WO2009077210A1 - Matrices de monétite et leur application en régénération osseuse - Google Patents

Matrices de monétite et leur application en régénération osseuse Download PDF

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WO2009077210A1
WO2009077210A1 PCT/EP2008/058694 EP2008058694W WO2009077210A1 WO 2009077210 A1 WO2009077210 A1 WO 2009077210A1 EP 2008058694 W EP2008058694 W EP 2008058694W WO 2009077210 A1 WO2009077210 A1 WO 2009077210A1
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monetite
synthetic
brushite
sulphate
bone
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PCT/EP2008/058694
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English (en)
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Faleh TAMIMI MARIÑO
Enrique Lopez Cabarcos
Jorge Rubio Retama
Jesus Torres Garcia
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Universidad Complutense De Madrid
Universidad Rey Juan Carlos
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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • C01B25/327—After-treatment
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0084—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of phosphorus-containing inorganic compounds, 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic 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
    • A61L27/02—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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • 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
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • 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
    • C04B28/344—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 the phosphate binder being present in the starting composition solely as one or more phosphates
    • 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
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • 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
    • A61L2300/414—Growth factors
    • 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

Definitions

  • This invention belongs to the technical sector of biomaterials, more precisely, to the field of calcium phosphates used in bone regeneration.
  • the synthetic monetite matrices of the present invention result in osteoinductive materials that can be used in dentistry maxillofacial surgery, periodontal and other applications were bone regeneration is needed.
  • the succedaneous material must be biodegradable, biocompatible and osteoinductor, that is, it must attract mesenchymal cells located near the implant and favour their differentiation into osteoblasts while also acting as a mould for the formation of new bone.
  • Calcium phosphates are of special interest in bone regeneration as they are similar to the mineral phase of natural bone and they are susceptible to osseous reshaping and resorption.
  • the most commonly used calcium phosphate matrices include hydroxyapatite, tricalcium phosphate, or brushite. These materials can be administrated in form of cement pastes, implantable solids, powders or granular formulations.
  • cements that set after their implantation it is worth mentioning those that result in the formation of hydroxyapatite as Norian®, or those that result in brushite as Chronoss Inject®.
  • Formulation in the form of cements allows for the administration in locations of difficult access by means of high calibre syringes. However, these cements may result in exothermic reactions during setting, pH changes, or formation of crystalline structures that do not favour osteoinduction.
  • osteoinductive materials in the form o solid matrices in the form of powder, granules or as preformed implants.
  • preformed implants include, for example, patent US- 4610692, which describes a tricalcium phosphate preformed implant soaked with antibiotics.
  • patents US-5866155, US-6203574 or US-2005209704 describe processes where the preconfigured implant is formulated as the product of the fusion of calcium phosphate granules with other polymers to provide a shape to the implant.
  • the incorporation of large masses and more so if they contain polymeric materials may result in local pH alterations and a negative effect in the osteogenic capacity of the implant.
  • powder or granulated formulations permit an easier colonization of the implanted material by osteogenic cells, and the adaptation to corporal cavities of irregular shape.
  • Examples of the direct use of bovine bone granulates are represented by BioOss® an Orthoss® for use in dentistry.
  • BioOss® an Orthoss® for use in dentistry.
  • use of these preparations obtained from biological material represents problems of possible contamination with infectious agents and require strict quality control.
  • other natural matrices in the form of granules have been developed.
  • Examples of hydroxyapatite granules of coralline origin include Interpore200® and Interpore ⁇ OO®.
  • a preferred approximation is the use of synthetic matrices.
  • Gen-ox® o Engipore® incorporate granulates of pure synthetic hydroxyapatite.
  • Other commercial examples of granular synthetic matrices are Chronos® or Cerasorb® made of tricalcium phosphate beta. The latter is marketed in the form of particles of different sizes, from 150 to 2000 ⁇ m as needed, which are applied for alveolar regeneration after mixing with blood from the patient.
  • Bi-Ostetic® is formed by 1-2 mm particles of a mixture of hydroxyapatite and tricalcium phosphate.
