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WO2012101428A1 - Procédé - Google Patents

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Publication number
WO2012101428A1
WO2012101428A1 PCT/GB2012/050136 GB2012050136W WO2012101428A1 WO 2012101428 A1 WO2012101428 A1 WO 2012101428A1 GB 2012050136 W GB2012050136 W GB 2012050136W WO 2012101428 A1 WO2012101428 A1 WO 2012101428A1
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WO
WIPO (PCT)
Prior art keywords
monetite
aqueous phase
calcium salt
solid phase
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2012/050136
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English (en)
Inventor
Sanjukta Deb
Giuseppe CAMA
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Kings College London
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Kings College London
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Filing date
Publication date
Application filed by Kings College London filed Critical Kings College London
Publication of WO2012101428A1 publication Critical patent/WO2012101428A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • 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
    • C04B28/346—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 as a mixture of free acid and 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
    • 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
    • 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
    • C01B25/321—Methods for converting an alkaline earth metal ortho-phosphate into another ortho-phosphate
    • 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
    • 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
    • A61L2430/12—Materials or treatment for tissue regeneration for dental implants 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
    • 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

  • the invention relates to a method of making monetite.
  • Monetite can be used in dentistry, for example, as a bone substitute or as a support or scaffold for bone tissue engineering.
  • the invention also relates to a composition, a cement and a kit which can be used to make monetite. Further, the invention relates to the use of the composition and the cement in surgery or therapy, and a method of treatment which makes use of the method of the invention.
  • Autologous bone grafting is currently considered as the gold standard to restore bone defects. It is generally harvested from the iliac crest and this living bone contains the osteogenic factors that can stimulate bone formation; however, clinical benefits can vary as the cellular components may be damaged during transplantation and harvesting is also associated with donor site morbidity (Banwart (1995); Younger (1989)). Further, complications can occur and it is estimated about 8-39% show varying degrees of problems.
  • Synthetic bone substitutes are being extensively researched to produce a material that is osteoconductive, osteoinductive, has appropriate mechanical properties and has the ability to function as a delivery system for biologies.
  • the bone substitute should have mechanical properties similar to the bone being replaced and should allow cellular ingrowth, support new bone formation and degrade over time so that new bone can replace it.
  • Calcium phosphates have remained the material of choice for developing bone substitutes and or scaffolds for bone tissue engineering (De Groot (1983), Driskells (1973)). Calcium phosphates can be essentially divided into two categories: cements and ceramics. Hydroxyapatite (HA) derived grafts are ceramic in nature and are usually obtained through sintering at temperatures greater than 1000°C. a and ⁇ -tricalcium phosphate ( ⁇ , ⁇ -TCP), sintered hydroxyapatite (SHA) and tetracalcium phosphate are other phases that can be obtained via sintering methods.
  • HA Hydroxyapatite
  • ⁇ , ⁇ -TCP ⁇ -tricalcium phosphate
  • SHA sintered hydroxyapatite
  • tetracalcium phosphate are other phases that can be obtained via sintering methods.
  • grafts examples include Cerabone ® , Endobon ® , ChronOS ® ( ⁇ -tricalcium phosphate), Bone Save ® (composite of HA and TCP) and Actifuse ABX ® (silicate substituted porous HA).
  • Brown and Chow demonstrated that by mixing one or several calcium phosphate powders with a liquid phase, a cement paste could be obtained which had the ability to harden at both room and physiological temperatures.
  • CPCs calcium phosphate cements
  • CPC cements are dense in nature, resorb slowly, are mechanically weak and require additives to promote fracture healing.
  • Some examples of CPC cements in clinical use are Norian SRS (Synthes), Hydroset (Stryker), ChronOSTMInject (Synthes), BoneSource ® (Stryker) and Calcibon ® (Biomet).
  • Calcium phosphate cements are obtained by mixing various calcium phosphate precursor phases with water or aqueous solutions as a result of precipitation of another phase.
  • two types of cement are generally obtained: for pH > 4.2, the reaction product is hydro xyapatite (HA) (Chow (1991)), and for pH ⁇ 4.2, the product is dicalcium phosphate dihydrate (DCPD), also known as brushite (Mirtchie (1989)). Hydroxyapatite based materials have a low resorption rate due to its poor solubility at physiological pH.
  • DCPA dicalcium phosphate anhydrous
  • the hardening process of CPCs is determined by two mechanisms which occur in supersaturated solution via nucleation and crystal growth.
  • the latter is composed of several processes, starting with transport of ions from the bulk solution to the nuclei surface, followed by adsorption on energetically favourable sites.
  • the main products of this process are generally hydroxyapatite (HA) or dicalcium phosphate dihydrate (DCPD), commonly referred to as 'brushite'.
  • HA hydroxyapatite
  • DCPD dicalcium phosphate dihydrate
  • 'brushite' the main products of this process.
  • cements formed at a pH lower than about 4.2 need to be characterized because different phases can precipitate due to various kinetic factors.
  • the most thermodynamically stable phase may not necessarily be the one that precipitates first because its precipitation kinetics
  • monetite as a bone substitute scaffold.
  • Preformed monetite can be obtained by modification of a or ⁇ -TCP blocks immersed in phosphoric acid solution (Laetitia (2008)) or by hydrothermal modification of brushite matrices that are obtained from calcium phosphate cement formulations.
  • One of the main reasons for exploring the monetite phase is due to the fact that brushite in vivo tends to precipitate as insoluble HA slowing its replacement by bone (Tamimi (2009)).
  • monetite is slightly less soluble and appears not to transform to HA.
