方便、明晰地辅助说明本发明实施例的目的。
本发明一实施例提供一种复合多孔生物陶瓷的金属假体的制备方法。参阅图1，图1是本发明一实施例的复合多孔生物陶瓷的金属假体的制备方法的流程图。所述复合多孔生物陶瓷的金属假体的制备方法包括：
步骤S1：采用医用金属材料制备金属框架；
步骤S2：在所述金属框架内填充造孔剂，以获得造孔构架与金属框架的复合体；
步骤S3：将预制的陶瓷浆液灌入所述造孔构架与金属框架的复合体中，以获得陶瓷坯体与金属框架的复合体；
步骤S4：去除所述陶瓷坯体与金属框架的复合体中的造孔剂，并烧结所述陶瓷坯体与金属框架的复合体后获得多孔生物陶瓷和金属的复合体。
下面更为详细的介绍本实施例提供的复合多孔生物陶瓷的金属假体的制备方法：
按照步骤S1，采用医用金属材料制备金属框架。可以根据待修复部位的力学要求，预先通过有限元建模和托布力学计算对所述金属框架进行模拟设计，以获得所述金属框架的设计参数。所述设计参数包括所述金属框架的结构、密度以及增强柱的形态、尺寸和数量等。根据所述金属框架的设计参数，可以选用合适的医用金属材料来制作所述金属框架。例如，根据所述金属框架的设计参数，可以通过切削加工、翻砂铸模、3D打印、焊接和编织等方法中的至少一种制备所述金属框架。
所述金属框架的材质可以包括镁及其合金、钛及其合金、钽及其合金、锌及其合金、铜及其合金、铁及其合金、不锈钢和钴铬钼合金中的至少一种，需要说明的是，所述金属框架的材质不仅限于上述的材料，还可包括其它符合生物相容性和相应的力学强度要求的医用金属材料。
所述金属框架可以是假体的形态和尺寸，也可以是非假体的形态和尺寸。当所述金属框架为非假体的形态和尺寸时，可以通过将所述金属框架载入模具的方法制备所需的假体的形态和尺寸。
另外，可以在所述步骤S1之前或在所述步骤S1之后且在所述步骤S2之前，预制一模具，所述模具的尺寸和形态与所述金属框架和/或所述多孔生物陶瓷和金属的复合体相匹配，以使得能够将所述金属框架载入所述模具内，进而在后续步骤中限定性填充造孔剂和灌注陶瓷浆液，从而确保在步骤S4中形成的多孔生物陶瓷和金属的复合体的形态和尺寸能够被有效控制。可以通过模具铸形、切削加工、3D打印、焊接、堆积、拼接和编织等方法中的至少一种制备所述模具。所述模具的材质可以包括吸水性能好的材料或者非吸水性的材料，吸水性能好的材料可以包括石膏，非吸水性的材料可以包括塑料 或金属材料。其中，当所述模具的材质为非吸水性的材料时，所述模具用于可挥发性液体(如酒精等)所配置的陶瓷浆液，以进行间歇性分层灌浆的方法。
按照步骤S2，在所述金属框架内填充造孔剂，以获得造孔构架与金属框架的复合体。所述造孔构架与金属框架的复合体的制备步骤包括：首先，在所述金属框架内填满所述造孔剂；或者，也可以先将所述金属框架载入一预制的模具内，并加以固定，再在所述模具和所述金属框架内均填满所述造孔剂；可以通过不同频率和不同振幅的震动将所述造孔剂填入所述金属框架和所述模具中；然后，在所述金属框架和所述模具内注入有机溶剂，以溶解所述造孔剂的表层；接着，在所述金属框架和所述模具内注入水以终止溶解，并使所述造孔剂粘结，并进一步烘干，以获得造孔构架与金属框架的复合体。
其中，所述造孔剂可以包括规则颗粒或非规则颗粒或规则颗粒与非规则颗粒的混合物。所述造孔剂可以包括有机微球；所述造孔剂可以包括聚苯乙烯、聚乙烯、聚丙烯、聚氯乙烯、聚酰胺、聚氨酯和聚甲基丙烯酸甲酯中的至少一种。需要说明的是，所述造孔剂的材质不仅限于上述的材料，还可包括其它能够被有机溶剂溶解、高温烧结后不残留任何有害物质且不与基体材料发生化学反应的材料。
所述造孔剂的直径可以为50μm～5000μm(例如为100μm、1000μm、4000μm等)。需要说明的是，所述造孔剂的直径不仅限于上述的范围，所述造孔剂的直径可以根据修复部位的血管化和组织再生要求而定，所述造孔剂的直径能直接正向影响多孔陶瓷的孔隙率。