  • Collagraft® is other granulated material of hydroxyapatite and calcium tri-phosphate additionally made to contain collagen.
  • Other osteoinductive synthetic materials incorporated in commercial products as Calmatrix® include calcium sulphate.
  • Dehydrated calcium phosphate or "monetite” [CaHPO 4 ] is a material significantly different of brushite, which can be found as a mineral in the nature or that can be synthesized by dehydration of brushite mineral.
  • Monetite in the form of powder mixed with blood has also been the subject of bone regeneration studies (Getter L et al. 1972 J. Oral Surg. 30: 263- 268).
  • the publication describes the utilization of a monetite powder of undetermined size or crystalline structure, and does not mention the origin of the monetite used.
  • Patent US-3913229 the publication date is previous to the development of brushite cements and it can therefore be inferred that the monetite used is of natural origin or by conversion of a natural brushite.
  • Monetite has also been proposed as an additive in hydroxyapatite cements (Barralet et al. 2004 Biomaterials, 25(11 ): 2187- 2195).
  • the present invention incorporates a new synthetic biomaterial for bone regeneration, a method for their production, and its application in dentistry, maxillofacial surgery, periodoncy, traumatology surgery, and other indications in which bone regeneration is necessary.
  • the material is based on biocompatible, biodegradable and osteoconductive elements.
  • the present invention incorporates synthetic monetite [CaHPO 4 ] matrices with different degrees of porosity, in the form of granules or preformed blocks, produced by means of setting of a brushite [CaHPO 4 -2H 2 O] cement and subsequent heat treatment.
  • the matrices can be made in moulds with the desired size and shape, modified by erosion, or pulverisation.
  • the matrices can incorporate other bioactive agents that promote bone regeneration.
  • the present invention refers to a new synthetic biomaterial for bone regeneration and tissue engineering in dental surgery and traumatology based on monetite [CaHPO 4 ] solids in the form of porous granules or matrices generated by the conversion of a synthetic material of brushite [CaHPO 4 -2H 2 O].
  • the material is easily applied to the patient and has demonstrated to be highly osteoinductive.
  • the material in its most simple form avoids the use of other polymers and reagents, and can be produced in a sterile in a granular form or as preformed matrices.
  • a first aspect is referred to a synthetic monetite matrix (CaHPO 4 ) characterised by having a crystal size of between 0.5 and 25 microns.
  • CaHPO 4 synthetic monetite matrix
  • induced porosity between 0 and 20% and more preferably with a total porosity between 35-60%.
  • the production method for these matrices incorporates the following steps.
  • the solid phase comprises a first component that includes a basic calcium phosphate, as for example [alpha]- tricalcium phosphate, [beta]-tricalcium phosphate, hydroxyapatite, tetracalcium phosphate, octacalcium phosphate and/or calcium oxide; and a second component that includes an acid calcium phosphate, as for example monocalcium phosphate unhydrate or monocalcium phosphate monohydrate.
  • the solid component can also incorporate additives to control the setting time of the cement so that, at 25 0 C, the setting time is between 1 and 300 minutes, and preferably between 1 and 20 minutes.
  • additives include, with out restriction, sodium pyrophosphate, calcium pyrophosphate, potassium pyrophosphate, strontium chloride, strontium renalate, strontium pyrophosphate, sodium acetate, potassium acetate, sodium citrate, potassium citrate, sodium phosphocitrate, potassium phosphor citrate, sodium sulphate, potassium sulphate, calcium sulphate hemihydrate, sodium dihydrogen pyrophosphate, magnesium sulphate, sodium bisphosphonate, potassium bisphosphonate, chondroitin 4- sulphate, chondroitin 6-sulphate, glycolic acid, sodium glycolate, and/or calcium glycolate.
  • Barium salts such as barium titanate, sulfate, or fluoride, can be incorporated as additives to control the setting time of the cement, and can
  • the liquid phase can incorporate an acid that includes, with out restriction, phosphoric, glycolic, tartaric, citric, succinic, malic, lactic, hydrochloric and/or sulphuric acid at a concentration between 0.5 y 3.5 M.
