CN112500151B - 生物活性陶瓷支架与柔性可调的三维生坯及其制备方法 - Google Patents

生物活性陶瓷支架与柔性可调的三维生坯及其制备方法 Download PDF

Info

Publication number
CN112500151B
CN112500151B CN202011369740.4A CN202011369740A CN112500151B CN 112500151 B CN112500151 B CN 112500151B CN 202011369740 A CN202011369740 A CN 202011369740A CN 112500151 B CN112500151 B CN 112500151B
Authority
CN
China
Prior art keywords
green body
treatment
dimensional
dimensional green
adjustable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202011369740.4A
Other languages
English (en)
Other versions
CN112500151A (zh
Inventor
王小英
黎珊珊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
South China University of Technology SCUT
Original Assignee
South China University of Technology SCUT
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by South China University of Technology SCUT filed Critical South China University of Technology SCUT
Priority to CN202011369740.4A priority Critical patent/CN112500151B/zh
Publication of CN112500151A publication Critical patent/CN112500151A/zh
Application granted granted Critical
Publication of CN112500151B publication Critical patent/CN112500151B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/01—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
    • C04B35/447—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on phosphates, e.g. hydroxyapatite
    • 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
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B28—WORKING CEMENT, CLAY, OR STONE
    • B28B—SHAPING CLAY OR OTHER CERAMIC COMPOSITIONS; SHAPING SLAG; SHAPING MIXTURES CONTAINING CEMENTITIOUS MATERIAL, e.g. PLASTER
    • B28B1/00—Producing shaped prefabricated articles from the material
    • B28B1/001—Rapid manufacturing of 3D objects by additive depositing, agglomerating or laminating of material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B28—WORKING CEMENT, CLAY, OR STONE
    • B28B—SHAPING CLAY OR OTHER CERAMIC COMPOSITIONS; SHAPING SLAG; SHAPING MIXTURES CONTAINING CEMENTITIOUS MATERIAL, e.g. PLASTER
    • B28B11/00—Apparatus or processes for treating or working the shaped or preshaped articles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00—Processes of additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y40/00—Auxiliary operations or equipment, e.g. for material handling
    • B33Y40/20—Post-treatment, e.g. curing, coating or polishing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • B33Y70/10—Composites of different types of material, e.g. mixtures of ceramics and polymers or mixtures of metals and biomaterials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
    • C—CHEMISTRY; METALLURGY
    • C03—GLASS; MINERAL OR SLAG WOOL
    • C03B—MANUFACTURE, SHAPING, OR SUPPLEMENTARY PROCESSES
    • C03B19/00—Other methods of shaping glass
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B28/00—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements
    • C04B28/34—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing cold phosphate binders