所述有机溶剂可以包括丙酮、双丙酮、溴氯甲烷、甲基异丁基甲酮和氯仿中的至少一种。需要说明的是，所述有机溶剂的种类不仅限于上述的范围，根据选用的所述有机溶剂的不同种类，可以控制所述有机溶剂对所述造孔剂的表层的溶解速度。所述有机溶剂的体积浓度可以为1％～100％。
可以根据所述造孔剂之间的连接尺寸定义对所述造孔剂表层的溶解时间，例如溶解的时间可以为1min～30min。在终止溶解之后，可以将整个所述模具及其内部的结构置于40℃～60℃的环境中烘烤20h～30h，以使得溶解了表 层的且相互粘结的所述造孔剂之间进一步粘结固化，形成造孔构架与金属框架的复合体。
另外，也可通过加温方法熔融所述造孔剂的表层，实现所述造孔剂之间相互粘结。
另外，在所述步骤S2之后且在所述步骤S3之前，可以对所述造孔构架与金属框架的复合体中的金属框架进行表面处理和/或表面涂层，以便增强金属与陶瓷界面的结合力，达到更理想的临床疗效。所述表面处理包括抛光、打磨、腐蚀、电镀、微纳雕刻和抗氧化处理等中的至少一种，所述表面涂层包括羟基磷灰石和/或磷酸三钙的等离子喷涂等。
按照步骤S3，将预制好的陶瓷浆液灌入所述造孔构架与金属框架的复合体中，以获得陶瓷坯体与金属框架的复合体。在将预制好的所述陶瓷浆液灌入所述模具内之后，进行干燥处理后脱去所述模具，并将脱去所述模具后的结构继续在40℃～60℃的环境中烘烤20h～30h，以获得所述陶瓷坯体与金属框架的复合体。
其中，可以通过将陶瓷原料粉体和液体介质经搅拌或研磨混合，或者依次经过搅拌和研磨混合，来获得预制的所述陶瓷浆液。所述陶瓷原料粉体与所述液体介质的质量比可以为10％～90％(例如为20％、50％、80％等)，预制的所述陶瓷浆液需具有很好的流动性，以便所述陶瓷浆液能够渗入到所述造孔构架与金属框架的复合体的间隙中。所述陶瓷原料粉体可以包括纯磷酸钙(羟基磷灰石、磷酸三钙)、掺杂磷酸钙、纯碳酸钙、掺杂碳酸钙、纯氧化铝、掺杂氧化铝、纯氧化锆、掺杂氧化锆、二氧化钛和铝镁尖晶石中的至少一种；所述液体介质可以包括纯水、乙醇、乙二醇、异丙醇和乙酸乙酯中的至少一种。需要说明的是，所述陶瓷原料粉体和所述液体介质的种类不仅限于上述的范围，所述陶瓷原料粉体可以是任何能满足生物相溶性的陶瓷粉体，根据所述陶瓷原料粉体的种类选择合适种类的所述液体介质。
另外，预制的所述陶瓷浆液中可以添加有造微孔剂和/或生物活化剂和/或抗菌剂。所述陶瓷浆液中添加的造微孔剂可以在烧结后形成相应量的微孔，使得有利于材料的降解；所述造微孔剂的成分和所述造孔剂的成分可以相同 或不同，只要所述造微孔剂在烧结后能够被去除即可，例如所述造微孔剂可以为有机材料或碳等；所述造微孔剂也可以包括规则颗粒或非规则颗粒或规则颗粒与非规则颗粒的混合物；所述造微孔剂的直径可以为0.1μm～10μm(例如为1μm、5μm、9μm等)，所述造微孔剂占所述陶瓷浆液的质量百分比为0.1％～40％(例如为1％、10％、30％等)。所述陶瓷浆液中添加的生物活化剂能够增加材料的生物活性，有利于血管化和组织再生；所述生物活化剂可以包括镁、锌和锶微粒中的至少一种。所述陶瓷浆液中添加的抗菌剂使得材料具有抗菌作用；所述抗菌剂可以包括银和/或铜。所述生物活化剂和抗菌剂的直径可以均为0.01μm～100μm(例如为1μm、10μm、50μm、90μm等)，所述生物活化剂和抗菌剂占所述陶瓷浆液的质量百分比可以均为0.1％～40％(例如为1％、10％、30％等)。需要说明的是，所述造微孔剂、生物活化剂和抗菌剂的材料种类和配比不仅限于上述的范围。
按照步骤S4，去除所述陶瓷坯体与金属框架的复合体中的造孔剂，并经烧结所述陶瓷坯体与金属框架的复合体后获得多孔生物陶瓷和金属的复合体。可以通过将所述陶瓷坯体与金属框架的复合体置于100℃～600℃(例如为200℃、500℃等)的温度下6h～30h(例如为10h、20h等)，以气化并消除所述造孔剂，使得陶瓷具有多孔结构；所述烧结的温度可以为800℃～1600℃(例如为900℃、1500℃等)，所述烧结的时间可以为1h～10h(例如为2h、9h等)。需要说明的是，上述的温度和时间不仅限于上述的范围，可以根据需要进行调整。