  • the components of the cement can also include additives that increase the porosity of the resulting matrix through the liberation of gas during the setting process, as for example, and with out restriction, calcium carbonate, calcium bicarbonate, sodium bicarbonate, or hydrogen peroxide, or other salts.
  • porosity of the resulting matrix can also be increased by means of the incorporation to the cement of additives that following setting and dissolution result in the formation of pores.
  • additives include, with out restriction, organic or inorganic salts, sugars, sugar alcohols, aminoacids, proteins, polysaccharides or polymers.
  • the cement may also incorporate additives to control the rheology of the cement.
  • additives comprise, with out limitation, chondroitin A- sulfate, chondroitin 6-sulfate, a silica gel, a silica gel with chondroitin 4- sulfate, a silica gel with chondroitin 6-sulfate, strontium chloride, strontium renalate, and any salt containing strontium, sodium pyrophosphate calcium pyrophosphate and or any salt or acid containing pyrophosphate groups.
  • Biocompatible agents such as, and with out restriction, collagen, chitosan, albumin, fibronectin, hyaluronic acid, hyaluronate salts, dextran, alginate, xanthan gum or celluloses, can also be incorporated to control the rheology of the cement. Specially, it can incorporate high molecular weight hyaluronic acid.
  • the liquid phase can also contain additives to control the cohesion of the cement which can be selected between chondroitin 4-sulfate, chondroitin
  • the concentration of the chondroitin 4-sulfate and the chondroitin 6-sulfate in the liquid phase is between 1 and 6% while the concentration of the silica gel can be between 1 and 15g/L.
  • the powder components are mixed with the liquid phase in a proportion powder (grams) to liquid (ml) that can be between 0.2 and 10 g/ml, preferably between 1 and 3 g/ml.
  • a paste is formed that subsequently sets and solidifies to form a material which consists mainly of brushite (dicalcium phosphate dihydrate or CaHPO 4 ⁇ H 2 O).
  • the cement can be made to set in moulds with the desired final shape of the cement block, as granules, rods, sheets, sponges, or other shapes.
  • the set brushite cement in a second step, can be pulverised in the form of granules, or its shape adapted to the intended use by fragmentation, abrasion, or filing.
  • the size of the granules may be between 0.05 and 4.0 mm.
  • Preferably the size of the granules is in the range between 0.2 and
  • the set brushite cement is converted to monetite by means of thermal treatment between 80 y 300 0 C during a period between 5 minutes and 12 hours, and a relative humidity between 0 y 100%.
  • the temperature is selected between 121 and 160 0 C and is applied for 20 minutes to 2 hours. Under appropriate conditions, this process allows to obtain sterile monetite matrices.
  • the proportion of calcium to phosphorous of the monetite matrix varies between 1 and 1.7.
  • the resulting material can have an acid pH.
  • the material can be washed with buffer solutions or distilled water for a period up to 4 days.
  • the buffer solutions can be phosphate buffers, citrate buffer, Hank ' s medium, and/or any buffer solution with a pH between 6 and 8. This washing process can be carried out before and/or after the thermal treatment.
  • the monetite matrices can be combined with bioactive agents that favour the bone regeneration process such as for example, growth factors, hormones, polysaccharides, cells, proteins, peptides, antiinfectives, analgesics, antiinflamatory agents, antibiotics, antigens, or any of their combinations thereof.
  • bioactive agents that favour the bone regeneration process such as for example, growth factors, hormones, polysaccharides, cells, proteins, peptides, antiinfectives, analgesics, antiinflamatory agents, antibiotics, antigens, or any of their combinations thereof.
  • the growth factors include, with out restriction, platelet derived growth factor platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), bone morphogenic proteins (BMP), transforming growth factor-beta-1 (TGF- ⁇ - 1 ), growth hormone (GH), insulin like growth factor-1 (IGF1 ), insulin like growth factor-2 (IGF2), fibroblast growth factor (FGF) or any of their combinations thereof.