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/01—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
    • C04B35/16—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on silicates other than clay
    • C04B35/18—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on silicates other than clay rich in aluminium oxide
    • C04B35/195—Alkaline earth aluminosilicates, e.g. cordierite or anorthite
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
    • C04B2111/00034—Physico-chemical characteristics of the mixtures
    • C04B2111/00181—Mixtures specially adapted for three-dimensional printing (3DP), stereo-lithography or prototyping
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
    • C04B2111/00474—Uses not provided for elsewhere in C04B2111/00
    • C04B2111/00836—Uses not provided for elsewhere in C04B2111/00 for medical or dental applications
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
    • C04B2235/02—Composition of constituents of the starting material or of secondary phases of the final product
    • C04B2235/30—Constituents and secondary phases not being of a fibrous nature
    • C04B2235/32—Metal oxides, mixed metal oxides, or oxide-forming salts thereof, e.g. carbonates, nitrates, (oxy)hydroxides, chlorides
    • C04B2235/3205—Alkaline earth oxides or oxide forming salts thereof, e.g. beryllium oxide
    • C04B2235/3206—Magnesium oxides or oxide-forming salts thereof
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
    • C04B2235/02—Composition of constituents of the starting material or of secondary phases of the final product
    • C04B2235/30—Constituents and secondary phases not being of a fibrous nature
    • C04B2235/32—Metal oxides, mixed metal oxides, or oxide-forming salts thereof, e.g. carbonates, nitrates, (oxy)hydroxides, chlorides
    • C04B2235/3205—Alkaline earth oxides or oxide forming salts thereof, e.g. beryllium oxide
    • C04B2235/3208—Calcium oxide or oxide-forming salts thereof, e.g. lime
    • C04B2235/3212—Calcium phosphates, e.g. hydroxyapatite
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
    • C04B2235/65—Aspects relating to heat treatments of ceramic bodies such as green ceramics or pre-sintered ceramics, e.g. burning, sintering or melting processes
    • C04B2235/656—Aspects relating to heat treatments of ceramic bodies such as green ceramics or pre-sintered ceramics, e.g. burning, sintering or melting processes characterised by specific heating conditions during heat treatment
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
    • C04B2235/65—Aspects relating to heat treatments of ceramic bodies such as green ceramics or pre-sintered ceramics, e.g. burning, sintering or melting processes
    • C04B2235/656—Aspects relating to heat treatments of ceramic bodies such as green ceramics or pre-sintered ceramics, e.g. burning, sintering or melting processes characterised by specific heating conditions during heat treatment
    • C04B2235/6567—Treatment time