所述多孔生物陶瓷和金属的复合体中的陶瓷可以是可降解(如磷酸三钙)、部分降解(如双相陶瓷)和非降解(如羟基磷灰石)的，根据临床用途来确定。
下面根据上述步骤S1～步骤S4，举例说明所述复合多孔生物陶瓷的金属假体的制备方法。
实施例一
制备17cm的股骨上段复合羟基磷灰石(HA)多孔生物陶瓷的钛合金假体：所述陶瓷原料粉体为纯HA；所述金属框架为叠加式网状结构，其网眼尺 寸为1mm～6mm；产品的多孔微结构要求为孔隙率70％±5％、孔径500μm±50μm以及孔内连接径120μm±20μm。
步骤S1，根据病人CT影像片数据建立有限元缺损模型，并采用拓布力学计算方法设计出相应假体的金属框架，3D打印制备出假体的钛合金框架，清洗并烘干该钛合金框架；
步骤S2，根据上述的设计参数，采用3D打印技术制备出内腔与钛合金框架相匹配的石膏模具，并将钛合金框架固定在石膏模具内；向石膏模具内震动填入500μm～600μm粒径的有机微球，通过称重获知填入有机微球20.1g，达到填满目标；向石膏模具内注入体积浓度为85％的丙酮，以溶解有机微球的表层，溶解时间为7min，向石膏模具内注入纯水以停止溶解，使得溶解了表层的有机微球之间相互粘结；将石膏模具置于50℃的环境中烘烤24小时；
步骤S3，将纯HA粉体与纯水按照质量比为65:35的比例配置陶瓷浆液；向石膏模具内灌入陶瓷浆液，待陶瓷浆液完全吸干后，脱去石膏模具，并将脱去石膏模具后的结构继续置于50℃的环境中烘烤24h，以获得陶瓷坯体与金属框架的复合体；
步骤S4，将陶瓷坯体与金属框架的复合体置于300℃的温度下12h，以气化并去除有机微球，使得HA陶瓷具有多孔结构。将去除了有机微球之后的结构继续在1250℃的温度下烧结4h，以形成复合HA多孔生物陶瓷的钛合金假体。参阅图2和图3，从图2中可看到复合HA多孔生物陶瓷的钛合金假体中的金属框架11、多孔陶瓷12和金属增强柱13；从图3中可看出，复合HA多孔生物陶瓷的钛合金假体中的陶瓷具有宏孔(例如B1和B2)，且孔隙之间相互连通、具有内连接结构(例如A1和A2)。
实施例二
制备复合β-磷酸三钙(β-TCP)多孔生物陶瓷的钛合金腰椎融合器：所述陶瓷原料粉体为纯β-TCP；所述金属框架为叠加式网状结构，其网眼尺寸为1mm～3mm；所得钛合金腰椎融合器的多孔微结构要求为孔隙率60％±5％、孔径250μm±50μm以及孔内连接径100μm±20μm。
步骤S1，通过有限元建立模型设计出相应腰椎融合器的金属框架，并采 用3D打印的方法制备出腰椎融合器的钛合金框架，清洗并烘干所述钛合金框架；
步骤S2，根据上述的设计参数，采用3D打印技术制备出内腔与钛合金框架相匹配的塑料模具；并将钛合金框架固定在塑料模具内；向塑料模具内震动填入200μm～300μm粒径的有机微球，通过称重确定整个塑料模具中被填实；向塑料模具内注入体积浓度为90％的丙酮，以溶解有机微球的表层，溶解时间为5min，向塑料模具内注入纯水以停止溶解，使得溶解了表层的有机微球之间相互粘结；将塑料模具置于50℃的环境中烘烤24小时；
步骤S3，将纯β-TCP粉体与无水酒精按照质量比65:35的比例配置陶瓷浆液；以0.1mL/min的速度向塑料模具内灌入陶瓷浆液，待陶瓷浆液干燥成型后脱去塑料模具，并将脱去塑料模具后的结构继续置于50℃的环境中烘烤24h，以获得陶瓷坯体与金属框架的复合体；
步骤S4，将陶瓷坯体与金属框架的复合体置于300℃的温度下12h，以气化并去除有机微球，使得β-TCP陶瓷具有多孔结构；将去除了有机微球之后的结构继续在1180℃的温度下烧结4h，以形成复合β-TCP多孔生物陶瓷的钛合金腰椎融合器。
