WO2010037881A1 - Method for the low-temperature preparation of bioceramic parts with patterned and interconnected three-dimensional porosity. - Google Patents
Method for the low-temperature preparation of bioceramic parts with patterned and interconnected three-dimensional porosity. Download PDFInfo
- Publication number
- WO2010037881A1 WO2010037881A1 PCT/ES2009/000480 ES2009000480W WO2010037881A1 WO 2010037881 A1 WO2010037881 A1 WO 2010037881A1 ES 2009000480 W ES2009000480 W ES 2009000480W WO 2010037881 A1 WO2010037881 A1 WO 2010037881A1
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- WIPO (PCT)
- Prior art keywords
- pieces
- bioceramic
- mold
- preparation
- porosity
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 239000003462 bioceramic Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000011148 porous material Substances 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 16
- 239000013543 active substance Substances 0.000 claims abstract description 12
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 9
- 239000007943 implant Substances 0.000 claims abstract description 7
- 239000007900 aqueous suspension Substances 0.000 claims abstract description 6
- 230000008929 regeneration Effects 0.000 claims abstract description 5
- 238000011069 regeneration method Methods 0.000 claims abstract description 5
- 239000000725 suspension Substances 0.000 claims description 15
- 239000000919 ceramic Substances 0.000 claims description 13
- 229920000936 Agarose Polymers 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 7
- 239000005312 bioglass Substances 0.000 claims description 6
- 239000001506 calcium phosphate Substances 0.000 claims description 6
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 6
- 238000013461 design Methods 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 229920001661 Chitosan Polymers 0.000 claims description 4
- 238000001879 gelation Methods 0.000 claims description 4
- 229920002307 Dextran Polymers 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 3
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 3
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 230000008468 bone growth Effects 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000003102 growth factor Substances 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000013335 mesoporous material Substances 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000004633 polyglycolic acid Substances 0.000 claims description 2
- 239000004626 polylactic acid Substances 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 238000007711 solidification Methods 0.000 claims description 2
- 230000008023 solidification Effects 0.000 claims description 2
- 229920002988 biodegradable polymer Polymers 0.000 claims 1
- 239000004621 biodegradable polymer Substances 0.000 claims 1
- 210000001519 tissue Anatomy 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 229910010293 ceramic material Inorganic materials 0.000 abstract description 4
- 239000007767 bonding agent Substances 0.000 abstract 1
- 230000010354 integration Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 108010059993 Vancomycin Proteins 0.000 description 5
- 238000007596 consolidation process Methods 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 5
- 229960003165 vancomycin Drugs 0.000 description 5
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000000151 deposition Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- 229910000389 calcium phosphate Inorganic materials 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000000835 fiber Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
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- 238000001727 in vivo Methods 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229920000249 biocompatible polymer Polymers 0.000 description 2
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- 230000003993 interaction Effects 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 238000005245 sintering Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000012815 thermoplastic material Substances 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 241001330002 Bambuseae Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000004068 calcium phosphate ceramic Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 229920000609 methyl cellulose Polymers 0.000 description 1
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- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000005459 micromachining Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000003361 porogen Substances 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
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- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
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- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000009489 vacuum treatment Methods 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- C04B35/624—Sol-gel processing
-
- 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
- C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
- C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
- C04B35/632—Organic additives
- C04B35/636—Polysaccharides or derivatives 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
- C04B37/00—Joining burned ceramic articles with other burned ceramic articles or other articles by heating
-
- 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
- C04B38/00—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof
-
- 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
- C04B2111/00474—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
- C04B2235/3208—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
- C04B2235/60—Aspects relating to the preparation, properties or mechanical treatment of green bodies or pre-forms
- C04B2235/602—Making the green bodies or pre-forms by moulding
- C04B2235/6027—Slip casting
-
- 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
- C04B2235/60—Aspects relating to the preparation, properties or mechanical treatment of green bodies or pre-forms
- C04B2235/606—Drying
Definitions
- the present invention falls within the technical field t of implant manufacturing in orthopedic surgery for filling bone defects, for cell growth supports in tissue engineering (Tissue Enginneering Scaffolds) and as bioreactors.
- the proposed preparation method allows the incorporation of biological or pharmacologically active substances and can act as controlled release systems.
- the application of tissue engineering to the therapeutic repair of bone tissues has become a promising solution. This entails sowing and adhering in vivo human cells on a structure. The cells, once implanted, proliferate, migrate and differentiate into specific tissue while secreting components necessary to create the required tissue. The choice of the structure to be implanted is crucial to allow the cells to behave in an appropriate manner to produce tissues of a certain shape and size.
- the materials used for the regeneration of bone tissue include both synthetic and inorganic natural ceramic materials, such as hidoxyapatite and tricalcium phosphate since these ceramics simulate the natural composition of the bone.
- the porosity of the structure is a fundamental aspect to allow the penetration of blood, oxygen and nutrients necessary for the cells.
- the conventional manufacturing techniques of these structures are not able to control the pore size, pore geometry, spatial distribution, and, above all, the construction of interconnected internal channels that allow blood, oxygen , nutrients, etc. circulate throughout the entire structure.
- US2004 / 0002770 describes a method of obtaining ceramics with compression controlled porosity of a polymer on the porous ceramic material. Although a homogeneous distribution of the pores can be achieved in terms of shape and size, the interconnection between the pores is not equally controllable.
- Silicon consisting of depositing layers of material on a silicon wafer with a predetermined shape (Microfabrication Technology for Vascularized Tissue Engineering. Borenstein et al., Biomedical Devices 4: 3 (2002), 167-175) or Molten Deposition Modeling ( Fused Deposition Modeling, FDM) where three-dimensional objects are constructed directly from 3D CAD data; A temperature controlled head extrudes thermoplastic material in layers, forming a three-dimensional structure by superposition of layers.
- a thermoplastic material polycaprolactone is usually used, which. is a bioreabsorbable polymer (Fused Deposition modeling of novel sc ⁇ ffold hrchitectures for tissue engineering ⁇ pplic ⁇ tions. Zein et al.
- US 2004/0062809 describes a process of preparing a biocompatible polymer with a three-dimensional structure and designed porosity. To do this, use a mold on which the biocompatible material is formed. Once such formation is completed, the mold is removed by dissolution (using a solvent) or by enzymatic digestion.
- EP 1 449 818 describes a process for obtaining a porous structure of sintered calcium phosphate consisting of mixing powders of calcium phosphate precursors and pressurizing them between 5 and 500 MPa on a metal, wooden or bamboo that are then removed.
- a group of rods are arranged on the same plane in parallel in the same direction; over this group another overlaps in the same direction or in a different direction. Finally, more groups of rods can be added perpendicular to the first groups. Once the powders are compacted, the rods are removed giving rise to a porous piece. For the piece to have an appropriate hardness it must be sintered at an elevated temperature, between 500 and 1300 ° C.
- the present invention overcomes the above limitations since it allows a porosity design not only in two but in the three directions of space through a previously designed mold and the mold is removed mechanically without the need for a thermal, chemical or any other type of treatment that may alter the composition of the piece.
- the bioceramic piece is formed on the same mold by gelation of an aqueous suspension at room temperature without the need to apply pressure.
- the presence of a binding agent means that no further sintering treatment is necessary.