Landscapes

  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Ceramic Engineering (AREA)
  • Manufacturing & Machinery (AREA)
  • Materials Engineering (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Transplantation (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Structural Engineering (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Mechanical Engineering (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Civil Engineering (AREA)
  • Composite Materials (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials For Medical Uses (AREA)

Abstract

本发明公开了生物活性陶瓷支架与柔性可调的三维生坯及其制备方法。该方法包括：将流变助剂和阴离子多糖溶于水溶液中，与生物活性陶瓷粉末混合，形成生坯。利用挤出型三维(3D)打印机将上述生坯按照设定的形状挤出。然后，使用盐溶液进行交联，获得可塑的柔性生坯，按照需求二次成型后，进行相应的固化处理，得到具有复杂结构的生物活性陶瓷支架。该生物活性陶瓷支架的形状和孔隙结构可设计，使其符合促进细胞生长的要求，具有良好的机械性能和生物学性能。与现有技术相比，本发明可二次成型的柔性生坯适用于多种生物活性陶瓷，而且方法简单易行，可推广应用。

Description

生物活性陶瓷支架与柔性可调的三维生坯及其制备方法
技术领域
本发明属于3D打印及生物医用材料领域，具体涉及一种具有复杂结构的生物活性陶瓷支架与柔性可调的三维生坯及其制备方法。
背景技术
生物活性陶瓷支架因其具良好的生物相容性、生物可降解性以及骨诱导性而被广泛用于骨组织工程，其主要包括生物活性玻璃、磷酸钙骨水泥和羟基磷灰石等。由于形状可设、孔隙结构可调，3D打印成为了制备多孔生物活性陶瓷支架的主要方法，尤其是直接书写打印。
为了促进骨再生，最近的一些研究使用改进的喷嘴形成具有微通道的3D打印的生物活性陶瓷支架，例如空心管结构和莲藕状结构。但是，更复杂的结构(如皮质骨中相互连接的微通道结构(哈弗氏管))不可能直接通过现有的直接书写打印来制造。同时，具有一定曲率和孔隙结构的下颌骨、眶底和颅骨模型，很难直接通过直接书写打印获得。
生物活性陶瓷表现出强的离子和/或共价键，导致高硬度和低延展性机械性能，从而限制了其加工自由度。因此，在满足可打印的前提下，使生坯获得柔软性进行二次成型，制造相互连接的微通道结构或更复杂形状具有重要研究意义。目前，张等采用光固化墨水与陶瓷粉末进行混合打印，获得可二次变形的柔性生坯(Zhang D,Peng E,Borayek R,etal.Controllable Ceramic Green-Body Configuration for Complex CeramicArchitectures with Fine Features[J].Advanced Functional Materials,2019,29(12):1807082.)。但是，光固化墨水存在着陶瓷粉末含量低的问题，导致最后所得的支架力学性能差。相比之下，本发明可在较高的陶瓷粉末含量下，获得可二次变形的柔性生坯，进而获得力学性能较好的陶瓷支架。同时，目前对柔性生坯的应用主要在工艺陶瓷制品上，而针对生物活性陶瓷支架，特别是在生物医用材料上罕见报道。