从上述步骤S1至步骤S4可知，制备的所述多孔生物陶瓷和金属的复合体既具有金属优良的力学性能，又具有多孔陶瓷很好的组织修复能力，能够达到外科脊柱融合的要求。采用上述步骤中的方法和材料制备的金属框架结构，随后在其中加造互通性的多孔生物陶瓷，使得制备的融合器既有符合组织再生的三维立体空间，又能达到融合部位的力学要求；同时，根据修复部位的组织和器官再生要求，采用降解和/或非降解的陶瓷材料精准可控地制造出上述多孔陶瓷的微结构，其具有如微孔、宏孔、孔隙以及内连接的形态、尺寸和分布等，孔隙完全互通，使得更有利于血管和组织的长入，能够达到假体的永久性生物学固定。因此，使得所述多孔生物陶瓷和金属的复合体能够广泛应用于生物医学和兽医领域。
以采用上述实施例一的方法制备17厘米长的右胫骨中上段复合HA多孔生物陶瓷的钛合金假体进行应用为例，将该假体用于治疗17岁男性的右胫骨 近端骨肉瘤。在手术前，图4a所示的X线片和图4b所示的CT显示肿瘤已穿破骨皮质，图4c所示的MRI(磁共振成像)明确了肿瘤范围；在手术后3天，图4d显示已经可以下地活动；继续随访3、9、12个月，对应的X线片显示假体位置完好(如图4e～4g所示)，无松动、感染、假体断裂等并发症。在手术后的第12个月，患者的MSTS评分结果显示肢体功能评分达80％的满意临床疗效。
综上所述，本发明的复合多孔生物陶瓷的金属假体的制备方法，包括：步骤S1，采用医用金属材料制备金属框架；步骤S2，在所述金属框架内填充造孔剂，以获得造孔构架与金属框架的复合体；步骤S3，将预制的陶瓷浆液灌入所述造孔构架与金属框架的复合体中，以获得陶瓷坯体与金属框架的复合体；步骤S4，去除所述陶瓷坯体与金属框架的复合体中的造孔剂，并经烧结所述陶瓷坯体与金属框架的复合体后获得多孔生物陶瓷和金属的复合体。通过本发明的复合多孔生物陶瓷的金属假体的制备方法制备的多孔生物陶瓷和金属的复合体既具备金属的坚固性和耐用性又具备多孔生物陶瓷优良的组织修复功能，有利于大段骨缺损的修复和重建。本发明的技术方案能为患者量身定制多孔生物陶瓷和金属的复合体的形态、尺寸、机械和生物性能，可行性高、重复性好以及实用性强，能够达到精准治疗的目标。本发明的技术方案能够调控多孔生物陶瓷和金属的复合体的微结构和组分，实现陶瓷部分的组织修复能力和降解性能。同时，本发明的技术方案制备的多孔生物陶瓷和金属的复合体具有促进组织再生和/或抗菌作用，拓展了临床应用范围。
本发明一实施例提供一种复合多孔生物陶瓷的金属假体，采用本发明提供的所述复合多孔生物陶瓷的金属假体的制备方法制备。
由于采用本发明提供的所述复合多孔生物陶瓷的金属假体的制备方法制备所述复合多孔生物陶瓷的金属假体，即制备多孔生物陶瓷和金属的复合体，使得所述多孔生物陶瓷和金属的复合体既具有金属优良的力学性能，又具有多孔陶瓷很好的组织修复能力，能够达到外科植入假体的要求。所述多孔生物陶瓷和金属的复合体既有符合组织再生的三维立体空间，又能达到修复部位的力学要求。同时，所述多孔生物陶瓷和金属的复合体中的陶瓷具有多孔 的微结构，如微孔、宏孔、孔隙以及内连接的形态、尺寸和分布等，其孔隙完全互通，使得更有利于血管和组织的长入，达到假体的永久性生物学固定。并且，所述多孔生物陶瓷和金属的复合体能够作为人工关节的装载基座，使装载基座更稳定、更持久、更耐用。上述效果使得所述多孔生物陶瓷和金属的复合体能够广泛应用于生物医学和兽医领域。
上述描述仅是对本发明较佳实施例的描述，并非对本发明范围的任何限定，本发明领域的普通技术人员根据上述揭示内容做的任何变更、修饰，均属于权利要求书的保护范围。

Claims (15)

  1. 一种复合多孔生物陶瓷的金属假体的制备方法，其特征在于，包括：
    步骤S1，采用医用金属材料制备金属框架；
    步骤S2，在所述金属框架内填充造孔剂，以获得造孔构架与金属框架的复合体；