- This also makes possible the incorporation of a biological or pharmacologically active substance into the initial composition of the ceramic, this substance being perfectly distributed throughout the entire structure. Parts of any bioceramics are obtained with interconnected pores in the three directions of space, with an appropriate hardness to while easy to mold for use as implants for bone tissue regeneration.
- the proposed invention consists of a forming technique whereby bioceramics with a porosity designed and interconnected in the three directions of space can be prepared at low temperature.
- bioceramics with a porosity designed and interconnected in the three directions of space can be prepared at low temperature.
- the fact of working at these temperatures allows the inclusion, during the manufacturing process, of biologically or pharmacologically active substances (drugs, hormones, bone growth factors, proteins, etc.) for their subsequent release as well as different cell populations.
- the method is based on solidification by gelation, at a temperature between 30 and 45 0 C, an aqueous suspension of a ceramic (hydroxyapatite, tricalcium phosphate, bioglasses, mesoporous materials siliceous base, etc. or combination thereof) and a binder with thermogel characteristics (agarose, gelane, etc. alone or mixed with substances such as gelatin, chitosan, alginates, dextrans).
- a ceramic hydroxyapatite, tricalcium phosphate, bioglasses, mesoporous materials siliceous base, etc. or combination thereof
- a binder with thermogel characteristics agarose, gelane, etc. alone or mixed with substances such as gelatin, chitosan, alginates, dextrans.
- the consolidation takes place in a short time (less than 5 minutes), within a mold whose design determines the porosity of the piece due to the presence of a three-dimensional framework of rigid filaments. Pore size, geometry and
- the wet piece can be easily manipulated and cut to obtain the desired shape. Also, the piece, which contains a high percentage of water, can be dried in an oven or freeze-dried, which allows its perfect conservation, which is of great importance in the event that biologically or pharmacologically active substances are introduced. Lyophilization hardly modifies the dimensions of the pieces and allows a rapid recovery of the original state in the presence of a fluid. In addition to the advantages outlined (working temperature below 45 0 C, absence of aggressive solvents and versatility in the design of porosity and interconnection of pores) the proposed system is extraordinarily simple and economical.
- thermogel solution is prepared; For this, a certain amount of solid product is weighed and placed in a thermostated container containing an aqueous solution in continuous agitation. The temperature is increased until the melting / solubilization of the product occurs, at which time the working temperature can be lowered and the ceramic and other possible components added. The working temperature depends on the thermal stability of the substances included in this stage. The system is kept under stirring for a while to achieve a homogeneous distribution of the components. Finally, the suspension is poured into the mold.
- the mold basically consists of a removable parallelepiped that lacks an upper side, whereby the suspension is added.
- Two of the sides (hereinafter X and Y) are constituted by a base on which a series of rigid filaments (as a fakir bed) have been fixed perpendicularly according to the previously established design.
- the mold is designed / manufactured in a way that ensures sufficient sealing during the consolidation process in both the X and Y dimensions and at the base of the mold (hereinafter Z).
- the filaments of the dimensions X and Y are removed and the filaments are introduced along the third dimension Z, so that they pass through the intersections of the dimensions X and Y
- the mold is extracted and, when fresh, the pieces are made with the desired shape (cylinders, plates, buckets, etc.) through the use of different types of cutting utensils.
- the pieces obtained can be used wet or dry; The drying process can be carried out by lyophilization or in an oven (at a temperature close to 37 ° C), giving rise to porous pieces that will have different characteristics.
- the porosity of the pieces as well as the pore size (between 300 and 1000 ⁇ m) will be determined by the dimensions of the rigid filaments, the number of filaments in each direction, their geometry and the drying process.
- the three-dimensional scaffolds synthesized in the present invention can be used as supports for the regeneration of different types of tissue, since all the components used in the tested formulations have shown good biocompatibility and, in some cases biodegradability.
- Figure 1 (a) shows a diagram of the top view of the mold with the filaments in the X and Y directions removed while Figure 1 (b) shows a photograph from the top view of the mold where the filaments are observed. They can move on the X and Y axes.
- Figure 2 (a) shows a diagram of the top view of the mold with the filaments in the X and Y directions inside
- Figure 2 (b) shows a photograph of the mold from a top view and with the filaments in the X and Y directions inside.
- Figure 3 (a) represents a diagram of the introduction of the filaments in the Z direction into the mold, while Figure 3 (b) shows a photograph of this introduction into the mold.
- Figure 4 shows different examples of parts prepared by the procedure described in the present invention.
- the three-dimensional framework that will be used for the preparation of porous pieces is designed and constructed, determining the size of the mold and the dimensions of the rigid filaments.
- a 2 cm side cubic mold and 1 mm diameter stainless steel cylindrical filaments have been used.
- the agarose powder is introduced into water into a glass reactor in a proportion of 2.5% weight / volume.
- the temperature of the suspension is raised to 85 ° C, such that the agarose melts, continuously stirring the suspension.
- the system is cooled and, when the suspension reaches 4O 0 C, 10% weight / volume of the carbonatehydroxyapatite ceramic is added.
- the mixture is stirred for a few minutes and poured in the designed mold.
- the suspension thus formed is allowed to stand a few minutes at room temperature, resulting in its consolidation.
- the filaments of the X and Y directions are mechanically removed and the filaments are introduced along the third dimension so that they pass through the intersections of the X and Yv directions
- the base containing the filaments along Z is mechanically removed, obtaining a cubic block consisting of agarose / hydroxyapatite / water, with interconnected three-dimensional porosity. Visually, 1000 ⁇ m pores can be seen in the wet part in all three directions.
- This piece can be easily cut with a blade, making cubes and other smaller parallelepipeds, cylinders, etc. The construction of 0.5 cm side cubic pieces was selected.
- Pieces were dried by lyophilization (freeze at -80 0 wet product C for 4 hours and after vacuum treatment for 24 hours). During the process the material loses all water, approximately 89%, undergoes a slight contraction (less than 10%) and maintains its external shape.
- the pieces have a three-dimensional porosity with pore sizes of 900-950 ⁇ m, as well as others of smaller size, between 0.5 and 100 ⁇ m, characteristic of the material and the drying process.
- the characterization of the dry pieces by X-ray diffraction indicates the presence of diffraction peaks corresponding to hydroxyapatite and an amorphous background due to agarose.
- the FTIR spectrum indicates the presence of the two components, with no interaction between them.
- the material obtained behaves like a hydrogel. Thus, in the presence of an aqueous fluid, it immediately captures the fluid, swelling slightly, and recovering the initial behavior of an elastic and easily manageable material. This small swelling allows the perfect adjustment of the material to a bone defect when introduced as an implant in vivo and rehydrates when it comes into direct contact with the blood.
- Example 2
- This example describes the incorporation of the antibiotic vancomycin into porous bioceramic pieces of a sol-gel bioglass
- the three-dimensional framework that will be used for the preparation of porous pieces is designed and constructed, determining the size of the mold and the dimensions of the rigid filaments.
- a cubic mold of 4 cm side and stainless steel cylindrical filaments of 1 mm in diameter have been used.
- the filaments of the X and Y directions are mechanically removed and the filaments are introduced along the third dimension, so that they pass through the intersections of the X and Y directions. After a few minutes it is removed mechanically the base containing the filaments along Z, obtaining a cubic block consisting of agarose / bioglass / vancomycin / water, with interconnected three-dimensional porosity. Visually, 1000 ⁇ m pores can be seen in the wet part in all three directions. This piece can be easily cut with a blade. The construction of cylindrical pieces of 13x4 mm was selected. These pieces were dried by lyophilization.