发明内容
为了克服现有技术存在的不足，本发明的目的是提供一种具有复杂结构的生物活性陶瓷支架与柔性可调的三维生坯及其制备方法。
本发明目的是提供一种具有复杂结构的生物活性陶瓷支架及其可控生坯的制备方法，适用于3D打印。
本发明的目的至少通过如下技术方案之一实现。
本发明将生物活性陶瓷粉末和流变助剂/阴离子多糖水溶液混合获得生坯，获得按照设定的形状打印三维支架后使用盐溶液进行交联，然后二次成型后固化，得到具有复杂结构的生物活性陶瓷支架。
本发明结合阴离子多糖可离子交联的特性以及流变助剂的粘弹性，制备可控可打印的生坯。然后，结合3D打印技术以及二次成型的处理制备具有复杂结构的生物活性陶瓷支架，该支架的形状以及孔隙结构可调，形状保真度高，且具有良好的机械性能及生物学性能。制备方法简单易行，成本低廉。
本发明提供的柔性可调的三维生坯的制备方法，包括如下步骤：
(1)可打印生坯的制备：将生物活性陶瓷粉末与流变助剂/阴离子多糖水溶液混合，搅拌均匀，得到可打印生坯；
(2)柔性三维生坯的制备：将步骤(1)所述可打印生坯转移至挤出型三维打印机中，选用普通针头或者同轴针头，按照需求进行3D打印处理，得到3D打印制品，将所述3D打印制品浸泡在盐溶液中进行交联处理，可获得所述柔性可调的三维生坯。
本发明提供的柔性可调的三维生坯是通过使用不同的3D打印针头和打印模型的方式来有效调控支架本身的孔道结构、可加工度以及对应陶瓷支架的力学性能，所述的三维生坯可通过调节阴离子多糖水溶液的浓度、盐溶液的浓度及处理时间，获得不同弹性模量。
进一步地，步骤(1)所述生物活性陶瓷粉末包括磷酸钙骨水泥(即磷酸氢钙、磷酸三钙或磷酸四钙中的一种或一种以上按任意比例的组合物)、生物活性玻璃(由SiO2，Na2O，CaO和P2O5等基本成分组成的硅酸盐玻璃)、羟基磷灰石、镁黄长石及β-磷酸三钙等中的一种。
进一步地，步骤(1)所述流变助剂/阴离子多糖水溶液为流变助剂、阴离子多糖及水混合均匀得到的溶液；所述流变助剂为锂皂石、Pluronic F-127、卡波姆、纳米纤维素中的一种；所述阴离子多糖为海藻酸钠、羧甲基壳聚糖、羧甲基纤维素、卡拉胶水溶液中的一种以上；在步骤(1)所述流变助剂/阴离子多糖水溶液中，流变助剂的质量百分比浓度为1％-20％，阴离子多糖的质量百分比浓度为2％-10％。
进一步地，步骤(1)所述生物活性陶瓷粉末与流变助剂/阴离子多糖水溶液的质量比为1:0.4-0.8。
进一步地，步骤(2)所述盐溶液为氯化钙溶液及氯化钾溶液中的一种及以上；所述盐溶液的质量百分比浓度为1-10％；交联处理的时间为1min-30min。
进一步地，当步骤(1)所述阴离子多糖选用了海藻酸钠、羧甲基壳聚糖或羧甲基纤维素，步骤(2)所述盐溶液选用氯化钙溶液；当步骤(1)所述阴离子多糖选用了卡拉胶，步骤(2)所述盐溶液选用氯化钾溶液。
本发明提供一种由上述的制备方法制得的柔性可调的三维生坯，弹性模量为50-500kPa。
本发明提供的使用柔性可调的三维生坯制备具有复杂结构的生物活性陶瓷支架的方法，包括如下步骤：
将所述柔性可调的三维生坯进行二次变形处理，得到二次处理的生胚，然后固化处理，得到所述具有复杂结构的生物活性陶瓷支架。
进一步地，所述二次变形处理为卷曲、折叠、扭曲、修剪、压缩、扎孔和模具成型中的一种以上；当打印所得柔性可调的三维生坯的厚度、宽和长中任意两者比例在1:1.5-1:200内，所述二次变形处理包括卷曲及模具成型中的一种以上；当打印所得柔性可调的三维生坯的厚度、宽和长中任意两者比例在1:10-1:200内，所述二次变形处理包括折叠，当打印所得柔性可调的三维生坯的厚度、宽和长中任意两者比例在1:1-1:200内，所述二次变形处理中的扭曲；修剪、压缩和扎孔等处理不受柔性可调的三维生坯形状限制。