  • monetite is osteoconductive and resorbable in vivo (Gbureck (2007); Tamimi (2007); Habibovic (2008)), it forms an excellent candidate as a bone graft substitute or as a porous matrix for bone tissue engineering.
  • monetite scaffolds cannot be formed in situ as the process of making monetite requires the chemical conversion of a solid calcium phosphate phase by a hydrothermal process which requires high temperatures, often in excess of 100°C. Therefore, previously, monetite could only be used in the form of a pre-formed scaffold.
  • the inventors have devised a new method for obtaining monetite from chemical formulations typical of hydraulic cements. This method allows monetite to be obtained as the final product of the setting reaction of a hydraulic cement and thus allows the use of monetite as a mouldable and injectable paste to treat bone defects, as well as preformed scaffold or a cell seeded scaffold since it does not require the use of relatively high temperatures.
  • the invention provides a method of making monetite comprising mixing an aqueous phase and a solid phase comprising a basic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion; and forming monetite.
  • the invention provides a method of making monetite comprising mixing an aqueous phase and a solid phase comprising a basic calcium salt and an acidic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion; and forming monetite.
  • the invention provides a method of making monetite comprising mixing an aqueous phase comprising an acid and a retardant with a solid phase comprising a basic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion; and forming monetite.
  • the invention also provides a composition for forming monetite comprising a basic calcium salt, and an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein, when mixed with an aqueous phase, the composition sets to form monetite.
  • the invention provides a composition for forming monetite comprising a basic calcium salt, an acidic calcium salt, and an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein, when mixed with an aqueous phase, the composition sets to form monetite.
  • the invention additionally provides a cement for forming monetite comprising: an aqueous phase; and a solid phase comprising a basic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein the cement sets to form monetite.
  • the invention provides a cement for forming monetite comprising: an aqueous phase; and a solid phase comprising a basic calcium salt and an acidic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein the cement sets to form monetite.
  • the invention provides a cement for forming monetite comprising: an aqueous phase comprising an acid and a retardant; and a solid phase comprising a basic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein the cement sets to form monetite.
  • a cement for forming monetite comprising: an aqueous phase comprising an acid and a retardant; and a solid phase comprising a basic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein the cement sets to form monetite.
  • the invention provides a composition or a cement as described above for use in therapy or surgery.
  • composition and the cement may generally be used in bone regeneration and, in particular, may be used in traumatology surgery, maxillofacial surgery, periodontal surgery, orthognathic 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.
  • the invention provides a kit for forming monetite comprising: a basic calcium salt; and an inorganic salt comprising a mono or divalent metal cation and a halide anion.
  • the invention provides a kit for forming monetite comprising: a basic calcium salt; an acidic calcium salt; and an inorganic salt comprising a mono or divalent metal cation and a halide anion.
  • the invention provides a kit for forming monetite comprising: a basic calcium salt; an acid; a retardant; and an inorganic salt comprising a mono or divalent metal cation and a halide anion.
  • the invention provides a method of treatment comprising administering to a subject an effective amount of a composition comprising a basic calcium salt, and an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein, when mixed with an aqueous phase, the composition sets to form monetite.
  • the invention provides a method of treatment comprising administering to a subject an effective amount of a composition comprising a basic calcium salt, an acidic calcium salt, and an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein, when mixed with an aqueous phase, the composition sets to form monetite.
  • the invention also provides a method of treatment comprising administering to a subject an effective amount of a cement comprising an aqueous phase and a solid phase comprising a basic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein the cement sets to form monetite.
  • the invention provides a method of treatment comprising administering to a subject an effective amount of a cement comprising an aqueous phase and a solid phase comprising a basic calcium salt and an acidic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein the cement sets to form monetite.
  • the invention provides a method of treatment comprising administering to a subject an effective amount of a cement comprising: an aqueous phase comprising an acid and a retardant; and a solid phase comprising a basic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein the cement sets to form monetite.
  • the invention provides a method of making monetite comprising: mixing a solid phase comprising a basic calcium salt with an aqueous phase, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion; and forming monetite.
  • the basic calcium salt and the acidic calcium salt contained in the solid phase react together to form monetite.
  • the method of the invention allows the formation of monetite without the method involving the use of a hydrothermal step requiring high temperatures to produce the monetite, as with previously known methods.
  • the method of the invention allows monetite to be formed at room temperature and under physiological conditions.
  • the presence of the inorganic salt affects the reaction kinetics thereby allowing the production of monetite rather than brashite. This means that monetite can be formed in situ, for example, in a bone cavity in a subject.
  • Monetite is preferred to brushite since it has better physical properties and is osteoconductive and resorbable in vivo.
  • the solid phase comprises the components which react together to form the monetite. Preferably, all the components of the solid phase (including any optional additional components) are fully mixed prior to being mixed with the aqueous phase.
  • the solid phase comprises a basic calcium salt and an acidic calcium salt
  • the solid phase comprises a basic calcium salt and an acidic calcium salt which, when mixed with an aqueous phase, react together to form the monetite.
  • the basic calcium salt may be a basic calcium phosphate.
  • the basic calcium salt may be selected from a-tricalcium phosphate, ⁇ - tricalcium phosphate, hydroxyapatite, tetracalcium phosphate, octacalcium phosphate and calcium oxide.
  • the basic calcium salt is ⁇ -tricalcium phosphate.
  • the acidic calcium salt may be an acidic calcium phosphate.
  • the acidic calcium salt may be selected from monocalcium phosphate anhydrous or monocalcium phosphate monohydrate.
  • the acidic calcium salt is monocalcium phosphate monohydrate.