- the material loses all the water, approximately 84%, undergoes a slight contraction (between 5 and 10%) while retaining its external shape.
- the pieces have a three-dimensional porosity with pore sizes of 900-950 ⁇ m, as well as others of smaller size, between 0.5 and 100 ⁇ m, characteristic of the material and the drying process.
- the characterization of dry pieces by X-ray diffraction indicates that it is an amorphous material.
- the FTIR spectrum indicates the existence of the three components, with no interaction between them.
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Abstract
Method for the low-temperature preparation of bioceramic parts with patterned and interconnected three-dimensional porosity. The method is based on the gelification of an aqueous suspension of a ceramic material and a biocompatible bonding agent inside a mould. The method allows the introduction, during the manufacturing process, of biological or pharmacologically active substances. The mould pattern determines essentially the porosity of the part. The size of the pore, the geometry and the degree of porosity may be modified in the three spatial directions. The size of the pore which can be achieved as well as the fact that the pores are interconnected facilitates the vascularization process, the integration of the implanted material and, in most cases, the subsequent regeneration of the tissue. The ultimate aim of these parts is the application thereof as implants for regeneration of the bone tissue in tissue engineering.
Description
TITULO TITLE
Método para la preparación a baja temperatura de piezas de biocerámicas con porosidad tridimensional diseñada e interconectada.Method for the low temperature preparation of bioceramics pieces with three-dimensional porosity designed and interconnected.
SECTOR DE LA TÉCNICASECTOR OF THE TECHNIQUE
La presente invención se encuadra dentro del campo técnico t de fabricación de implantes en cirugía ortopédica para relleno de defectos óseos, para soportes de crecimiento celular en ingeniería de tejidos (Tissue Enginneering Scaffolds) y como bioreactores. El método de preparación propuesto permite la incorporación de sustancias biológicas o farmacológicamente activas pudiendo actuar como sistemas de liberación controlada.The present invention falls within the technical field t of implant manufacturing in orthopedic surgery for filling bone defects, for cell growth supports in tissue engineering (Tissue Enginneering Scaffolds) and as bioreactors. The proposed preparation method allows the incorporation of biological or pharmacologically active substances and can act as controlled release systems.
ESTADO DEL ARTE La aplicación de ingeniería de tejidos a la reparación terapéutica de tejidos óseos se ha convertido en una solución prometedora. Esto conlleva sembrar y adherir in vivo células humanas sobre una estructura. Las células, una vez implantadas, proliferan, migran y se diferencian en tejido específico mientras segregan componentes necesarios para crear el tejido requerido. La elección de la estructura a implantar es crucial para que permita a las células comportarse de una manera adecuaba para producir tejidos de una determinada forma y tamaño. Los materiales utilizados para la regeneración de tejido óseo incluyen tanto materiales cerámicos sintéticos como naturales inorgánicos, como la hidoxiapatita y el fosfato tricálcico ya que estas cerámicas simulan la composición natural del hueso.STATE OF THE ART The application of tissue engineering to the therapeutic repair of bone tissues has become a promising solution. This entails sowing and adhering in vivo human cells on a structure. The cells, once implanted, proliferate, migrate and differentiate into specific tissue while secreting components necessary to create the required tissue. The choice of the structure to be implanted is crucial to allow the cells to behave in an appropriate manner to produce tissues of a certain shape and size. The materials used for the regeneration of bone tissue include both synthetic and inorganic natural ceramic materials, such as hidoxyapatite and tricalcium phosphate since these ceramics simulate the natural composition of the bone.
Además de su composición, la porosidad de la estructura es un aspecto fundamental para permitir la penetración de sangre, oxígeno y nutrientes necesarios para las células. Sin embargo, las técnicas convencionales de fabricación de estas estructuras no son capaces de controlar el tamaño de poro, la geometría de los poros, la distribución espacial, y, sobre todo, la construcción de canales internos interconectados que permita a la sangre, el oxígeno, nutrientes, etc. circular a través de toda la estructura.
Existen numerosos trabajos que describen métodos de obtener piezas de biocerámicas con una porosidad relativamente controlada. Así, el documento US2004/0002770 describe un método de obtención de cerámicas con porosidad controlada por compresión de un polímero sobre el material cerámico poroso. Aunque se puede conseguir una distribución homogénea de los poros en cuanto a forma y tamaño, la interconexión entre los poros no es igualmente controlable.In addition to its composition, the porosity of the structure is a fundamental aspect to allow the penetration of blood, oxygen and nutrients necessary for the cells. However, the conventional manufacturing techniques of these structures are not able to control the pore size, pore geometry, spatial distribution, and, above all, the construction of interconnected internal channels that allow blood, oxygen , nutrients, etc. circulate throughout the entire structure. There are numerous works that describe methods of obtaining bioceramics with a relatively controlled porosity. Thus, US2004 / 0002770 describes a method of obtaining ceramics with compression controlled porosity of a polymer on the porous ceramic material. Although a homogeneous distribution of the pores can be achieved in terms of shape and size, the interconnection between the pores is not equally controllable.
Actualmente existe un creciente interés en desarrollar nuevas técnicas de prototipado que permiten controlar la arquitectura de la pieza, esto es, la forma, tamaño e interconexiones de los poros. Dentro de estas técnicas están el Micromecanizado deThere is currently a growing interest in developing new prototyping techniques that allow controlling the architecture of the piece, that is, the shape, size and interconnections of the pores. Among these techniques are the Micromachining of
Silicio que consiste en depositar capas de material sobre una oblea de silicio con una forma predeterminada (Microfabrication Technology for Vascularized Tissue Engineering. Borenstein et al., Biomedical Devices 4:3 (2002), 167-175) o el Modelado por Deposición Fundida (Fused Deposition Modeling, FDM) donde se construyen objetos tridimensionales de forma directa a partir de datos 3D CAD; un cabezal de temperatura controlada extruye material termoplástico por capas llegando a formar, por superposición de capas, una estructura tridimensional. Como material termoplástico se suele utilizar la policaprolactona, que. es un polímero bioreabsorbible (Fused Deposition modeling of novel scαffold hrchitectures for tissue engineering αpplicαtions. Zein et al. Biomaterials 23(2002), 1169-1185). Una de las técnicas más utilizadas es la llamada Fabricación de Sólidos de Forma Libre (Solid Freeform Fabrication, SFF), fundamentada en la utilización de un porógeno tridimensional o plantilla producido a partir de mallas sinterizadas de fibras de nylon u otro polímero similar, que hace que la matriz resultante de la infiltración y polimerización del material de reticulación sea la estructura inversa o negativo del témplate, consiguiéndose una gran regularidad geométrica de poros y canales interconectados. Para conseguir este negativo, la plantilla debe eliminarse.Silicon consisting of depositing layers of material on a silicon wafer with a predetermined shape (Microfabrication Technology for Vascularized Tissue Engineering. Borenstein et al., Biomedical Devices 4: 3 (2002), 167-175) or Molten Deposition Modeling ( Fused Deposition Modeling, FDM) where three-dimensional objects are constructed directly from 3D CAD data; A temperature controlled head extrudes thermoplastic material in layers, forming a three-dimensional structure by superposition of layers. As a thermoplastic material, polycaprolactone is usually used, which. is a bioreabsorbable polymer (Fused Deposition modeling of novel scαffold hrchitectures for tissue engineering αpplicαtions. Zein et al. Biomaterials 23 (2002), 1169-1185). One of the most used techniques is the so-called Manufacturing of Free Form Solids (SFF), based on the use of a three-dimensional porogen or template produced from sintered meshes of nylon fibers or another similar polymer, which makes that the matrix resulting from the infiltration and polymerization of the crosslinking material is the inverse or negative structure of the template, achieving a great geometric regularity of interconnected pores and channels. To get this negative, the template must be deleted.
El trabajo publicado por Liang y Weng (Artificiαlly controlling ofinner structure to porous hydroxyαpαtite cerαmic by using solidified coαted flbers, Material Letters 60 (2006) 3569-3572) describe la fabricación de piezas cerámicas de hidroxiapatita a
partir de una estructura tridimensional de fibra que se construye para originar una determinada distribución de tamaños y conectividad de los poros. Sobre esta estructura de fibra se añade una suspensión de aglutinante e hidroxiapatita. Una vez consolidada la pieza, se retira la estructura de fibra por pirólisis.The work published by Liang and Weng (Artificiαlly controlling ofinner structure to porous hydroxyαpαtite cerαmic by using solidified coαted flbers, Material Letters 60 (2006) 3569-3572) describes the manufacture of ceramic pieces of hydroxyapatite a from a three-dimensional fiber structure that is constructed to cause a certain distribution of pore sizes and connectivity. A binder and hydroxyapatite suspension is added to this fiber structure. Once the piece is consolidated, the fiber structure is removed by pyrolysis.
El documento US 2004/0062809 describe un proceso de preparación de un polímero biocompatible con una estructura tridimensional y porosidad diseñada. Para ello, emplea un molde sobre el que se forma el material biocompatible. Una vez finalizada tal formación, el molde se elimina por disolución (empleando un disolvente) o por digestión enzimática.US 2004/0062809 describes a process of preparing a biocompatible polymer with a three-dimensional structure and designed porosity. To do this, use a mold on which the biocompatible material is formed. Once such formation is completed, the mold is removed by dissolution (using a solvent) or by enzymatic digestion.
En un trabajo previo publicado por los inventores de esta invención (Cabanas et al. Room Temperature synthesis of agarose/sol-gel glass pieces with tailored interconnected porosity, J. Biomedical Materials Research Part A5 2006) se describe un procedimiento de obtención de piezas de porosidad diseñada a partir de moldes tridimensionales de poliestireno sobre el que se vierte una suspensión de agarosa (aglutinante) y un material cerámico bioactivo. Una vez consolidada la pieza cerámica el molde se retira por tratamiento con una disolución acuosa de sosa.In a previous work published by the inventors of this invention (Cabanas et al. Room Temperature synthesis of agarose / sol-gel glass pieces with tailored interconnected porosity, J. Biomedical Materials Research Part A 5 2006) a method of obtaining parts is described of porosity designed from three-dimensional polystyrene molds on which an agarose suspension (binder) and a bioactive ceramic material are poured. Once the ceramic piece is consolidated, the mold is removed by treatment with an aqueous solution of soda.
Los métodos descritos anteriormente basados en técnicas de fabricación de moldes con porosidad controlada consiguen obtener piezas con una distribución de tamaño, forma e interconexión de los poros apropiada. Sin embargo, la etapa de eliminación del molde conlleva un tratamiento térmico o químico que puede dañar la estructura de la pieza cerámica. Por otro lado, estos tratamientos hacen que la inclusión de una sustancia biológica o farmacológicamente activa dentro de la pieza cerámica que actuará como implante, deba hacerse una vez obtenida la pieza lo cual puede tener el inconveniente.de no distribuirse de forma homogénea a través de toda la estructura y, además, dificulta el control de la cantidad de sustancia a incluir.The methods described above based on mold manufacturing techniques with controlled porosity manage to obtain parts with an appropriate distribution of size, shape and interconnection of the pores. However, the mold removal stage involves a thermal or chemical treatment that can damage the structure of the ceramic piece. On the other hand, these treatments mean that the inclusion of a biologically or pharmacologically active substance within the ceramic piece that will act as an implant must be done once the piece is obtained, which may have the disadvantage of not being distributed homogeneously through The entire structure and also makes it difficult to control the amount of substance to be included.
El documento EP 1 449 818 describe un proceso para obtener una estructura porosa de fosfato calcico sinterizado que consiste en mezclar polvos de precursores del fosfato calcico y presurizarlos entre 5 y 500 MPa sobre una varillas de metal, de madera o
bambú que después se retiran. Un grupo de varillas se disponen sobre un mismo plano de forma paralela en la misma dirección; sobre este grupo se superpone otro en la misma dirección o en una dirección distinta. Finalmente, se pueden añadir más grupos de varillas de forma perpendicular a los primeros grupos. Una vez compactados los polvos, se retiran las varillas dando lugar a una pieza porosa. Para que la pieza tenga una dureza apropiada debe ser sinterizada a una temperatura elevada, entre 500 y 1300°C. En el documento US 2005/0025807 se describe un proceso para obtener un cemento fraguado de fosfato calcico que también utiliza el mismo sistema de varillas como molde para obtener un material poroso. Después del fraguado, el material debe ser calentado entre 300 y 500°C para obtener la dureza apropiada, a menos que se utilice un polímero biocompatible (especialmente colágeno) como agente aglutinante. También se puede incluir en fármaco en la mezcla a fraguar para formar el cemento. En el año 2005, Ito (Three-dimensionalϊy perforated phosphate clacium phosphate ceramics. J. Wuhan University of Technology - Mat. Sci. Ed., 20. Suppl.) describió el mismo procedimiento de varillas para producir cerámicas porosas de fosfato calcico por compresión de una disolución de polvos de precursores a una presión de 36MPa y posterior sinterizado a temperaturas próximas a 1000 0C; también emplea aglutinantes como la metil celulosa.EP 1 449 818 describes a process for obtaining a porous structure of sintered calcium phosphate consisting of mixing powders of calcium phosphate precursors and pressurizing them between 5 and 500 MPa on a metal, wooden or bamboo that are then removed. A group of rods are arranged on the same plane in parallel in the same direction; over this group another overlaps in the same direction or in a different direction. Finally, more groups of rods can be added perpendicular to the first groups. Once the powders are compacted, the rods are removed giving rise to a porous piece. For the piece to have an appropriate hardness it must be sintered at an elevated temperature, between 500 and 1300 ° C. In US 2005/0025807 a process is described to obtain a calcium phosphate setting cement that also uses the same rod system as a mold to obtain a porous material. After setting, the material must be heated between 300 and 500 ° C to obtain the appropriate hardness, unless a biocompatible polymer (especially collagen) is used as the binding agent. It can also be included in drug in the mixture to be set to form the cement. In 2005, Ito (Three-dimensionalϊy perforated phosphate clacium phosphate ceramics. J. Wuhan University of Technology - Mat. Sci. Ed., 20. Suppl.) Described the same rod procedure to produce porous calcium phosphate ceramic by compression of a solution of powders of precursors at a pressure of 36MPa and subsequent sintering at temperatures around 1000 0 C; It also uses binders such as methyl cellulose.
La presente invención supera las limitaciones anteriores ya que permite un diseño de la porosidad no sólo en dos sino en las tres direcciones del espacio a través de un molde previamente diseñado y el molde se elimina de forma mecánica sin necesidad de un tratamiento térmico, químico o cualquier otro tipo de tratamiento que pueda alterar la composición de la pieza. La pieza de biocerámica se forma sobre el mismo molde por gelificación de una suspensión acuosa a temperatura ambiente sin necesidad de aplicar presión. La presencia de un agente aglutinante hace que no sea necesario un tratamiento posterior de sinterizado. Esto hace también posible la incorporación de una sustancia biológica o farmacológicamente activa a la composición inicial de la cerámica, quedando esta sustancia perfectamente distribuida a lo largo de toda la estructura. Se consiguen piezas de cualquier biocerámica con poros interconectaados en las tres direcciones del espacio, con una dureza apropiada a
la vez que fáciles de moldear para uso como implantes para la regeneración del tejido óseo.The present invention overcomes the above limitations since it allows a porosity design not only in two but in the three directions of space through a previously designed mold and the mold is removed mechanically without the need for a thermal, chemical or any other type of treatment that may alter the composition of the piece. The bioceramic piece is formed on the same mold by gelation of an aqueous suspension at room temperature without the need to apply pressure. The presence of a binding agent means that no further sintering treatment is necessary. This also makes possible the incorporation of a biological or pharmacologically active substance into the initial composition of the ceramic, this substance being perfectly distributed throughout the entire structure. Parts of any bioceramics are obtained with interconnected pores in the three directions of space, with an appropriate hardness to while easy to mold for use as implants for bone tissue regeneration.
DESCRIPCIÓNDESCRIPTION
Breve descripción de la invenciónBrief Description of the Invention
La invención que se propone consiste en una técnica de conformado mediante la cual se pueden preparar, a baja temperatura, piezas de biocerámicas con una porosidad diseñada e interconectada en las tres direcciones del espacio. El hecho de trabajar a estas temperaturas permite la inclusión, durante el proceso de fabricación, de sustancias biológica o farmacológicamente activas (fármacos, hormonas, factores de crecimiento óseo, proteínas, etc.) para su posterior liberación así como diferentes poblaciones celulares.The proposed invention consists of a forming technique whereby bioceramics with a porosity designed and interconnected in the three directions of space can be prepared at low temperature. The fact of working at these temperatures allows the inclusion, during the manufacturing process, of biologically or pharmacologically active substances (drugs, hormones, bone growth factors, proteins, etc.) for their subsequent release as well as different cell populations.
El método se basa en la solidificación por gelificación, a una temperatura comprendida entre 30 y 450C, de una suspensión acuosa de una cerámica (hidroxiapatita, fosfato tricálcico, biovidrios, materiales mesoporosos de base silícea, etc. o combinación de ellos) y un aglutinante con características de termogel (agarosa, gelano, etc. solos o mezclados con sustancias como gelatina, quitosano, alginatos, dextranos). La consolidación se produce en poco tiempo (menos de 5 minutos), dentro de un molde cuyo diseño determina la porosidad de la pieza debido a la presencia de un entramado tridimensional de filamentos rígidos. El tamaño de poro, la geometría y el porcentaje de porosidad pueden ser modificados en las tres direcciones del espacio.The method is based on solidification by gelation, at a temperature between 30 and 45 0 C, an aqueous suspension of a ceramic (hydroxyapatite, tricalcium phosphate, bioglasses, mesoporous materials siliceous base, etc. or combination thereof) and a binder with thermogel characteristics (agarose, gelane, etc. alone or mixed with substances such as gelatin, chitosan, alginates, dextrans). The consolidation takes place in a short time (less than 5 minutes), within a mold whose design determines the porosity of the piece due to the presence of a three-dimensional framework of rigid filaments. Pore size, geometry and porosity percentage can be modified in the three directions of space.
La pieza húmeda puede ser manipulada y cortada fácilmente para obtener la forma deseada. Asimismo, la pieza, que contiene un elevado porcentaje de agua, se puede secar en una estufa o ser liofilizada, lo que permite su perfecta conservación, lo cual es de gran importancia en el caso de que se introduzcan sustancias biológica o farmacológicamente activas. La liofilización apenas modifica las dimensiones de las piezas y permite una rápida recuperación del estado original en presencia de un fluido.
Además de las ventajas reseñadas (temperatura de trabajo inferior a 450C, ausencia de disolventes agresivos y versatilidad en el diseño de la porosidad e interconexión de los poros) el sistema propuesto es extraordinariamente simple y económico.The wet piece can be easily manipulated and cut to obtain the desired shape. Also, the piece, which contains a high percentage of water, can be dried in an oven or freeze-dried, which allows its perfect conservation, which is of great importance in the event that biologically or pharmacologically active substances are introduced. Lyophilization hardly modifies the dimensions of the pieces and allows a rapid recovery of the original state in the presence of a fluid. In addition to the advantages outlined (working temperature below 45 0 C, absence of aggressive solvents and versatility in the design of porosity and interconnection of pores) the proposed system is extraordinarily simple and economical.
Descripción detallada de Ia invenciónDetailed description of the invention
En primer lugar se prepara la disolución del termogel; para ello se pesa una determinada cantidad de producto sólido y se introduce en un contenedor termostatizado que contiene una disolución acuosa en continua agitación. Se aumenta la temperatura hasta que se produce la fusión/solubilización del producto, momento en el que se puede disminuir la temperatura de trabajo y añadir la cerámica y otros posibles componentes. La temperatura de trabajo depende de la estabilidad térmica de las sustancias que se incluyen en esta etapa. El sistema se mantiene en agitación durante un tiempo para conseguir una distribución homogénea de los componentes. Finalmente, se vierte la suspensión en el molde.First, the thermogel solution is prepared; For this, a certain amount of solid product is weighed and placed in a thermostated container containing an aqueous solution in continuous agitation. The temperature is increased until the melting / solubilization of the product occurs, at which time the working temperature can be lowered and the ceramic and other possible components added. The working temperature depends on the thermal stability of the substances included in this stage. The system is kept under stirring for a while to achieve a homogeneous distribution of the components. Finally, the suspension is poured into the mold.
El molde consiste, básicamente, en un paralelepípedo desmontable que carece de lado superior, por el que se añade la suspensión. Dos de los lados (en adelante X e Y) están constituidos por una base sobre la que se han fijado, perpendicularmente, una serie de filamentos rígidos (a modo de cama de fakir) según el diseño previamente establecido. El molde se diseña/fabrica de manera que asegure una estanqueidad suficiente durante el proceso de consolidación tanto en las dimensiones X e Y como en la base del molde (en adelante Z).The mold basically consists of a removable parallelepiped that lacks an upper side, whereby the suspension is added. Two of the sides (hereinafter X and Y) are constituted by a base on which a series of rigid filaments (as a fakir bed) have been fixed perpendicularly according to the previously established design. The mold is designed / manufactured in a way that ensures sufficient sealing during the consolidation process in both the X and Y dimensions and at the base of the mold (hereinafter Z).
Una vez que se ha producido la consolidación de la pieza se procede a retirar los filamentos de las dimensiones X e Y y se introducen los filamentos a lo largo de la tercera dimensión Z, de manera que transcurran por las intersecciones de las dimensiones X e Y. Finalizado el proceso, se extrae el molde y, en fresco, se procede a la elaboración de las piezas con la forma deseada (cilindros, placas, cubos, etc.) mediante el uso de diferentes tipos de utensilios de corte.
Finalmente, las piezas obtenidas pueden ser utilizadas húmedas o secas; el proceso de secado se puede realizar mediante liofilización o en estufa (a una temperatura próxima a 37°C), dando lugar a piezas porosas que presentarán distintas características.Once the consolidation of the piece has taken place, the filaments of the dimensions X and Y are removed and the filaments are introduced along the third dimension Z, so that they pass through the intersections of the dimensions X and Y Once the process is finished, the mold is extracted and, when fresh, the pieces are made with the desired shape (cylinders, plates, buckets, etc.) through the use of different types of cutting utensils. Finally, the pieces obtained can be used wet or dry; The drying process can be carried out by lyophilization or in an oven (at a temperature close to 37 ° C), giving rise to porous pieces that will have different characteristics.
La porosidad de las piezas así como el tamaño de poro (entre 300 y 1000 μm) vendrán determinados por las dimensiones de los filamentos rígidos, el número de filamentos en cada dirección, su geometría y por el proceso de secado.The porosity of the pieces as well as the pore size (between 300 and 1000 μm) will be determined by the dimensions of the rigid filaments, the number of filaments in each direction, their geometry and the drying process.
Las ventajas de trabajar en las condiciones de síntesis de la presente invención (bajas temperaturas y no utilización de solventes agresivos, ni tóxicos) son claras ya que permiten, por un lado la síntesis de andamios tridimensionales para regeneración tisular de biocerámicas que no puedan sufrir un tratamiento térmico (ej. Nanopartículas de carbonatohidroxiapatita precipitadas a 4O0C) y, por otro, la inclusión durante el proceso de fabricación de moléculas biológicas o farmacológicamente activas que en estas condiciones no perderán su actividad. Asimismo, durante el proceso de fabricación se pueden introducir otro tipo de sustancias, como polietilenglicol, dextrano, quitosano, ácido poliláctico, ácido poliglicólico, etc, que interaccionen con la sustancia activa controlando su liberación.The advantages of working in the synthesis conditions of the present invention (low temperatures and non-use of aggressive or toxic solvents) are clear since they allow, on the one hand the synthesis of three-dimensional scaffolds for tissue regeneration of bioceramics that cannot undergo heat treatment (eg carbonate-hydroxyapatite nanoparticles precipitated at 4O 0 C) and, on the other, the inclusion during the manufacturing process of biological or pharmacologically active molecules that under these conditions will not lose their activity. Also, during the manufacturing process other substances can be introduced, such as polyethylene glycol, dextran, chitosan, polylactic acid, polyglycolic acid, etc., that interact with the active substance controlling its release.
Los andamios tridimensionales sintetizados en la presente invención pueden utilizarse como soportes para la regeneración de distintos tipos de tejido, ya que todos los componentes empleados en las formulaciones ensayadas han mostrado una buena biocompatibilidad y, en algunos casos biodegradabilidad.The three-dimensional scaffolds synthesized in the present invention can be used as supports for the regeneration of different types of tissue, since all the components used in the tested formulations have shown good biocompatibility and, in some cases biodegradability.
Breve descripción de las figurasBrief description of the figures
La Figura 1 (a) muestra un esquema de la vista superior del molde con los filamentos en las direcciones X e Y extraídos mientras que la Figura l(b) se muestra una fotografía desde la vista superior del molde donde se observan los filamentos que se pueden mover sobre los ejes X e Y.Figure 1 (a) shows a diagram of the top view of the mold with the filaments in the X and Y directions removed while Figure 1 (b) shows a photograph from the top view of the mold where the filaments are observed. they can move on the X and Y axes.
La Figura 2(a) muestra un esquema de la vista superior del molde con los filamentos en las direcciones X e Y en su interior, mientras que la Figura 2(b) muestra una
fotografía del molde desde una vista superior y con los filamentos en las direcciones X e Y en su interior.Figure 2 (a) shows a diagram of the top view of the mold with the filaments in the X and Y directions inside, while Figure 2 (b) shows a photograph of the mold from a top view and with the filaments in the X and Y directions inside.
La figura 3 (a) representa un esquema de la introducción de los filamentos en la dirección Z dentro del molde, mientras que la Figura 3(b) muestra una fotografía de esta introducción en el molde.Figure 3 (a) represents a diagram of the introduction of the filaments in the Z direction into the mold, while Figure 3 (b) shows a photograph of this introduction into the mold.
La Figura 4 muestra diferentes ejemplos de piezas preparadas mediante el procedimiento descrito en la presente invención.Figure 4 shows different examples of parts prepared by the procedure described in the present invention.
Modo de realización de la invenciónEmbodiment of the invention
La invención se ilustra mediante los siguientes ejemplos, los cuales no son limitativos de su alcance.The invention is illustrated by the following examples, which are not limiting of its scope.
Ejemplo 1Example 1
Se describe la preparación de piezas porosas de nanopartículas de carbonatohidroxiapatita y agarosa, que incluye los siguientes pasos:The preparation of porous pieces of nanoparticles of carbonate hydroxyapatite and agarose is described, which includes the following steps:
Preparación del moldeMold Preparation
Inicialmente se diseña y construye el entramado tridimensional que se utilizará para la preparación de piezas porosas, determinando el tamaño del molde y las dimensiones de los filamentos rígidos. En este caso se ha utilizado un molde cúbico de 2 cm de lado y filamentos cilindricos de acero inoxidable de 1 mm de diámetro.Initially, the three-dimensional framework that will be used for the preparation of porous pieces is designed and constructed, determining the size of the mold and the dimensions of the rigid filaments. In this case, a 2 cm side cubic mold and 1 mm diameter stainless steel cylindrical filaments have been used.
Preparación de la suspensiónSuspension Preparation
Se introduce el polvo de agarosa en agua dentro de un reactor de vidrio en una proporción del 2,5% peso/volumen. Se eleva la temperatura de la suspensión a 85°C, tal que la agarosa se funde, agitando continuamente la suspensión. Se enfría el sistema y, cuando la suspensión alcanza 4O0C, se adiciona un 10% peso/volumen de la cerámica carbonatohidroxiapatita. La mezcla se agita durante unos minutos y se vierte
en el molde diseñado. La suspensión así formada se deja reposar unos minutos a temperatura ambiente, produciéndose la consolidación de la misma.The agarose powder is introduced into water into a glass reactor in a proportion of 2.5% weight / volume. The temperature of the suspension is raised to 85 ° C, such that the agarose melts, continuously stirring the suspension. The system is cooled and, when the suspension reaches 4O 0 C, 10% weight / volume of the carbonatehydroxyapatite ceramic is added. The mixture is stirred for a few minutes and poured in the designed mold. The suspension thus formed is allowed to stand a few minutes at room temperature, resulting in its consolidation.
Preparación de las piezas Una vez que la pasta está consolidada se retiran mecánicamente los filamentos de las direcciones X e Y y se introducen los filamentos a lo largo de la tercera dimensión de manera que transcurran por las intersecciones de las direcciones X e Yv Pasados unos minutos se retira mecánicamente la base conteniendo los filamentos a lo largo de Z, obteniéndose un bloque cúbico constituido por agarosa/hidroxiapatita/agua, con porosidad tridimensional interconectada. Visualmente, se pueden apreciar en la pieza húmeda poros de 1000 μm en las tres direcciones. Esta pieza se puede cortar fácilmente con una cuchilla, haciendo cubos y otros paralelepípedos más pequeños, cilindros, etc. Se seleccionó la construcción de piezas cúbicas de 0,5 cm de lado. Estas piezas se secaron mediante liofilización (congelación de producto húmedo a -800C durante 4 horas y posterior tratamiento a vacío durante 24 horas). Durante el proceso el material pierde todo el agua, aproximadamente un 89%, sufre una ligera contracción (inferior al 10%) y mantiene su forma externa. Las piezas presentan una porosidad tridimensional con tamaños de poros de 900-950 μm, así como otros de tamaño inferior, entre 0,5 y 100 μm, característicos del material y del proceso de secado.Preparation of the pieces Once the paste is consolidated, the filaments of the X and Y directions are mechanically removed and the filaments are introduced along the third dimension so that they pass through the intersections of the X and Yv directions After a few minutes The base containing the filaments along Z is mechanically removed, obtaining a cubic block consisting of agarose / hydroxyapatite / water, with interconnected three-dimensional porosity. Visually, 1000 μm pores can be seen in the wet part in all three directions. This piece can be easily cut with a blade, making cubes and other smaller parallelepipeds, cylinders, etc. The construction of 0.5 cm side cubic pieces was selected. These pieces were dried by lyophilization (freeze at -80 0 wet product C for 4 hours and after vacuum treatment for 24 hours). During the process the material loses all water, approximately 89%, undergoes a slight contraction (less than 10%) and maintains its external shape. The pieces have a three-dimensional porosity with pore sizes of 900-950 μm, as well as others of smaller size, between 0.5 and 100 μm, characteristic of the material and the drying process.
Características de las piezasCharacteristics of the pieces
La caracterización de las piezas secas por difracción de rayos X indica la presencia de máximos de difracción correspondientes a hidroxiapatita y un fondo amorfo debido a la agarosa. El espectro FTIR indica la presencia de los dos componentes, no apreciándose ninguna interacción entre ellos.The characterization of the dry pieces by X-ray diffraction indicates the presence of diffraction peaks corresponding to hydroxyapatite and an amorphous background due to agarose. The FTIR spectrum indicates the presence of the two components, with no interaction between them.
El material obtenido se comporta como un hidrogel. Así, en presencia de un fluido acuoso capta de modo inmediato el fluido, hinchándose ligeramente, y recuperando el comportamiento inicial de un material elástico y fácilmente manejable. Este pequeño hinchamiento permite el perfecto ajuste del material a un defecto óseo cuando se introduce como implante in vivo y se rehidrata al entrar en contacto directo con la sangre.
Ejemplo 2The material obtained behaves like a hydrogel. Thus, in the presence of an aqueous fluid, it immediately captures the fluid, swelling slightly, and recovering the initial behavior of an elastic and easily manageable material. This small swelling allows the perfect adjustment of the material to a bone defect when introduced as an implant in vivo and rehydrates when it comes into direct contact with the blood. Example 2
En este ejemplo se describe la incorporación del antibiótico vancomicina en piezas biocerámicas porosas de un biovidrio sol-gelThis example describes the incorporation of the antibiotic vancomycin into porous bioceramic pieces of a sol-gel bioglass
Preparación del moldeMold Preparation
Como en el ejemplo 1 se diseña y construye el entramado tridimensional que se utilizará para la preparación de piezas porosas, determinando el tamaño del molde y las dimensiones de los filamentos rígidos. En este caso se ha utilizado un molde cúbico de 4 cm de lado y filamentos cilindricos de acero inoxidable de 1 mm de diámetro.As in example 1, the three-dimensional framework that will be used for the preparation of porous pieces is designed and constructed, determining the size of the mold and the dimensions of the rigid filaments. In this case a cubic mold of 4 cm side and stainless steel cylindrical filaments of 1 mm in diameter have been used.
Preparación de la suspensiónSuspension Preparation
En primer lugar se prepara una mezcla constituida' por 6 gramos de un biovidrio sol- gel, de composición molar 70SiO2/26CaO/4P2Os y 0,4 gramos de vancomicina.First a mixture of 'by 6 grams of a sol - gel bioglass, of molar composition 70SiO 2 / 26CaO / 4P 2 Os and 0.4 grams of vancomycin is prepared.
Se introduce 1 gramo de agarosa en 40 mL de agua destilada dentro de un reactor de vidrio. Se eleva la temperatura de la suspensión a 85°C, hasta conseguir la fusión de la agarosa, agitando continuamente. Se enfría el sistema y, cuando la suspensión alcanza los 400C, se adiciona la mezcla biovidrio/vancomicina, se agita durante unos minutos y se vierte en el molde diseñado. La suspensión se deja reposar unos minutos a temperatura ambiente, produciéndose la consolidación de la misma.1 gram of agarose in 40 mL of distilled water is introduced into a glass reactor. The temperature of the suspension is raised to 85 ° C, until the agarose melts, stirring continuously. The system is cooled and, when the suspension reaches 40 0 C, bioglass / vancomycin mixture is added, stirred for a few minutes and poured into the mold designed. The suspension is allowed to stand for a few minutes at room temperature, causing its consolidation.
Preparación de las piezasPreparation of the pieces
Una vez que la pasta está consolidada se retiran mecánicamente los filamentos de las direcciones X e Y y se introducen los filamentos a lo largo de la tercera dimensión de, manera que transcurran por las intersecciones de las direcciones X e Y. Pasados unos minutos se retira mecánicamente la base conteniendo los filamentos a lo largo de Z, obteniéndose un bloque cúbico constituido por agarosa/biovidrio/vancomicina/agua, con porosidad tridimensional interconectada. Visualmente, se pueden apreciar en la pieza húmeda poros de 1000 μm en las tres direcciones. Esta pieza se puede cortar fácilmente con una cuchilla.
Se seleccionó la construcción de piezas cilindricas de 13x4 mm. Estas piezas se secaron mediante liofilización. Durante el proceso el material pierde todo el agua, aproximadamente un 84%, sufre una ligera contracción (entre un 5 y un 10%) conservando su forma externa. Las piezas presentan una porosidad tridimensional con tamaños de poros de 900-950 μm, así como otros de tamaño inferior, entre 0,5 y 100 μm, característicos del material y del proceso de secado.Once the paste is consolidated, the filaments of the X and Y directions are mechanically removed and the filaments are introduced along the third dimension, so that they pass through the intersections of the X and Y directions. After a few minutes it is removed mechanically the base containing the filaments along Z, obtaining a cubic block consisting of agarose / bioglass / vancomycin / water, with interconnected three-dimensional porosity. Visually, 1000 μm pores can be seen in the wet part in all three directions. This piece can be easily cut with a blade. The construction of cylindrical pieces of 13x4 mm was selected. These pieces were dried by lyophilization. During the process the material loses all the water, approximately 84%, undergoes a slight contraction (between 5 and 10%) while retaining its external shape. The pieces have a three-dimensional porosity with pore sizes of 900-950 μm, as well as others of smaller size, between 0.5 and 100 μm, characteristic of the material and the drying process.
Características de las piezasCharacteristics of the pieces
La caracterización de las piezas secas por difracción de rayos X indica que se trata de un material amorfo. El espectro FTIR indica la existencia de los tres componentes, no apreciándose ninguna interacción entre ellos.The characterization of dry pieces by X-ray diffraction indicates that it is an amorphous material. The FTIR spectrum indicates the existence of the three components, with no interaction between them.
Cuando se introducen las piezas en un solución de tampón fosfato a pH = 7,4 y a 370C, se observa la liberación paulatina de vancomicina mediante espectroscopia VIS- UV. Simultáneamente a este proceso tiene lugar un hinchamiento debido a la captación del fluido por parte del hidrogel, de modo que la pieza recupera su elasticidad inicial lo que permite su fácil manejo. Este pequeño hinchamiento hace que la pieza se ajuste al defecto óseo cuando se introduce como implante in vivo al estar en contacto directo con la sangre.
When the pieces are introduced into a phosphate buffer solution at pH = 7.4 and 37 0 C, the gradual release of vancomycin is observed by UV spectroscopy VIS - . Simultaneously to this process a swelling occurs due to the capture of the fluid by the hydrogel, so that the piece recovers its initial elasticity which allows its easy handling. This small swelling causes the piece to adjust to the bone defect when it is introduced as an implant in vivo when in direct contact with the blood.
Claims
1. Método para la preparación de piezas de biocerámicas que comprende las siguientes etapas:1. Method for the preparation of bioceramic pieces comprising the following stages:
(a) Preparar una suspensión acuosa de una cerámica biocompatible en un agente aglutinante con características de termogel.(a) Prepare an aqueous suspension of a biocompatible ceramic in a binder with thermogel characteristics.
(b) Diseñar un molde en forma de entramado tridimensional a base de filamentos según la porosidad deseada. (c) Introducir la suspensión en el molde(b) Design a mold in the form of three-dimensional network based on filaments according to the desired porosity. (c) Insert the suspension into the mold
(d) Dejar consolidar la suspensión en el molde por gelificación(d) Allow to consolidate the suspension in the mold by gelation
(e) Retirar mecánicamente el molde (í) Extraer la pieza(e) Mechanically remove the mold (í) Remove the part
2. Método para la preparación de piezas biocerámicas, según reivindicación 1, donde la cerámica es hidroxiapatita, fosfato tricálcico, un biovidrio, material mesoporoso de base silícea o combinación de ellos.2. Method for the preparation of bioceramic pieces, according to claim 1, wherein the ceramic is hydroxyapatite, tricalcium phosphate, a bioglass, siliceous base mesoporous material or combination thereof.
3. Método para la preparación de piezas biocerámicas, según reivindicación 1, donde el polímero biodegradable es agarosa o gelano, pudiendo mezclarse con otras sustancias tales como gelatina, quitosano o alginatos.3. Method for preparing bioceramic pieces, according to claim 1, wherein the biodegradable polymer is agarose or gelane, and can be mixed with other substances such as gelatin, chitosan or alginates.
4. Método para la preparación de piezas biocerámicas, según reivindicación 1, donde el molde es una estructura tridimensional desmontable a base de filamentos rígidos constituidos por un material inerte y dispuestos en las tres direcciones del espacio.4. Method for the preparation of bioceramic pieces, according to claim 1, wherein the mold is a removable three-dimensional structure based on rigid filaments constituted by an inert material and arranged in the three directions of space.
5. Método para la preparación de piezas biocerámicas, según reivindicación 1, donde las piezas se secan posteriormente en estufa o por liofilización. 5. Method for the preparation of bioceramic pieces, according to claim 1, wherein the pieces are subsequently dried in an oven or by lyophilization.
6. Método para la preparación de piezas biocerámicas, según reivindicación 1, donde la solidificación por gelación se realiza a una temperatura comprendida entre 30 y 45°C.6. Method for the preparation of bioceramic pieces, according to claim 1, wherein gelation solidification is carried out at a temperature between 30 and 45 ° C.
7. Método para la preparación de piezas biocerámicas, según reivindicaciones anteriores, donde se puede añadir a la suspensión acuosa sustancias biológica o farmacológicamente activas.7. Method for preparing bioceramics according to previous claims, where biological or pharmacologically active substances can be added to the aqueous suspension.
8. Método para la preparación de piezas biocerámicas, según reivindicaciones anteriores, donde las sustancias biológica o farmacológicamente activa son fármacos, hormonas, factores de crecimiento óseo o proteínas.8. Method for the preparation of bioceramic pieces, according to previous claims, wherein the biologically or pharmacologically active substances are drugs, hormones, bone growth factors or proteins.
9. Método para la preparación de piezas biocerámicas, según reivindicaciones anteriores, donde la suspensión acuosa puede contener sustancias que interaccionen con la sustancia activa controlando su liberación como polietilenglicol, dextrano, quitosano, ácido poliláctico o ácido poliglicólico.9. Method for the preparation of bioceramic pieces, according to previous claims, wherein the aqueous suspension may contain substances that interact with the active substance controlling its release as polyethylene glycol, dextran, chitosan, polylactic acid or polyglycolic acid.
10. Piezas de biocerámicas obtenidas a través del método reivindicado con una porosidad interconectada y diseñada en las tres direcciones del espacio e • incluso dentro de la misma dirección con un tamaño de poro comprendido entre 300 y 1000 μm. • •10. Bioceramics pieces obtained through the claimed method with an interconnected porosity and designed in the three directions of space and • even within the same direction with a pore size between 300 and 1000 μm. • •
11. Piezas de biocerámicas, según reivindicación 10, que incluyen una o varias sustancias biológicamente activas.11. Bioceramics pieces according to claim 10, which include one or more biologically active substances.
12. Piezas de biocerámicas, según reivindicaciones 10 y 11, que incluyen sustancias que faciliten la liberación controlada de la sustancia activa12. Bioceramics pieces, according to claims 10 and 11, which include substances that facilitate the controlled release of the active substance
13. Uso de las piezas biocerámicas reivindicadas como implantes para la regeneración de tejido óseo. 13. Use of the claimed bioceramic pieces as implants for the regeneration of bone tissue.
14. Uso de las piezas biocerámicas reivindicadas como sistema de liberación de sustancias. 14. Use of the claimed bioceramic pieces as a substance release system.
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| ES200802813A ES2335851B1 (en) | 2008-10-03 | 2008-10-03 | METHOD FOR LOW TEMPERATURE PREPARATION OF BIOCERAMIC PARTS WITH THREE-DIMENSIONAL POROSITY DESIGNED AND INTERCONNECTED. |
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| EP1500405A1 (en) * | 2002-05-01 | 2005-01-26 | Japan Science and Technology Agency | Method for preparing porous composite material |
| EP2014256A1 (en) * | 2007-07-12 | 2009-01-14 | Straumann Holding AG | Composite bone repair material |
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| EP2014256A1 (en) * | 2007-07-12 | 2009-01-14 | Straumann Holding AG | Composite bone repair material |
Non-Patent Citations (2)
| Title |
|---|
| MAREK POTOCZEK: "Hydroxyapatite foams produced by gelcasting using agarose", MATERIALS LETTERS, vol. 62, 31 July 2007 (2007-07-31), pages 1055 - 1057 * |
| SANCHEZ-SALCEDO, S. ET AL.: "Hydroxyapatite/beta- tricalcium phosphate/agarose macroporous scaffolds for bone tissue engineering", CHEMICAL ENGINEERING JOURNAL, vol. 137, 13 February 2008 (2008-02-13), pages 62 - 71 * |
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