进一步地，所述固化处理包括恒温恒湿箱孵育处理和烧结处理中的一种以上；所述恒温恒湿箱孵育处理包括：将所述二次处理的生胚转移至温度为35-45℃，湿度为100％的恒温恒湿箱孵育7-14d；所述烧结处理包括：先将二次处理的生胚常温干燥24-48h，然后在350℃-450℃保持0.5-1h，然后升温至900℃-1350℃保持1h-5h；当所述柔性三维生坯为磷酸钙骨水泥打印完成后得到的，则固化处理采用恒温恒湿箱孵育处理；当所述柔性三维生坯为生物活性玻璃或羟基磷灰石打印完成后得到的，则固化处理采用烧结处理。
本发明提供一种由上述的制备方法制得的具有复杂结构的生物活性陶瓷支架。
与现有技术相比，本发明具有如下优点和有益效果：
(1)本发明解决了生物活性陶瓷加工自由度低的问题；本发明制备的生物活性陶瓷生坯具有良好的柔韧性，可使生坯在打印后二次变形或者修剪，方法简便，成本低；目前生物活性陶瓷打印的空心管结构需要使用抛光机才能暴露，而本发明只需要使用普通刀片切；
(2)与目前柔性生坯的制备方法对比，该方法所获得的具有复杂结构的生物活性陶瓷支架粉末含量高；
(3)本发明制备的具有复杂结构的生物活性陶瓷支架可兼备薄和一定曲率的结构，或者相互连接的微通道结构等复杂结构，组织贴合程度高以及氧气/养分的传输能力快，修复效果比普通结构的好。
附图说明
图1为实施例1磷酸钙骨水泥3d打印后二次处理的电镜图；
图2为实施例5中的镁黄长石柔性生坯(柔性可调的三维生坯)的压缩压缩循环的应力-应变关系图。
具体实施方式
以下结合附图和实例对本发明的具体实施作进一步说明，但本发明的实施和保护不限于此。需指出的是，以下若有未特别详细说明之过程，均是本领域技术人员可参照现有技术实现或理解的。所用试剂或仪器未注明生产厂商者，视为可以通过市售购买得到的常规产品。
实施例1
取1.2g纳米纤维素/海藻酸钠水溶液(纳米纤维素质量分数为1％，海藻酸钠质量分数为10％)与2g的α-磷酸三钙(磷酸钙骨水泥)粉末混合均匀，得到可打印生坯。
将得到的可打印生坯转移至挤出型3D打印机中，选用同轴针头(外针头尺寸为18G，内针头尺寸为23G)进行3D打印，打印完成后浸没至5wt％氯化钙溶液交联5min，得到柔性可调的三维生坯。该柔性可调的三维生坯内部具有空心管通道，其弹性模量为200kpa。
用刀片对上述柔性可调的三维生坯进行裁剪，将内部空心管通道暴露出来。采用自制的微针阵列(针的密度可调)对该结构进行处理，获得相互连接的微通道结构，然后在温度为35℃，湿度为100％的恒温恒湿箱孵育7d，得到具有相互连接的微通道结构的磷酸钙骨水泥支架(结构如附图1所示)。
实施例2
取1.5g海藻酸钠水溶液(海藻酸钠质量分数为10％)与2gα-磷酸三钙(磷酸钙骨水泥)粉末混合均匀，得到可打印生坯。将得到的可打印生坯转移至挤出型3D打印机中，选用同轴针头(外针头尺寸为18G，内针头尺寸为23G)进行3D打印，打印完成后浸没至7wt％氯化钙溶液交联3min，得到柔性可调的三维生坯。该柔性可调的三维生坯内部具有空心管通道，其弹性模量为50kpa，厚度与长度的比例在为1:5。
对上述柔性可调的三维生坯进行弯曲定型，使其具有一定曲率的支架。然后将该支架置于温度为45℃，湿度为100％的恒温恒湿箱孵育14d，得到具有一定曲率的空心管通道的磷酸钙骨水泥支架。
实施例3
取0.8g锂皂石/羧甲基纤维素水溶液(锂皂石质量分数为3％，羧甲基纤维素质量分数为2％)与2g生物活性玻璃45S5S粉末混合均匀，得到可打印生坯。
将得到的可打印生坯转移至挤出型3D打印机中，选用18G针头进行3D打印，打印完成后浸没至10wt％氯化钙溶液交联1min，得到柔性可调的三维生坯。该柔性可调的三维生坯无空心通道，其弹性模量为500kpa，厚度与长度的比例在为1:10。