  • PDGF platelet derived growth factor platelet derived growth factor
  • VEGF vascular endothelial growth factor
  • BMP bone morphogenic proteins
  • TGF- ⁇ - 1 growth hormone
  • GH growth hormone
  • IGF1 insulin like growth factor-1
  • IGF2 insulin like growth factor-2
  • FGF fibroblast growth factor
  • the proteins include, with out restriction, collagen, fibronectin, albumin or any of their combinations thereof.
  • undefined media can also be incorporated to promote bone regeneration, such as, with out restriction, blood, serum or plasma.
  • stabilising agents such as trehalose, sucrose, raffinose, manitol, albumin or collagen can be added to the solution containing the bioactive.
  • bioactive agents that can be incorporated to the monetite is strontium that, as previously described, can be incorporated to the cement as an additive to control the setting time.
  • strontium as any of its salts and in concentrations up to 10%, permits that blocks, granules, rods, sponges or pellets can be employed in the treatment of osteoporosis.
  • Blocks and granules of monetite resulting from the thermal treatment of synthetic brushite, with different degrees of porosity, and with the optional addition of bioactive agents, are biocompatible, biodegradable and osteoinductive. These materials are an excellent material for the elaboration of alloplastic grafts with application in bone regeneration, periodontal surgery and implant surgery.
  • the granular formulation of monetite facilitates a controlled resorption of the material resulting in improved bone regeneration both quantitatively and qualitatively.
  • blocks refers to a three dimensional monetite or brushite matrix of any shape and size. Blocks can be formed in a mould with a predetermined shape and size, or result from the erosion, abrasion or crushing of a three dimensional matrix for obtainment of the desired shape and size.
  • the cement described in the present invention has a special interest and application in the elaboration of materials for multiple treatments in bone regeneration with application in traumatology surgery, maxillofacial surgery, periodontal surgery, orthognatic surgery, oral surgery, neurosurgery, palatine fissure treatment, periodontal treatment, treatment of dental conducts, treatment of osteoporotic bone, and alveolar regeneration and horizontal alveolar regeneration, or bone regeneration.
  • bone regeneration matrices comprising the synthetic monetite matrix as described above and their use in therapy.
  • Figure 1 X-ray diffraction spectra of the synthetic matrix demonstrating phase change from brushite (A) to monetite (B) by thermal treatment (y axis: intensity in arbitrary units; x axis: theta 2 angle).
  • FIG. 1 Scanning electron micrographs of the synthetic matrices demonstrating the change in crystalline structure form brushite (A) to monetite (B) after thermal treatment.
  • the white bar indicates 10 ⁇ m.
  • FIG. 4 Biopsy from a rabbit calvarium following grafting with granules of brushite (A) and monetite (B). The bone defect grafted with monetite granules resulted in increased bone regeneration.
  • Figure 5 Optic micrograph of bone defect in a rabbit treated with monetite granules. Complete regeneration of the defect, in black remaining monetite granules surrounded by newly formed bone marked with crosses on grey areas.
  • Figure 7 Inherent nanoporosity of synthetic monetite crystals as measured by mercury porosimeter.
  • EXAMPLE 1 Osteoinduction with monetite granules produced from brushite cements.
  • the brushite and monetite granules obtained were applied separately to a bone regeneration model. Cavities 1 cm in diameter in rabbit calvaria were filled with 0,25 g of the bone inducing materials to be evaluated, that is monetite or brushite. After 4 weeks, post-mortem analysis of the animals demonstrated a higher bone density and larger amount of mineral tissue, and increased resorbtion and tissue increase, in the defects that were made to contain the monetite granules (See Figures 4 and 5).
  • EXAMPLE 2 Monetite granules that incorporate strontium chloride as a regulator of the rheology of the brushite cement from which they are made of.
  • the brushite matrices were washed in a phosphate buffer pH 7.4 for 2 days to neutralise their acid pH. To induce the conversion from brushite to monetite and sterilize the material, the resulting brushite blocks were thermally treated in dry heat for 2 hours at 160 0 C. The resulting granules were implanted in the calvaria of New Zeeland rabbits were they demonstrated the capacity to regenerate bone.
  • EXAMPLE 4 Monetite granules that incorporate hialuronic acid as a modulator of the rheology of the brushite cement from which they are made of.
  • the resulting brushite blocks were thermally treated in dry heat for 2 hours at 160 0 C.
  • the resulting granules were implanted in the calvaria of New Zeeland rabbits were they demonstrated the capacity to regenerate bone.
  • EXAMPLE 6 Monetite granules containing doxicyclin.
  • the brushite granules were thermally treated for 20 minutes in the autoclave at 121 0 C, 1 bar of pressure and a relative humidity of 100%. Part of the material was soaked in a sterile 0.5% collagen solution containing fibroblast growth factor (FGF) and 10% trehalose and was after left to dry by evaporation in a laminar airflow cabinet. Trehalose was added to avoid possible degradation of the FGF during the drying process and subsequent storage at room temperature waiting to perform cell based assays. Granules were added to a tissue culture plate previously seeded with a human fibroblast cell line (MRC-5) in a serum-free medium. After 72 hours fibroblasts were found to preferentially colonise the FGF containing material.
  • FGF fibroblast growth factor
  • EXAMPLE 8 Preformed porous monetite blocks embedded in collagen and populated by osteoblasts.
  • the material was then washed in an aqueous 0.01% collagen solution in Dulbecco's Minimum Essential Medium (DMEM) for 6 hours at 37 0 C and then washed with fresh DMEM.
  • DMEM Dulbecco's Minimum Essential Medium
  • the material was then exposed to suspensions of 3*10 5 rat bone marrow derived mesenchymal stem cells previously enriched for 4 passages in osteogenic-supplemented medium (DMEM + 15% Foetal Calf Serum + 100 nM dexamethasone, 50 ug/mL L-ascorbic acid-2-phosphate). After 5 days of culture in osteogenic-suplemented medium osteoblasts were found to be adhered to the granules. The cell-populated materials were implanted in bone defects in rats were they demonstrated their capacity to regenerate bone.
  • DMEM Dulbecco's Minimum Essential Medium
  • EXAMPLE 9 Comparative Bone regeneration capabilities of different monetite granules.
  • Monetite samples have an inherent nanoporosity (broadly defined as 5 - 5,000 nanometre pores) of 30-40% of volume due to the nanometric spaces between the mineral crystals (see Figure 7).
  • material porosity broadly defined as the space occupied by the larger 5 - 1 ,000 micron pores, was optimized for improved cell in-growth capacity and bone induction.
  • monetite granules with different porosities were manufactured by means of incorporating different amounts of sodium bicarbonate in the powder reaction mixture of cement leading to the formation of brushite.
  • rabbit bone marrow stromal stem cells in the presence of the monetite granules. Briefly, rabbit femur bone marrow was harvested and suspended in 10ml of minimum essential medium with Earle's salt, and glutamine and nonessential amino acid (E-MEM). The medium was supplemented with 1 mM sodium pyruvate, 1.5 g/L sodium bicarbonate, 60 mg/mL kanamycin sulfate and 15% fetal calf serum. Bone marrow suspensions were aliquoted and to them 0.5 g of the granular material was added.
  • E-MEM glutamine and nonessential amino acid
  • EXAMPLE 10 Bone regeneration capabilities of monetite granules tested in human patients.
  • Monetite granules were produced by mixing 0.8 g of calcium monophosphate anhydrous and 1.4 g of [beta]-tricalcium phosphate and to the mixture 1 ml/g of a 1 M solution of phosphoric acid was added. Once the cement was set, the brushite solid was pulverised and sieved to obtain a particle size between 0.2 and 2 mm. The resulting brushite granules were treated for 30 minutes in the autoclave at 121 0 C, 1 bar of pressure and a relative humidity of 100%, resulting in their conversion to monetite.