  • the ratio of the basic calcium salt to the acidic calcium salt in the solid phase may be any suitable ratio which allows the formation of monetite.
  • the molar ratio of the basic calcium salt to the acidic calcium salt may be between 1 :4 and 4: 1, more preferably between 1 :3 and 3: 1, more preferably still between 1 :2 and 2: 1, even more preferably between 1.5: 1 and 1 : 1.5 and, more preferably still between 1.2: 1 and 1 : 1.2. In one embodiment, the molar ratio may be about 1 : 1.
  • the solid phase comprises a basic calcium salt
  • the solid phase comprises a basic calcium salt which, when mixed with an aqueous phase, reacts to form the monetite.
  • the basic calcium salt may be a basic calcium phosphate.
  • the basic calcium salt may be selected from a-tricalcium phosphate, ⁇ -tricalcium phosphate, hydroxyapatite, tetracalcium phosphate, octacalcium phosphate and calcium oxide.
  • the basic calcium salt is ⁇ -tricalcium phosphate.
  • the aqueous phase can be any suitable aqueous liquid which, when mixed with the solid phase, causes the components in the solid phase to react together to form monetite.
  • the aqueous phase may be water or an aqueous solution.
  • the aqueous phase may comprise an acid such as glycolic, tartaric, citric, succinic, malic, lactic, or a salt thereof.
  • the aqueous phase comprises citric acid or a salt thereof such as monosodium citrate or trisodium citrate.
  • the concentration of the acid or salt thereof may be between 0.3M and 4M, preferably between 0.4M and 3M, and more preferably still between 0.5M and 2M.
  • the concentration of the acid or salt thereof is between 0.5M and 1M.
  • the acid is preferably a weak acid.
  • the aqueous phase does not comprise a strong acid such as hydrochloric or sulphuric acid.
  • a strong acid is defined as one having a pK a ⁇ -1.74.
  • the aqueous phase preferably should not comprise phosphoric acid.
  • a strong acid such as hydrochloric or sulphuric acid, or phosphoric acid causes the rapid dissolution of one or both of the calcium salts.
  • this can cause the pH of the solution to drop to a relatively low level.
  • the rapid dissolution and/or relatively low pH of the solution favours fast reaction kinetics in terms of crystal growth which causes the formation of brushite instead of monetite.
  • the aqueous phase should favour slow crystal growth kinetics which allow the formation of monetite rather than brushite.
  • the aqueous phase may comprise a strong acid such as phosphoric acid.
  • the aqueous phase preferably comprises a retardant such as citric acid.
  • the aqueous phase preferably comprises an acid. More preferably, the aqueous phase comprises a strong acid.
  • the strong acid is phosphoric acid.
  • the concentration of the acid is between 0.3M and 4M, more preferably between 0.4M and 3M, even more preferably between 0.5M and 2M and more preferably still between 0.5M and 1.5M. In one embodiment, the concentration of the acid is about 1M and is preferably phosphoric acid.
  • the aqueous phase can act as a retardant solution.
  • the composition can harden to form a solid cement very quickly. This does not allow enough surgical handling time.
  • salt solutions such as citric acid or pyrophosphate ions
  • the aqueous phase preferably comprises a retardant.
  • a retardant is a compound which increases the time it takes for the final product to form. A retardant increases the setting time of the cement, i.e.
  • any suitable retardant can be used.
  • aconitic acid, citric acid or a salt thereof is used as a retardant.
  • citric acid or a salt thereof is used as the retardant.
  • citric acid is used as a retardant.
  • the concentration of the retardant may be between 0.3M and 4M, preferably between 0.3M and 3M, more preferably between 0.3M and 2M, even more preferably between 0.3M and 1M, and more preferably still between 0.3M and 0.7M. In one embodiment, the concentration of the retardant (e.g. citric acid) is about 0.5M.
  • the inorganic salt comprises a mono or divalent metal cation and a halide anion.
  • the mono or divalent metal cation is selected from a group 1 or 2 metal.
  • the metal cation is selected from sodium, potassium, magnesium, calcium and strontium.
  • the metal cation may be a monovalent cation.
  • the metal cation may be selected from a group 1 metal such as sodium or potassium.
  • the halide anion may be selected from fluoride, chloride or bromide.
  • the halide anion is chloride.
  • the inorganic salt is selected from sodium chloride, potassium chloride, magnesium chloride, calcium chloride and strontium chloride. More preferably, the inorganic salt is selected from sodium chloride and potassium chloride.
  • the inorganic salt is sodium chloride. In one embodiment, the inorganic salt is not strontium chloride.
  • the inorganic salt may be contained in the solid phase, aqueous phase or both. In one embodiment, the inorganic salt is contained in the solid phase. In another embodiment, the inorganic salt is contained in the aqueous phase. In yet another embodiment, the inorganic salt is contained in both the aqueous phase and the solid phase.
  • the weight ratio of the inorganic salt relative to the total weight of the basic calcium salt and acidic calcium salt combined may be between 1 : 199 and 4: 1. In some embodiments, the ratio of the inorganic salt relative to the total weight of the basic calcium salt and acidic calcium salt combined may be between 1 : 19 and 7:3, between 1 :2 and 2: 1, between 4:6 and 6:4, or about 1 : 1.
  • the inorganic salt makes up at least about 5% by weight of the composition comprising the calcium salts and inorganic salt.
  • the composition comprises at least about 10% by weight inorganic salt.
  • the composition may comprise at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%o, or at least about 70%o by weight inorganic salt.
  • the weight ratio of the inorganic salt relative to the weight of the basic calcium salt may be between 1 : 199 and 4: 1. In some embodiments, the ratio of the inorganic salt relative to the weight of the basic calcium salt may be between 1 : 19 and 7:3, between 1 :2 and 2: 1, between 1 : 1 and 1 :2, or about 0.6: 1. In one embodiment, the inorganic salt makes up at least about 5%o by weight of the composition comprising the calcium salt and inorganic salt. Preferably, the composition comprises at least about 10% by weight inorganic salt. In some embodiments, the composition may comprise at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%>, or at least about 70%> by weight inorganic salt.
  • the advantage of having the inorganic salt in the solid phase is that it causes formation of pores in the monetite.
  • the degree of porosity of the monetite can be manipulated by varying the salt content of the solid phase.
  • the salt crystals are incorporated into the structure of the monetite during its formation and can subsequently be dissolved out of the monetite to leave pores.
  • the size of the particles of the inorganic salt will have an effect on the size of the pores that are formed in the monetite.
  • the salt is in the form of spherical crystals having a diameter ranging between 10 ⁇ and 900 ⁇ .
  • the salt crystals may have a diameter of between 50 ⁇ and 250 ⁇ or between 100 ⁇ and 200 ⁇ .
  • the presence of interconnecting pores in the monetite matrix advantageously allows cell ingrowth, proliferation and differentiation. Pores, introduced in the microstructure of the monetite, create an osteoconductive matrix which allows cell adhesion, proliferation and bone growth. The size of the pores required depend on cell types used for seeding.
  • the concentration of the inorganic salt may be at least about 1M. In some embodiments, the concentration of the inorganic salt may be at least about 1.5M, 2M, 2.5M, 3M, 3.5M, 4M, 4.5M, or at least about 5M. The concentration may be up to a point where the aqueous phase is saturated with the inorganic salt. The actual concentration of the saturated salt solution will depend on the identity of the inorganic salt. Preferably, the aqueous phase is saturated with respect to the inorganic salt. In one embodiment, a super saturated sodium chloride solution may be used for the conversion to monetite.
  • the solid phase (P) and aqueous phase (L) can be mixed in any suitable way so that formation of monetite takes place.
  • the basic calcium salt and acidic calcium salt are mixed together to form the solid phase before being mixed with the aqueous phase.
  • the ratio of the solid phase to the aqueous phase when mixed together may be between 4: 1 to 1: 1 (P:L). These are weight/volume ratios. The viscosity and thus the injectability can be varied by changing P:L ratios.
  • the ratio of the solid phase to the aqueous phase when mixed together may be between 4: 1 to 1 : 1 (P:L).
  • the ratio of the solid phase to the liquid phase is about 2: 1, wherein the liquid phase preferably comprises phosphoric acid.
  • the method may be carried out under any suitable conditions which allow the formation of monetite.
  • the method is carried out at less than 60°C.
  • the method may be carried out at less than 55°C, less than 50°C, less than 45°C, less than 40°C, less than 35°C, less than 30°C, less than 25°C or less than 20°C.
  • monetite formation takes place at less than 60°C, less than 55°C, less than 50°C, less than 45°C, less than 40°C, less than 35°C, less than 30°C, less than 25°C or less than 20°C.
  • the method is carried out at above 0°C.
  • the method is carried out at above 10°C or above 15°C.
  • monetite formation may take place at about body temperature (about 37°C) and/or at about room temperature (20-25°C).
  • the method is carried out at ambient temperature.
  • the method does not involve a step of heating the components to form monetite.
  • the components are not heated above 60°C, above 55°C, above 50°C, above 45°C, above 40°C, above 35°C, above 30°C, above 25°C or are not heated above 20°C.
  • the components of the method could be heated up to a temperature of about 50-55°C and could still be used in situ in a subject, since it may take 30 seconds or more at such a temperature to cause burns. Therefore, an elevated temperature of up to about 50- 55°C could be used in the method for a short period of time without causing harm to the subject.
  • the method may be carried out at a relative humidity of 30% to 100%.
  • the method should be carried out at a pH which allows the formation of monetite.
  • the method should be carried out at a pH of less than or equal to 5 or, more preferably, less than or equal to 4.2.
  • the method may be carried out at a pH of less than 4.2, 4, 3.5, 3, 2.5 or less than 2.
  • the method is preferably carried out at a pH of at least about 1, 1.5, 2, 2.5, 3 or at least about 3.5.
  • the method is carried out for a period of time which allows the formation of monetite to take place.
  • the setting time When referring to cements used to form monetite, the time that it takes to form the monetite.
  • the amount of time that it takes for the monetite to form and for the cement to set varies.
  • the temperature at which the method is carried out may cause a variation in the setting time, i.e. the time it takes for the formation of monetite.
  • monetite formation takes place in less than 36 hours, less than 30 hours, less than 24 hours, less than 18 hours, less than 12 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, or less than 30 mins.
  • monetite formation takes place in less than 36 hours, less than 30 hours, less than 24 hours, less than 18 hours, less than 12 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, less than 45 mins, or less than 35 mins.
  • the identity of the inorganic salt used in the method may affect the amount of time that it takes for the monetite to form. Therefore, the period of time for which the basic calcium salt and the acidic calcium salt contained in the solid phase must be left, once mixed with the aqueous phase, before they react together to form monetite varies depending on the inorganic salt.
  • the salt is sodium chloride
  • monetite formation occurs relatively quickly so the components of the solid phase only need to be left between about 2 and about 60 minutes before monetite formation takes place.
  • the salt is potassium chloride, calcium chloride or magnesium chloride the components of the solid phase are preferably left for more than about 24 hours to allow monetite formation to take place.
  • the method of the invention allows production of monetite from a basic calcium salt and an acidic calcium salt, or just a basic calcium salt.
  • conversion of the calcium salt(s) to monetite is at least 40%. This means that at least 40%o of the final product is monetite relative to the total amount of calcium compounds in the final product.
  • conversion of the calcium salt(s) to monetite is at least 45%o, at least 50%o, at least 55%o, at least 60%>, at least 65%>, at least 70%>, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or about 100%.
  • a cement paste is formed that hardens, solidifies and then sets to form a material which consists mainly of monetite.
  • the monetite When the monetite is formed, i.e. when it sets, it will be formed into a solid.
  • the monetite may form into a solid matrix.
  • the components can be put into moulds prior to setting so that the monetite forms in a particular shape.
  • the monetite may be formed into blocks, granules, rods, sheets, sponges, pellets or other shapes. Monetite blocks, once formed, may subsequently be pulverised to form granules, or their shape may be adapted to the intended use by fragmentation, abrasion or filing.
  • Cell seeded constructs can be used for bone tissue engineering.
  • the solid phase can also comprise further components as long as the solid phase, when mixed with the aqueous phase, is still capable of reacting to form monetite.
  • the solid phase may further comprise antibiotics or growth factors.
  • additives can be mixed with the solid phase and/or the aqueous phase.
  • additives may be included in the solid phase that increase the porosity of the resulting matrix through the liberation of gas during the setting process, for example, calcium carbonate, calcium bicarbonate, sodium bicarbonate, hydrogen peroxide, or other salts.
  • porosity of the resulting matrix can also be increased by incorporating soluble additives when the solid phase is mixed with the aqueous phase.
  • soluble additives are incorporated into the monetite matrix and can subsequently be dissolved, thereby creating pores where the additives used to present in the matrix.
  • examples of such soluble additives include organic or inorganic salts, sugars, sugar alcohols, amino acids, proteins, polysaccharides or water soluble polymers.
  • the solid phase may also incorporate additives to control the rheology of the components.
  • additives may comprise chondroitin 4-sulphate, chondroitin 6-sulphate, a silica gel, a silica gel with chondroitin 4-sulphate, a silica gel with chondroitin 6-sulphate, strontium chloride, strontium renalate, any salt containing strontium, sodium pyrophosphate, calcium pyrophosphate, and/or any salt or acid containing pyrophosphate groups.
  • Biocompatible agents such as collagen, chitosan, albumin, fibronectin, hyaluronic acid, hyaluronate salts, dextran, alginate, xanthan gum or celluloses can also be incorporated to control the rheology of the components.
  • the solid phase can incorporate high molecular weight hyaluronic acid, chitosan, hydroxypropyl methyl cellulose, polyethylene glycol (PEG) or polyacrylic acid.
  • the aqueous phase can also contain additives to control the cohesion of the components of the solid phase such as chondroitin 4-sulphate, chondroitin 6-sulphate, silica gel, or a combination of silica gel with chondroitin 4-sulphate or chondroitin 6-sulphate.
  • concentration of the chondroitin 4-sulphate and the chondroitin 6-sulphate in the aqueous phase may be between 1 and 6% while the concentration of the silica gel can be between 1 and 15g/L.
  • the monetite matrices once formed, can be combined with bioactive agents that favour the bone regeneration process such as for example, growth factors, hormones, polysaccharides, cells, proteins, peptides, anti-infectives, analgesics, anti-inflammatory agents, antibiotics, antigens, MMP inhibitors or any combination thereof. Incorporation of such agents can be carried out by means of adsorption or immersion in solutions containing the bioactive agent.
  • the growth factors may include platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), bone morphogenic proteins (BMP), transforming growth factor-beta- 1 (TGF- ⁇ - ⁇ ), growth hormone (GH), insulin like growth factor- 1 (IGF1), insulin like growth factor-2 (IGF2), fibroblast growth factor (FGF) or any combination thereof.
  • PDGF platelet derived growth factor
  • VEGF vascular endothelial growth factor
  • BMP bone morphogenic proteins
  • TGF- ⁇ - ⁇ growth hormone
  • IGF1 insulin like growth factor- 1
  • IGF2 insulin like growth factor-2
  • FGF fibroblast growth factor
  • the proteins may include collagen, fibronectin, albumin or any of their combinations thereof.
  • undefined media can also be incorporated to promote bone regeneration, such as 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.
  • strontium or any of its salts and in concentrations up to 10%, permits that blocks, granules, rods, sponges or pellets can be used in the treatment of osteoporosis.
  • the invention also relates to compositions, cements, the use of these compositions and cements, kits and methods of treatment which will be described in detail below.
  • the invention also provides a composition for forming monetite comprising a basic calcium salt, optionally an acidic calcium salt, and an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein, when mixed with an aqueous phase, the composition sets to form monetite.
  • the basic calcium salt may be ⁇ -tricalcium phosphate.
  • the acidic calcium salt may be monocalcium phosphate monohydrate.
  • the inorganic salt may be selected from sodium chloride, potassium chloride, magnesium chloride and calcium chloride.
  • the composition can be mixed with an aqueous phase to form a cement paste which will then harden and set, forming solid monetite.
  • the invention additionally provides a cement for forming monetite comprising: an aqueous phase; and a solid phase comprising a basic calcium salt and optionally an acidic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein the cement sets to form monetite.
  • the basic calcium salt may be ⁇ -tricalcium phosphate.
  • the acidic calcium salt may be monocalcium phosphate monohydrate.
  • the inorganic salt may be selected from sodium chloride, potassium chloride, magnesium chloride and calcium chloride.
  • the aqueous phase may be water or may comprise citric acid, monosodium citrate or trisodium citrate. Since the cement comprises an aqueous phase, it will harden and set, forming solid monetite.
  • the invention provides a kit for forming monetite comprising: a basic calcium salt; optionally an acidic calcium salt; and an inorganic salt comprising a mono or divalent metal cation and a halide anion.
  • the basic calcium salt may be ⁇ -tricalcium phosphate.
  • the acidic calcium salt if present, may be monocalcium phosphate monohydrate.
  • the inorganic salt may be selected from sodium chloride, potassium chloride, magnesium chloride and calcium chloride.
  • the kit of the invention can be used to prepare the composition of the invention or the cement of the invention as described above.
  • the kit may further comprise a further component which can be added to an aqueous liquid to form an aqueous phase for use with the other components of the kit.
  • the kit may further comprise citric acid, monosodium citrate or trisodium citrate.
  • the invention provides a composition or a cement as described above for use in surgery or therapy.
  • the composition and the cement may generally be used in bone regeneration and, in particular, may be used in traumatology surgery, maxillofacial surgery, periodontal surgery, orthognathic 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.
  • the composition and the cement are used in bone regeneration in non-load bearing bones.
  • the invention provides a method of treatment comprising administering to a subject an effective amount of a composition comprising a basic calcium salt, optionally an acidic calcium salt, and an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein, when mixed with an aqueous phase, the composition sets to form monetite.
  • the composition can be administered in any suitable way.
  • the composition may be administered into, for example, a bone cavity in which it is desired to promote bone regeneration.
  • the inorganic salt in the composition will have been incorporated into the monetite, therefore, once the inorganic salt dissolves in the aqueous environment, a porous monetite matrix will remain in the bone cavity. This porous monetite matrix will form a scaffold on which bone regeneration can take place.
  • the method of treatment can further comprise administering an aqueous phase.
  • Preferred properties of the aqueous phase are as described above.
  • the invention also provides a method of treatment comprising administering to a subject an effective amount of an aqueous phase and a solid phase comprising a basic calcium salt and optionally an acidic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein monetite is formed.
  • the solid phase and the aqueous phase can be administered concurrently or sequentially.
  • the solid phase and the aqueous phase are administered concurrently in the form of a cement paste, i.e. a composition in which the solid phase and aqueous phase have been mixed.
  • the invention provides a method of treatment comprising administering to a subject an effective amount of a cement comprising an aqueous phase and a solid phase comprising a basic calcium salt and optionally an acidic calcium salt, wherein the solid phase, aqueous phase or both comprises an inorganic salt comprising a mono or divalent metal cation and a halide anion, and wherein the cement sets to form monetite.
  • the components of the solid phase and the aqueous phase are mixed to form a cement paste which is able to harden and set to form solid monetite.
  • a site of interest in a subject For example, this might be a bone cavity in which it is desired to promote bone regeneration.
  • the cement paste should be administered to the site of interest before it has set. This allows it to be moulded into a shape which is desired in the treatment process.
  • the cement paste can be administered in any suitable way as long as the site of interest is filled or coated with the cement paste in an appropriate manner.
  • the cement paste may be injected into a bone cavity thus taking on the shape of the bone cavity itself.
  • the cement paste will (continue to) harden until it has fully set at which point it will have converted into monetite.
  • the monetite Once the monetite has formed at the site of interest, it can then form a scaffold for and promote bone regeneration.
  • the solid phase comprises the inorganic salt so that the salt is incorporated into the solid monetite thereby creating a porous monetite matrix. This is advantageous in terms of the promotion of bone regeneration.
  • Preferred features of the methods of treatment are as described above with regard to the method of forming monetite.
  • the subject to which the components for forming monetite are administered can be any subject having a skeletal system for which monetite can be used as a bone regeneration scaffold.
  • the subject may be a vertebrate.
  • the subject is a mammal. In one embodiment, the subject is human.
  • Figure 1 shows a comparison between the FTIR spectrum of commercial monetite (bottom spectrum) and the spectrum of cement made using NaCl crystals in the solid phase (top spectrum);
  • Figure 2 shows a comparison among FTIR spectrum of commercial monetite and those of the cements produced at different temperature (23 or 37 ° C) by using as liquid phase a monosodium citrate solution saturated with respect to NaCl crystals;
  • Figure 3 shows a comparison of the FTIR spectra of commercial monetite and cements made using different salts in the base formulation
  • Figure 4 is an XRD pattern of calcium phosphate powders obtained by grinding cement made with NaCl crystals in the base formulation
  • Figure 5 is a graph showing the results of a MTT test wherein the osteoblast like cells were exposed to 100 ml of elution fluid for 24 hrs;
  • Figure 6 is a graph showing the results of a MTT test wherein the osteoblast like cells were exposed to 100 ml of elution fluid for 48 hrs.
  • Figure 7 shows the X-Ray patterns of monetite cements.
  • the monetite references pattern JCPDS00- 009-0080
  • JCPDS00- 009-0080 is shown on the bottom of the figure as spikes extending up from the y-axis.
  • Figure 8 shows the result of a cell proliferation test using the Alamar blue assay.
  • Figure 9 is a scanning electron microscopy image of a monetite cement seeded with human osteoblasts (HOB) after 48 hours.
  • Figure 10 is a scanning electron microscopy image of a monetite cement seeded with human osteoblasts (HOB) after 48 hours.
  • Figure 11 is a scanning electron microscopy image of a monetite cement seeded with human osteoblasts (HOB) after 48 hours.
  • Figure 12 is a scanning electron microscopy image of a monetite cement seeded with human osteoblasts (HOB) after 7 days.
  • Figure 13 is a scanning electron microscopy image of a monetite cement seeded with human osteoblasts (HOB) after 7 days.
  • Figure 14 is a scanning electron microscopy image of a monetite cement seeded with human osteoblasts (HOB) after 7 days.
  • Figure 15 is a scanning electron microscopy image of a monetite cement seeded with human osteoblasts and shows that the cells were able to proliferate and to cover the scaffold surface.
  • Figure 16 is a scanning electron microscopy image of a monetite cement seeded with human osteoblasts and shows that the cells were able to proliferate and to cover the scaffold surface.
  • Figure 17 is a scanning electron microscopy image of a monetite cement seeded with human osteoblasts and shows that the cells were able to proliferate and to cover the scaffold surface.
  • Figure 18 is a graph showing the relative expression of osteogenic markers (Runx-2, alkaline phosphotase (ALP) and osteocalcin (OSC)) at 10 days after seeding.
  • Figure 19 is a graph showing the relative expression of osteogenic markers (Runx-2, alkaline phosphotase (ALP) and osteocalcin (OSC)) at 21 days after seeding.
  • Figure 20 shows the FTIR spectrum of commercial monetite (top) and that obtained using the method of the invention (bottom).
  • Figure 21 shows the FTIR spectra of CPCs made using a solution of NaCl (4mol/L and 5mol/L for cements A and B respectively) in distilled water as the liquid phase.
  • Figure 22 shows the FTIR spectra of CPCs made using a solution of 0.5M sodium citrate also containing 4mol/L (cement D ) or 5mol/L (cement E) NaCl as the liquid phase.
  • Figure 23 shows the FTIR spectra of CPCs made using a liquid phase containing NaCl (6mol/L) in distilled water (cement C) or in 0.5M sodium citrate solution (cement F).
  • Monetite calcium phosphate cements have been produced by manually mixing a solid powder phase with a liquid phase.
  • the solid phases consisting of:
  • the liquid phase can be any of the following:
  • a monosodium citrate solution (CiFLOvNa) with molar concentration ranging between 0.5 and 2 mol/1 where, the solution can optionally be saturated with respect to NaCl;
  • a trisodium citrate solution (C 6 H 5 0 7 Na 3 ) with molar concentration ranging between 0.5 and 2 mol/1 where, the solution can optionally be saturated with respect to NaCl; or
  • the final setting time of the cements made using salts such as MgCi 2 , CaC3 ⁇ 4 and KC1 were found to be longer than 24 hrs. Different concentrations of solid salts were added to the reaction mixture and the conversion occurred at different concentrations for the salts. Higher concentrations yielded better results however the reaction kinetics were slow. Strontium chloride also yielded monetite with concentration of 50% by weight of the calcium phosphate powder (or calcium phosphate powder + salt) and can set within 2 minutes. The test was carried out at normal laboratory atmosphere (20-23°C and 50-60% humidity) and at 37°C.
  • Tablel Setting time of monetite cements made adding NaCl crystals in the solid phase. The results are shown as an average with the standard deviation of the measurements.
  • Table 2 shows the setting time of monetite calcium phosphate cement obtained by mixing the calcium phosphate powders with an aqueous saturated solution of NaCl. Setting temperature 23°C 37°C
  • FIG. 1 A comparison of the FTIR spectra of pure commercial monetite and the monetite cement obtained from the experiments of the addition of salt is shown in Figure 1.
  • the composition of the experimental cement as seen from the spectra is identical and a complete conversion to monetite is observed.
  • the FTIR spectra of monetite are characterized by the O-H in plane bending at 1404 and 1345 cm "1 .
  • the main IR bands characteristic of the phosphate group can be detected at 1128, 1062 and 991 cm "1 due to PO stretching modes of the P(3 ⁇ 4 fragment.
  • the P-O(H) stretching mode is observed at 1630 and 885cm " 1 .
  • the spectrum of the experimental cement shows all the characteristic peaks assigned to monetite [16].
  • F2 ⁇ -TCP + MCMP + sodium chloride crystals + monosodium citrate solution giving rise to monetite.
  • F3 ⁇ -TCP + MCMP + NaCl salt solution + monosodium citrate solution (0.5M) giving rise to monetite.
  • MTT test was performed in order to assess the cytotoxicity of the monetite scaffolds made by using NaCl salts in the base chemical formulation.
  • the biological test is a colorimetric assay measuring the metabolic activity of enzymes that reduce the yellow tetrazolium MTT salts to formazan crystal giving a purple colour. The concentration of the formazan is determined by a spectrophotometric measure with optical density equal to 570nm. The reduction of the MTT, take place only when reductive enzymes are active, and therefore conversion is a measure of viable cells.
  • the graphs shown in Figures 5 and 6 are the results of MTT test wherein the osteoblast like cells were exposed to 100 ml of elution fluid for 24 hrs ( Figure 5) and 48 hrs ( Figure 6) respectively.
  • Elution fluid was obtained by placing monetite samples in HOB medium for 24 and 72 hrs.
  • the optical density measurements of the investigated materials were compared to those obtained for the non -toxic control (Thermanox) and toxic control (media with 10% of alcohol).
  • the material did not show any toxicity effect on the osteoblast viability.
  • Monetite is a cytocompatible material and these tests confirm that the method of production does not alter any of the biological properties.
  • X-Ray analysis Figure 7 shows the X-Ray patterns of a monetite cement made by using a solution of distilled water containing 6M of NaCl salt as the liquid phase (upper pattern) and a solution of monosodium citrate (0.5M).
  • the solid phase for both cements was an equimolar mixture of ⁇ -TCP and MCPC powders.
  • the result described by the lower pattern is for a cement in which the solid phase also contained an amount of NaCl equal to 60% by weight with respect to the calcium phosphate powders (The X-Ray pattern was detected once that the NaCl was dissolved in water by keeping the cement for 3 days in distilled water).
  • the monetite references pattern JCPDSOO-009-0080
  • the results show the main product of the setting reaction is monetite.
  • the Alamar blue assay gives a quantification of the reducing environment of the cells.
  • cells when cells are metabolising they maintain a reducing environment within their cytosol and this reduced state can be measured spectrophotometrically through the conversion of fluorometric/colorimetic REDOX indicators.
  • This application focuses on quantification of the reduction of the intracellular environment by alamarBlue®.
  • the reducing environment of the cells in the alamarBlue® assay is measured through the conversion of resazurin (oxidised form) to resorufin (reduced form). This results in colorimetric (absorbance) and fluorescence changes.
  • Figure 8 shows the result of the cell proliferation test.
  • Human osteoblasts HOB
  • HOB Human osteoblasts
  • the same amount of cells was seeded on the surface of plastic control scaffolds (thermanox).
  • the assay was performed after 3, 7, 14 and 21 days from the seeding of the cells.
  • Figures 9-17 show the images of the monetite cements seeded with human osteoblasts (HOB).
  • Figures 9-14 show the ability of the cells to spread and adhere at the scaffold surface after 48 hrs ( Figures 9-11) and 7 days ( Figures 12-14) from the seeding.
  • Figures 15-17 show that the cells were able to proliferate and to cover the scaffold surface.
  • Osteogenic expression of human osteoblasts was assessed by analysing the changes in expression of osteogenic markers (Runx-2, alkaline phosphotase (ALP) and osteocalcin (OSC)) at 10 ( Figure 18) and 21 ( Figure 19) days from the seeding by qRT-PCR procedure.
  • the results of the osteogenic expression were normalized with respect to the control.
  • Figure 20 shows the FTIR spectrum of commercial monetite (on the top) and that obtained by using a solution of phosphoric acid (H 3 PO 4 , 2M) containing 6M of NaCl crystals and 0.5 M of citric acid as the liquid phase.
  • the liquid phase was mixed with ⁇ -TCP powder in a powder to liquid ratio (R: P/L) equal to 2.
  • CPCs calcium phosphate cements
  • cements were prepared.
  • Cement A, B and C were obtained using distilled water with a molar concentration of NaCl equal to 4M, 5M and 6M respectively.
  • Cements D, E and F were obtained with a liquid phase of 0.5M monosodium citrate solution and also containing 4M, 5M or 6M of NaCl respectively.
  • Figures 21 , 22 and 23 show the FITR spectra of these cements relative to pure monetite.
  • Monetite can also be obtained by using as liquid phase a solution of 0.5M sodium citrate containing 4 mol/L NaCl (cement D, Figure 22). In this case the spectrum is very similar to that of monetite except for the presence of some brushite peaks reported in figure as ⁇ - ⁇ and v-OH mode.
  • a Monetite cement can also be obtained by mixing a solid phase of ⁇ -tricalcium phosphate particles and NaCl crystals with a phosphoric acid solution containing citric acid as a retardant of the setting time. Further, a monetite cement can be obtained as reported above where the NaCl is present in both solid and liquid phase.
  • Monetite cements were made using the following formulations:

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Abstract

L'invention concerne un procédé de fabrication de la monétite qui consiste : à mélanger une phase solide comprenant un sel de calcium basique et éventuellement un sel de calcium acide avec une phase aqueuse : La phase solide, la phase aqueuse ou les deux phases comprennent un sel inorganique comprenant un cation métallique mono ou divalent et un anion halogénure ; et formant la monétite. L'invention concerne également des compositions, des ciments et des trousses permettant de former la monétite, ainsi que l'utilisation de ces compositions et ciments.
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WO2017219654A1 (fr) * 2015-07-01 2017-12-28 李亚屏 Endoprothèse biologique composite à base de sulfate de calcium-phosphate de calcium contenant du magnésium, dégradable, poreuse
DE102016224453A1 (de) 2016-12-08 2018-06-14 Innotere Gmbh Strukturierte mineralische Knochenersatzformkörper
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Publication number Priority date Publication date Assignee Title
DE102013221575B3 (de) * 2013-10-23 2014-10-30 Innotere Gmbh Formstabile Knochenersatzformkörper mit verbleibender hydraulischer Aktivität
US9849211B2 (en) 2013-10-23 2017-12-26 Innotere Gmbh Dimensionally stable molded bone replacement element with residual hydraulic activity
WO2017219654A1 (fr) * 2015-07-01 2017-12-28 李亚屏 Endoprothèse biologique composite à base de sulfate de calcium-phosphate de calcium contenant du magnésium, dégradable, poreuse
US10828396B2 (en) 2015-07-01 2020-11-10 Yaping Li Degradable magnesium-containing calcium phosphate-calcium sulfate porous composite biological scaffold
DE102016224453A1 (de) 2016-12-08 2018-06-14 Innotere Gmbh Strukturierte mineralische Knochenersatzformkörper
DE102016224453B4 (de) 2016-12-08 2019-02-07 Innotere Gmbh Strukturierte mineralische Knochenersatzformkörper
CN109020330A (zh) * 2018-09-04 2018-12-18 东南大学 一种基于废电池原料的导热水泥基复合材料及其制备方法

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