对上述柔性可调的三维生坯进行折叠和模具定型，使其具有一定曲率的薄的支架，然后常温干燥24h后置于马弗炉中进行烧结，先在350℃保持1h，然后升温至1350℃保持5h，得到具有一定曲率的薄的生物活性玻璃支架。
实施例4
取1.1g卡波姆/羧甲基壳聚糖水溶液(卡波姆质量分数为2％，羧甲基壳聚糖质量分数为6％)与2g羟基磷灰石粉末混合均匀，得到可打印生坯。
将得到的可打印生坯转移至挤出型3D打印机中，选用21G针头进行3D打印，打印完成后浸没至1wt％氯化钙溶液交联30min，得到柔性可调的三维生坯。该柔性可调的三维生坯通道，其弹性模量为300kpa，厚度与宽度的比例在为1:200。
对上述柔性可调的三维生坯进行折叠并卷曲，使其具有层状同心圆结构(类似山楂卷)。然后常温干燥48h后置于马弗炉中进行烧结，先在450℃保持0.5h，然后升温至900℃保持3h，得到具有层状同心圆结构的羟基磷灰石支架。
实施例5
取1.4g Pluronic F-127/卡拉胶水溶液(Pluronic F-127质量分数为20％，卡拉胶质量分数为4％)与2g镁黄长石粉末混合均匀，得到可打印生坯。
将得到的可打印生坯转移至挤出型3D打印机中，选用同轴针头(外针头尺寸为19G，内针头尺寸为25G)进行3D打印，打印完成后浸没至3wt％氯化钾溶液交联15min，得到柔性可调的三维生坯。该柔性可调的三维生坯内部具有空心管通道，其弹性模量为180kpa。
对上述柔性可调的三维生坯进行裁剪、压缩并固定，使其空心管通道变扁(横截面从圆形变成椭圆形)，然后常温干燥36h后置于马弗炉中进行烧结，先在400℃保持1h，然后升温至1200℃保持1h，得到具有椭圆状通道结构的镁黄长石支架。
实施例6
取1.6g Pluronic F-127/卡拉胶/海藻酸钠水溶液(Pluronic F-127质量分数为15％，卡拉胶质量分数为2％，海藻酸钠质量分数为4％)与2gβ-磷酸三钙粉末混合均匀，得到可打印生坯。
将得到的可打印生坯转移至挤出型3D打印机中，选用22G针头进行3D打印，打印完成后浸没至盐溶液(氯化钾的质量分数为3wt％，氯化钙的质量分数为3wt％)交联10min，得到柔性可调的三维生坯。该柔性可调的三维生坯细长但无空心通道，其弹性模量为450kpa，厚度与长度的比例在为1:1。
对上述柔性可调的三维生坯进行扭曲并固定，使其具有麻绳的扭纹结构。然后常温干燥42h后置于马弗炉中进行烧结，先在380℃保持0.8h，然后升温至1100℃保持2h，得到具有扭纹结构的β-磷酸三钙棒。
实验一、对比有和没有离子交联处理的生物活性陶瓷加工自由度
测定方法：使用同样比例的配方(此处的配方为实施例2制备的可打印生坯的配方)进行生物活性玻璃45S5S的3D打印，打印完后采取3种处理，观察所得现象：(1)直接裁切和模具定型后固化；(2)先离子交联后裁切和模具定型，再固化；(3)无处理直接固化后裁切和模具定型。结果如表1所示。
表1
序号 现象
(1) 空心通道结构塌陷，印后无法转移至模具中
(2) 获得空心通道结构，并与模具的设计形状相贴合
(3) 无法完整裁切，支架崩裂；硬度太大，无法贴合模具形状。
图1为实施例1磷酸钙骨水泥3d打印后二次处理的电镜图，可见在结合3d打印及二次处理后，获得了相互连接的微通道结构。
图2为实施例5镁黄长石柔性生坯(柔性可调的三维生坯)压缩循环的应力-应变关系图，可见在循环压缩5次后，该生坯仍具有足够的回弹性恢复，故随后需要固定处理才能获得具有椭圆状通道结构的镁黄长石支架。其他实施例制备的柔性可调的三维生坯同样能在压缩后实现回弹性恢复，可参照图2所示。
以上实施例仅为本发明较优的实施方式，仅用于解释本发明，而非限制本发明，本领域技术人员在未脱离本发明精神实质下所作的改变、替换、修饰等均应属于本发明的保护范围。