  • metal implants were implanted following standard periodontal surgical procedures. Briefly, the gum of patients was cut open to permit the implantation of metal screw-on fixtures. Locations treated with monetite showed a bone-like appearance while locations treated with the commercial bovine hydroxyapatite retained a granular structure similar to the day it was implanted. The drill used to perforate the newly formed bone for subsequent implantation was hollow to permit the extraction of a biopsy for subsequent analysis. Metal implants were inserted at the drill points and the gum was re-sutured.

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Abstract

La présente invention concerne des matrices de monétite synthétiques de différents degrés de porosité et leur application en régénération osseuse. Ces matrices sont produites à partir d'un ciment de brushite obtenu par mélange d'une phase solide contenant un phosphate de calcium basique et un phosphate de calcium acide, et l'incorporation d'une phase aqueuse. La matrice de brushite solide obtenue est ensuite convertie en monétite par traitement à la chaleur. Ces matrices de monétite synthétiques peuvent être transformées en granules ou en pièces préformées de porosités différentes, et peuvent être conçues pour incorporer des agents biologiques actifs qui stimulent la formation osseuse.
PCT/EP2008/058694 2007-10-15 2008-07-04 Matrices de monétite et leur application en régénération osseuse WO2009077210A1 (fr)

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WO2011065987A1 (fr) * 2009-11-25 2011-06-03 Healionics Corporation Granules de matériaux poreux biocompatibles
US8591645B2 (en) 2011-09-09 2013-11-26 Ossdsign Ab Hydraulic cements with optimized grain size distribution, methods, articles and kits
US8647393B2 (en) 2009-11-25 2014-02-11 Healionics Corporation Implantable medical devices having microporous surface layers and method for reducing foreign body response to the same
US8709149B2 (en) 2008-11-12 2014-04-29 Ossdsign Ab Hydraulic cements, methods and products
US20140120149A1 (en) * 2012-10-30 2014-05-01 The Royal Institution For The Advancement Of Learning/Mcgill University Calcium sulphate based composite
EP2647609A3 (fr) * 2012-04-02 2014-05-14 Evonik Industries AG Peptides riches en glutamine en tant qu'entraîneurs d'air dans des matéraux de construction
WO2014091469A1 (fr) * 2012-12-14 2014-06-19 Ossdsign Ab Compositions formant un ciment, ciments de monétite, implants et procédés permettant de corriger les défauts osseux
CN103933608A (zh) * 2014-04-23 2014-07-23 浙江大学 一种仿生结构人工骨及其制备方法
US8795377B2 (en) 2010-03-10 2014-08-05 Ossdsign Ab Implants and methods for correcting tissue defects
US9463046B2 (en) 2011-08-22 2016-10-11 Ossdsign Ab Implants and methods for using such implants to fill holes in bone tissue
US9676665B2 (en) 2011-09-09 2017-06-13 Ossdsign Ab Storage stable premixed hydraulic cement compositions, cements, methods, and articles
US10076416B2 (en) 2013-02-12 2018-09-18 Ossdsign Ab Mosaic implants, kits and methods for correcting bone defects
CN109331223A (zh) * 2018-09-25 2019-02-15 广州润虹医药科技股份有限公司 一种载药生物活性玻璃复合磷酸钙骨水泥及其应用
CN109381744A (zh) * 2018-09-14 2019-02-26 广州润虹医药科技股份有限公司 一种磷酸钙基骨修复支架及其制备方法
US10881519B2 (en) 2014-08-14 2021-01-05 Ossdsign Ab Bone implants for correcting bone defects
CN115887779A (zh) * 2022-09-21 2023-04-04 苏州大学 一种高强度-抗溃散透钙磷石水泥制备方法及其应用

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US8506985B2 (en) 2009-02-10 2013-08-13 Azurebio, S.L. Bone regeneration materials based on combinations of monetite and other bioactive calcium and silicon compounds
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WO2010094813A1 (fr) * 2009-02-10 2010-08-26 Azurebio, S. L. Matériau de régénération osseuse formée à partir de combinaisons de monétite avec d'autres composés de calcium bioactifs
US8647393B2 (en) 2009-11-25 2014-02-11 Healionics Corporation Implantable medical devices having microporous surface layers and method for reducing foreign body response to the same
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