    步骤S3，将预制的陶瓷浆液灌入所述造孔构架与金属框架的复合体中，以获得陶瓷坯体与金属框架的复合体；
    步骤S4，去除所述陶瓷坯体与金属框架的复合体中的造孔剂，并烧结所述陶瓷坯体与金属框架的复合体后获得多孔生物陶瓷和金属的复合体。
  2. 如权利要求1所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，在所述步骤S1中，通过切削加工、翻砂铸模、3D打印、焊接和编织的方法中的至少一种制备所述金属框架；所述金属框架的材质包括镁及其合金、钛及其合金、钽及其合金、锌及其合金、铜及其合金、铁及其合金、不锈钢和钴铬钼合金中的至少一种。
  3. 如权利要求1或2所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，在所述步骤S1中，预先通过有限元建模和托布力学计算对所述金属框架进行模拟设计，以获得所述金属框架的设计参数，所述设计参数包括结构、密度以及增强柱的形态、尺寸和数量；根据所述设计参数，选用合适的医用金属材料来制作所述金属框架。
  4. 如权利要求1所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，在所述步骤S1之前或在所述步骤S1之后且在所述步骤S2之前，预制一模具，所述模具的尺寸和形态与所述金属框架和/或所述多孔生物陶瓷和金属的复合体相匹配；在步骤S2中，将所述金属框架固定在预制的所述模具内，并在所述模具和所述金属框架内均填满所述造孔剂；在步骤S3中，将预制的陶瓷浆液灌入所述模具内，待所述陶瓷浆液干燥后脱去所述模具，以获得所述陶瓷坯体与金属框架的复合体。
  5. 如权利要求4所述的复合多孔生物陶瓷的金属假体的制备方法，其特 征在于，通过模具铸形、切削加工、3D打印、焊接、堆积、拼接和编织的方法中的至少一种制备所述模具；所述模具的材质包括石膏、塑料或金属材料。
  6. 如权利要求1或4所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，在所述步骤S2中，所述造孔构架与金属框架的复合体的制备步骤包括：首先，在所述金属框架内填满所述造孔剂；然后，在所述金属框架内注入有机溶剂，以溶解所述造孔剂的表层；接着，在所述金属框架内注入水以终止所述溶解，并使所述造孔剂粘结，烘干后获得造孔构架与金属框架的复合体。
  7. 如权利要求6所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，在所述步骤S2中，通过不同频率和不同振幅的震动将所述造孔剂填入所述金属框架内。
  8. 如权利要求6所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，所述造孔剂包括规则颗粒或非规则颗粒或规则颗粒与非规则颗粒的混合物；所述造孔剂包括有机微球；所述造孔剂包括聚苯乙烯、聚乙烯、聚丙烯、聚氯乙烯、聚酰胺、聚氨酯和聚甲基丙烯酸甲酯中的至少一种；所述造孔剂的直径为50μm～5000μm；所述有机溶剂包括丙酮、双丙酮、溴氯甲烷、甲基异丁基甲酮和氯仿中的至少一种。
  9. 如权利要求1所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，通过将陶瓷原料粉体和液体介质经搅拌和/或研磨混合，来获得所述步骤S3中的预制的所述陶瓷浆液；所述陶瓷原料粉体与所述液体介质的质量比为10％～90％；所述陶瓷原料粉体包括纯磷酸钙、掺杂磷酸钙、纯碳酸钙、掺杂碳酸钙、纯氧化铝、掺杂氧化铝、纯氧化锆、掺杂氧化锆、二氧化钛和铝镁尖晶石中的至少一种；所述液体介质包括纯水、乙醇、乙二醇、异丙醇和乙酸乙酯中的至少一种。
  10. 如权利要求9所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，在所述步骤S3中，预制的所述陶瓷浆液中添加有造微孔剂和/或生物活化剂和/或抗菌剂。
  11. 如权利要求10所述的复合多孔生物陶瓷的金属假体的制备方法，其 特征在于，所述造微孔剂的成分和所述造孔剂的成分相同或不同，所述造微孔剂的直径为0.1μm～10μm，所述造微孔剂占所述陶瓷浆液的质量百分比为0.1％～40％；所述生物活化剂包括镁、锌和锶中的至少一种；所述抗菌剂包括银和/或铜；所述生物活化剂和所述抗菌剂的直径均为0.01μm～100μm，所述生物活化剂和所述抗菌剂占所述陶瓷浆液的质量百分比均为0.1％～40％。
  12. 如权利要求1所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，在所述步骤S2之后且在所述步骤S3之前，对所述造孔构架与金属框架的复合体中的金属框架进行表面处理和/或表面涂层。
  13. 如权利要求12所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，所述表面处理包括抛光、打磨、腐蚀、电镀、微纳雕刻和抗氧化处理中的至少一种，所述表面涂层包括羟基磷灰石和/或磷酸三钙的等离子喷涂。
  14. 如权利要求1所述的复合多孔生物陶瓷的金属假体的制备方法，其特征在于，在所述步骤S4中，通过将所述陶瓷坯体与金属框架的复合体置于100℃～600℃的温度下6h～30h，以气化并消除所述造孔剂；在所述步骤S4中，所述烧结的温度为800℃～1600℃，所述烧结的时间为1h～10h。
  15. 一种复合多孔生物陶瓷的金属假体，其特征在于，采用如权利要求1至14中任一项所述的复合多孔生物陶瓷的金属假体的制备方法制备。
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Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112500150A (zh) * 2020-10-23 2021-03-16 南京航空航天大学 一种镁合金/生物陶瓷多孔支架及其制备方法和应用
CN112773571B (zh) * 2021-02-07 2022-10-11 季华实验室 聚合物-金属复合材料的骨科内置假体的制备方法
CN113912388B (zh) * 2021-11-05 2023-01-03 悦兴（厦门）生物科技有限公司 高强度骨科用陶瓷钢板及其制备方法
CN114569799B (zh) * 2022-03-24 2023-01-06 卢霄 承载模块化陶瓷的金属假体及其制备方法

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016479A1 (en) * 1997-10-01 1999-04-08 Phillips-Origen Ceramic Technology, Llc. Bone substitute materials
CN1850293A (zh) * 2006-04-26 2006-10-25 卢建熙 医用增强型多孔生物陶瓷、制备方法及其应用
CN102936141A (zh) * 2012-11-26 2013-02-20 卢建熙 一种含银抗菌生物陶瓷,制备方法及其应用
CN103656760A (zh) * 2013-12-09 2014-03-26 广西大学 个性化多孔甲状软骨支架制备方法
CN105251059A (zh) * 2015-11-16 2016-01-20 北京航空航天大学 一种用于尿道、输尿管的可降解修复支架及制备方法
CN106178122A (zh) * 2016-08-31 2016-12-07 东北大学 一种可吸收骨修复材料及其制备方法
CN106466494A (zh) * 2015-08-18 2017-03-01 重庆润泽医药有限公司 一种多孔材料及制备方法
CN107596449A (zh) * 2017-10-30 2018-01-19 陕西爱骨医疗股份有限公司 一种仿生人骨的制备方法
CN109789020A (zh) * 2016-07-22 2019-05-21 塞特克斯治疗公司 关节软骨修复
CN110404118A (zh) * 2019-08-16 2019-11-05 上海交通大学医学院附属第九人民医院 骨缺损修复支架及构建方法、制备方法、计算机可读存储介质、设备
CN110508788A (zh) * 2019-09-16 2019-11-29 天津理工大学 一种锌或锌合金或其复合材料组织工程支架的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1268583C (zh) * 2001-11-30 2006-08-09 卢建熙 可控微结构的多孔生物陶瓷、其制备方法及应用
WO2012021812A2 (en) * 2010-08-13 2012-02-16 Smith & Nephew, Inc. Patellar implants
CN105481466A (zh) * 2015-12-11 2016-04-13 华南协同创新研究院 一种ZrO2增韧多孔磷酸钙生物陶瓷材料及其制备方法和应用
CN110054491B (zh) * 2019-03-27 2022-02-15 昆明理工大学 一种纳米氧化锌掺杂羟基磷灰石多孔生物陶瓷的制备方法

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016479A1 (en) * 1997-10-01 1999-04-08 Phillips-Origen Ceramic Technology, Llc. Bone substitute materials
CN1290181A (zh) * 1997-10-01 2001-04-04 菲利普斯－奥里根陶瓷技术有限公司 骨代用品材料
CN1850293A (zh) * 2006-04-26 2006-10-25 卢建熙 医用增强型多孔生物陶瓷、制备方法及其应用
CN102936141A (zh) * 2012-11-26 2013-02-20 卢建熙 一种含银抗菌生物陶瓷,制备方法及其应用
CN103656760A (zh) * 2013-12-09 2014-03-26 广西大学 个性化多孔甲状软骨支架制备方法
CN106466494A (zh) * 2015-08-18 2017-03-01 重庆润泽医药有限公司 一种多孔材料及制备方法
CN105251059A (zh) * 2015-11-16 2016-01-20 北京航空航天大学 一种用于尿道、输尿管的可降解修复支架及制备方法
CN109789020A (zh) * 2016-07-22 2019-05-21 塞特克斯治疗公司 关节软骨修复
CN106178122A (zh) * 2016-08-31 2016-12-07 东北大学 一种可吸收骨修复材料及其制备方法
CN107596449A (zh) * 2017-10-30 2018-01-19 陕西爱骨医疗股份有限公司 一种仿生人骨的制备方法
CN110404118A (zh) * 2019-08-16 2019-11-05 上海交通大学医学院附属第九人民医院 骨缺损修复支架及构建方法、制备方法、计算机可读存储介质、设备
CN110508788A (zh) * 2019-09-16 2019-11-29 天津理工大学 一种锌或锌合金或其复合材料组织工程支架的制备方法

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