Claims (10)

1.一种柔性可调的三维生坯的制备方法，其特征在于，包括如下步骤：
(1)将生物活性陶瓷粉末与流变助剂/阴离子多糖水溶液混合，搅拌均匀，得到可打印生坯；所述流变助剂/阴离子多糖水溶液为流变助剂、阴离子多糖及水混合均匀得到的溶液；所述流变助剂为锂皂石、Pluronic F-127、卡波姆、纳米纤维素中的一种；所述阴离子多糖为海藻酸钠、羧甲基壳聚糖、羧甲基纤维素、卡拉胶水溶液中的一种以上；在步骤(1)所述流变助剂/阴离子多糖水溶液中，流变助剂的质量百分比浓度为1％-20％，阴离子多糖的质量百分比浓度为2％-10％；所述生物活性陶瓷粉末与流变助剂/阴离子多糖水溶液的质量比为1:0.4-0.8；
(2)将步骤(1)所述可打印生坯转移至挤出型三维打印机中，按照需求进行3D打印处理，得到3D打印制品，将所述3D打印制品浸泡在盐溶液中进行交联处理，所述盐溶液为氯化钙溶液及氯化钾溶液中的一种及以上；所述盐溶液的质量百分比浓度为1-10％；交联处理的时间为1min-30min，可获得所述柔性可调的三维生坯。
2.根据权利要求1所述的柔性可调的三维生坯的制备方法，其特征在于，步骤(1)所述生物活性陶瓷粉末包括磷酸钙骨水泥、生物活性玻璃、羟基磷灰石、镁黄长石及β-磷酸三钙中的一种。
3.根据权利要求1所述的柔性可调的三维生坯的制备方法，其特征在于，当步骤(1)所述阴离子多糖选用了海藻酸钠、羧甲基壳聚糖或羧甲基纤维素，步骤(2)所述盐溶液选用氯化钙溶液；当步骤(1)所述阴离子多糖选用了卡拉胶，步骤(2)所述盐溶液选用氯化钾溶液。
4.一种由权利要求1-3任一项所述的制备方法制得的柔性可调的三维生坯，其特征在于，弹性模量为50-500kPa。
5.一种使用权利要求4所述柔性可调的三维生坯制备具有复杂结构的生物活性陶瓷支架的方法，其特征在于，包括如下步骤：
将所述柔性可调的三维生坯进行二次变形处理，得到二次处理的生胚，然后固化处理，得到所述具有复杂结构的生物活性陶瓷支架。
6.根据权利要求5所述的方法，其特征在于，所述二次变形处理为卷曲、折叠、扭曲、修剪、压缩、扎孔和模具成型中的一种以上；所述固化处理包括恒温恒湿箱孵育处理和烧结处理中的一种以上；所述恒温恒湿箱孵育处理包括：将所述二次处理的生胚转移至温度为35-45℃，湿度为100％的恒温恒湿箱孵育7-14d；所述烧结处理包括：先将二次处理的生胚常温干燥24-48h，然后在350℃-450℃保持0.5-1h，然后升温至900℃-1350℃保持1h-5h；当所述柔性三维生坯为磷酸钙骨水泥打印完成后得到的，则固化处理采用恒温恒湿箱孵育处理；当所述柔性三维生坯为生物活性玻璃或羟基磷灰石打印完成后得到的，则固化处理采用烧结处理。
7.根据权利要求5所述的方法，其特征在于，当打印所得柔性可调的三维生坯的厚度、宽和长中任意两者比例在1:1.5-1:200内，所述二次变形处理包括卷曲及模具成型中的一种以上。
8.根据权利要求5所述的方法，其特征在于，当打印所得柔性可调的三维生坯的厚度、宽和长中任意两者比例在1:10-1:200内，所述二次变形处理包括折叠。
9.根据权利要求5所述的方法，其特征在于，当打印所得柔性可调的三维生坯的厚度、宽和长中任意两者比例在1:1-1:200内，所述二次变形处理中的扭曲；修剪、压缩和扎孔处理不受柔性可调的三维生坯形状限制。
10.一种由权利要求5-9任一项所述的制备方法制得的具有复杂结构的生物活性陶瓷支架。
CN202011369740.4A 2020-11-30 2020-11-30 生物活性陶瓷支架与柔性可调的三维生坯及其制备方法 Active CN112500151B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011369740.4A CN112500151B (zh) 2020-11-30 2020-11-30 生物活性陶瓷支架与柔性可调的三维生坯及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011369740.4A CN112500151B (zh) 2020-11-30 2020-11-30 生物活性陶瓷支架与柔性可调的三维生坯及其制备方法

Publications (2)

Publication Number Publication Date
CN112500151A CN112500151A (zh) 2021-03-16
CN112500151B true CN112500151B (zh) 2022-02-15

Family

ID=74967562

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011369740.4A Active CN112500151B (zh) 2020-11-30 2020-11-30 生物活性陶瓷支架与柔性可调的三维生坯及其制备方法

Country Status (1)

Country Link
CN (1) CN112500151B (zh)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113209376B (zh) * 2021-05-05 2022-07-26 西北工业大学 一种强韧兼顾功能型ha/cmcs复合生物陶瓷骨支架的常温中性制备方法
CN113698212A (zh) * 2021-08-18 2021-11-26 江苏富乐德半导体科技有限公司 一种陶瓷流延浆料及其制备方法
CN115845150A (zh) * 2021-09-24 2023-03-28 中国科学院理化技术研究所 一种活性粘土/磷酸镁/明胶复合多孔支架及其制备方法和应用
CN116570406B (zh) * 2023-07-12 2023-09-19 中科硅诺(太仓)生物材料科技有限公司 光固化3d打印制备而成的骨修复材料支架及其制备方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3912652B1 (en) * 2014-12-18 2023-11-15 CELLINK Bioprinting AB Bacterial cellulose nanofibrillar bioink for 3d bioprinting for cell culturing, tissue engineering and regenerative medicine applications
CN105749354A (zh) * 2014-12-19 2016-07-13 深圳先进技术研究院 一种含海藻酸钠的三维支架的常态成型方法
CN107376017B (zh) * 2017-08-24 2020-10-09 浙江大学 3d打印的海藻酸钠-i型胶原-陶瓷复合支架、制备方法及应用
CN108164269A (zh) * 2017-12-29 2018-06-15 华东理工大学 一种模量可调控凝胶注模生坯的制作方法
CN110075359B (zh) * 2019-03-26 2021-09-21 华南理工大学 一种超声辅助制备多孔骨水泥支架及其制备方法
CN109821073B (zh) * 2019-03-27 2021-09-21 四川大学 一种原位实时立体交联的骨组织工程支架材料及制备方法
CN110421835A (zh) * 2019-07-31 2019-11-08 华南理工大学 一种3d打印全贯通管状水凝胶支架及其制备方法
CN111848141A (zh) * 2020-07-24 2020-10-30 江苏师范大学 一种浆料直写成型3d打印用陶瓷膏体的制备方法

Also Published As

Publication number Publication date
CN112500151A (zh) 2021-03-16

Similar Documents

Publication Publication Date Title
CN112500151B (zh) 生物活性陶瓷支架与柔性可调的三维生坯及其制备方法
CN108295302B (zh) 一种医用聚乳酸改性磷酸钙骨水泥复合3d打印材料的制备方法
WO2020252957A1 (zh) 一种促进组织原位再生的可降解再生医学材料及其制备方法
CN105381505A (zh) 一种骨缺损修复支架的3d打印制备方法
CN106830899B (zh) 一种复合陶瓷材料及其制备方法与应用
CN101921061B (zh) 磷硅酸基玻璃的制备方法
CN107998455A (zh) 羟基磷灰石基骨组织工程支架及其粉末3d打印方法
CN107661540B (zh) 一种利用3d打印制备高强度羟基磷灰石-壳聚糖-二氧化硅杂化支架的方法
CN109010924A (zh) Bmp2-pla/hap复合材料骨修复支架的制备方法
CN109251330A (zh) 纳米甲壳素-pva水凝胶及其制备方法和应用
CN110304917A (zh) 用于骨组织工程的钛酸钡压电陶瓷支架及其制备方法
CN108144113A (zh) 一种生物活性玻璃多孔骨修复体材料及其制备方法
CN107029295B (zh) 可注射填充剂及其制备方法
CN108358658B (zh) 一种壳聚糖改性生物陶瓷材料及其制备方法
CN104984387A (zh) 一种骨组织工程蜂窝支架材料及其制备方法
CN111826809A (zh) 一种纸尿裤用无纺布材料的制备方法
CN111233457B (zh) 一种基于碳纤维为造孔剂和增强体制备多孔镁掺杂ha基复合材料的方法
CN112194802B (zh) 一种可生物降解的3d打印凝胶的制备、其产物和应用
CN102757625A (zh) 一种壳聚糖-聚乳酸多孔复合材料及其制备方法
CN106139232A (zh) 一种胶原蛋白‑再生纤维素复合敷料的制备方法
CN108638494A (zh) 一种磷酸钙多孔支架的制备方法
CN114366857A (zh) 一种可降解人工骨复合材料的制备方法
CN112521017A (zh) 生物活性多孔材料及其制备方法
CN108641135B (zh) 乳凝胶复合材料及其制备方法
CN114133230B (zh) 生物活性陶瓷材料的制备方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant