EP2512536A1 - Ciment osseux à base de phosphate de calcium, procédé pour sa préparation et utilisations associées - Google Patents

Ciment osseux à base de phosphate de calcium, procédé pour sa préparation et utilisations associées

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Publication number
EP2512536A1
EP2512536A1 EP10807669A EP10807669A EP2512536A1 EP 2512536 A1 EP2512536 A1 EP 2512536A1 EP 10807669 A EP10807669 A EP 10807669A EP 10807669 A EP10807669 A EP 10807669A EP 2512536 A1 EP2512536 A1 EP 2512536A1
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EP
European Patent Office
Prior art keywords
bone cement
comprised
better still
bone
calcium phosphate
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EP10807669A
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German (de)
English (en)
Inventor
Luisa Merello
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Individual
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Individual
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Publication of EP2512536A1 publication Critical patent/EP2512536A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0036—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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

Definitions

  • the present invention concerns a calcium phosphate bone cement buffered at physiological pH, with macro and microporosities , interconnected and capable of being modulated between them, of re-absorbability in vivo foreseeable and/or programmable and of interesting mechanical properties, a process, and its variants, for its preparation and the uses thereof, preferably in orthopaedic and maxillofacial surgery, to fill bone cavities, defects and/or discontinuities, preferably in the form of injectable paste or of preformed bone substitute.
  • the bone cements are materials currently object of great interest as biomaterials for the engineering of the bone tissue, due to the interesting combination of their physical-chemical, technological and biological properties.
  • a bone cement In order to be advantageously used, a bone cement must possess structural and functional characteristics such as to allow it to help and, preferably, accelerate the natural endogenous formation of new bone tissue.
  • the ideal bone cement should: a) provide a structural support that is temporary (that is, it must deteriorate as the bone tissue regenerates), but with mechanical properties correspondent to those required by the bone defect to be filled;
  • calcium phosphate cements are obtained by mixing one or more than one powders of different types of calcium phosphates with an appropriate quantity of an appropriate liquid phase, both appropriately formulated and in a definite weight ratio.
  • the dissolution reactions in the said liquid phase of the initial products (solids) and of precipitation of the final resulting product/s (defined, as a whole, as "setting" reactions) that are activated at the end of the said mixing process are temporarily overlapped and are responsible for the progressive and deep physical-chemical and rheological evolution of the system even if, from the thermal point of view, they always involve only moderate heat release: this renders the calcium phosphate cements realizable in simil-physiological conditions, and custom- made or modellable according to the site to be filled.
  • the bone cement looks like a solid and, from the microstructural point of view, like an assembly of polycrystallites with domains of . micro-nanometric dimensions, of a predominantly amorphous structure, constituted, as a way of non-limiting example, by
  • the pH of the reaction environment determines the type of cement obtainable: for example, brushite is obtained from formulations of cement set at pH values inferior to about 4,2, while hydroxyapatite is obtained from pH neutral-alkaline formulations.
  • the bone cements can be prepared at the moment of the application in the operating room (modellable or injectable cements), but today already pre-formed solid cements are being studied also, to be modelled/shaped/adapted appropriately to the application site before the implantation. Up to this day, the inventor does not know of the existence of available pre-formed cements like commercial products.
  • the known/commercial pre-formed products are constituted of calcium phosphate ceramics, obtained by means of an expensive process of sintering, generally produced in the form of blocks of different dimensions to be shaped at the moment of the use or of granules to be used as fillers of small bone cavities.
  • the known calcium phosphate bone cements present a series of technological-functional advantages, such as for example:
  • the calcium phosphate bone cements known are microporous solids not interconnected having an average diameter of the pores comprised between 1 ⁇ and 8 ⁇ and have a total porosity comprised in average between 30% and 50%. Consequently, the superficial area can arrive also up to 100 m 2 /g.
  • a functionally efficient bone cement should be characterized at least by a macro/microporous structure, with empty spaces formed by pores and channels interconnected between them, and by a pH close to neutrality.
  • the known cements provide mechanical performances widely variable, in relation to the formulative and process characteristics.
  • the brushite cements realize resistance values to the compression that can be compared to the values that can be reached by the sponged bone (10 Mpa)
  • the apatite ones come close to those of the cortical bone (100 MPa) . It can be asserted, therefore, that the mechanical performances of the cements are still on average insufficient to guarantee the cement itself to be able to support heavy loads, in analogy with the bone tissue.
  • the calcium phosphate cements degrade more easily calcium phosphate ceramics because they can offer the exposed tissues a greater surface, hot being sinterized; however, the re-absorption modalities differ significantly for the various types of cements.
  • the apatite cements are reabsorbed much more slowly than the brushite cements, because, in itself, the apatite is much less dissoluble than the brushite in tissue fluids; moreover, they result also less quickly phagocytized with respect to the brushite cements and the type of phagocytes involved also changes.
  • the consequence is that the permanence times in vivo of the apatite cements result too long, and so clinically not optimal, even if anyway better than those shown by the ceramic derivatives, while those of the brushite cements result too short.
  • the formulations of the brushite cements known have pH ⁇ 4,2 and the acidity of the cement at tissue level renders the brushite easily precipitable in setting phase but also more easily/too much dissoluble once the setting has taken place, above all in the case in which significant cement volumes more hardly perfusioned by the tissue fluids are used.
  • the magnesium stabilizes the brushite in vivo, inhibiting partially its conversion to apatite, anyway always in an unsatisfying measure from the point of view of a clinic application.
  • the known formulations of the various calcium phosphate bone cements are scarcely satisfying as regards the capacity of adherence to the bone tissue., above all if it is compact.
  • acrylic cements With reference to the acrylic cements, they can release reaction intermediates, or residues, toxic for the organism.
  • the aim of the present invention is that of answering in an adequate manner the need described above.
  • the Applicant has. now unexpectedly found that, by preparing through an appropriate specific process a bone cement comprising at least an appropriate calcium phosphate salt and an appropriate quantity of a chitosan, or of one of its appropriate derivatives, preferably mixed with one or more than one appropriate additives, it is possible to give an adequate answer to the technical problem described above.
  • a bone cement comprising at least a calcium phosphate salt, characterized in that it further comprises an efficient quantity of a chitosan, or of one of its derivatives, mixed with an efficient quantity of at least one stabilizer, as indicated in the independent claim attached.
  • the bone cement of the present invention comprises at least a calcium phosphate salt and is characterized in that it further comprises an efficient quantity of a chitosan, or of one of its derivatives, mixed with at least an efficient quantity of at least one stabilizer.
  • the said bone cement is further characterized in that it presents a highly porous structure, that can be appropriately modulated from about 5-10% (corresponding to the physiological porosity of the compact, bone) to about 50-90% (corresponding to the physiological porosity of the spongy bone) provided with macroporosities and of microporosities interconnected between them; the said macroporosities and microporosities are preferably constituted of pores and channels interconnected between them.
  • the said macroporosities have dimensions comprised on average between about 350 ⁇ and about 900 m; preferably, the macroporosities have dimensions comprised between about 450 pm and about 800 ⁇ ; better still, comprised between about 500 ⁇ and about 700 ⁇ .
  • the said microporosities have dimensions on average comprised between about 50 ⁇ and about 250 ⁇ ; preferably, the microporosities have dimensions comprised between about 75 ⁇ and about 225 ⁇ , better still, comprised between about 100 ⁇ and about 200 ⁇ .
  • the bone cement according to the present invention is further characterized in that it is buffered at a value of physiologic pH of about 7; preferably, comprised between about 6,5 pH and. about 7,5 pH; better still, between about 6,7 pH and about 7,3 pH.
  • the . said chitosan is a low molecular weight chitosan (or LMW) ; eventually, a medium molecular weight chitosan; preferably, the said molecular weight is comprised between 0,5 KDa and 40 KDa; better still, it is comprised between 1 KDa and 20 KDa; better still, comprised between 1 KDa and 10 KDa; better still, comprised between 1 KDa and 5 KDa.
  • the said chitosan LMW is, preferably, provided with a degree of deacetylation comprised between 70% and 90%; better still, comprised between 75% and 85%.
  • the preferred derivatives of the chitosan are to be selected, just as a way of non limiting example, from: phosphate chitosan; and/or chitosan cross-linked physically with sodium tripolyphosphate (TPP acronym) and/or with sodium sulfate; and/or chitosan fragments; and/or mixtures of it with polymers, such as collagen, hydroxypropyl methylcellulose, and/or with Mg salts, for example MgHP0 4 .3H 2 0 (Newbervite) , MgS0 4 .
  • TPP acronym sodium tripolyphosphate
  • Mg salts for example MgHP0 4 .3H 2 0 (Newbervite) , MgS0 4 .
  • the said at least one stabilizer is selected from the group comprising: ⁇ -glycerophosphate ( ⁇ -GP acronym) ; polyimine; polyhydric alcohol, triethylene glycol, glycerol, sorbitol, glucose, polyethylene glycol, sodium tripolyphosphate (TPP acronym) , sodium sulfate, chloride ions, such as CaCl 2 ; preferably, ⁇ - glycerophosphate .
  • ⁇ -glycerophosphate ⁇ -GP acronym
  • polyimine polyhydric alcohol, triethylene glycol, glycerol, sorbitol, glucose, polyethylene glycol, sodium tripolyphosphate (TPP acronym) , sodium sulfate, chloride ions, such as CaCl 2 ; preferably, ⁇ - glycerophosphate .
  • the bone cement according to the present invention further comprises an efficient quantity of at least one porogenous substance.
  • the said porogenous substance is preferably selected from the group comprising: a calcium, sodium, magnesium, ferrum phosphate salt; effervescent mixtures NaHCC>3 + citric acid; tartaric acid, ascorbic acid; preferably, a calcium sulfate salt; effervescent mixtures NaHC0 3 + citric acid; better still, calcium sulfate hemihydrate (CaS0 4 .1/2H 2 0, CSH acronym) .
  • the bone cement according to the present invention further comprises an efficient quantity of at least one pH correcting substance.
  • the said pH correcting substance is preferably selected from the group comprising: K 2 HPO 4 , acids and buffer systems biocompatible with pKa around neutrality, for example comprising: sodium carbonate, potassium, ammonium, magnesium, hydrochloric acid, potassium chlorides, calcium, ammonium, magnesium, stannose, sulfuric acid, sodium sulfates, potassium, calcium, ammonium, magnesium, cupric, aluminum, aluminum and sodium, aluminum and potassium, aluminum and ammonium, sodium hydroxides, potassium, calcium, ammonium, magnesium, calcium oxides, magnesium, sodium ferrocyanide, potassium, calcium, dicalcium pyrophosphate, sodium and aluminum acid phosphate, bone phosphate, calcium and sodium polyphosphate, calcium, aluminum, silicon dioxide, sodium silicates, calcium, magnesium, sodium and aluminum, potassium and aluminum, calcium and aluminum, agalite, bentonite, kaolin (aluminum silicate
  • the bone cement according to the present invention further comprises an efficient quantity of at least one additive selected from: retardants/plasticizants, such as citric acid, citrate sodium, citrate magnesium, pyrophosphate sodium, preferably, citrate sodium; and/or plasticizant s , such as triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, trioctyl citrate, acetyl trioctyl citrate, triesyl citrate, acetyl triesyl citrate, butyril triesyl citrate, trimetyl citrate; and/or dehydrators, such as sodium, magnesium, calcium, ferrum sulfates, preferably sodium sulfate, magnesium sulfate, calcium sulfate, better still, sodium sulfate; and/or, antioxidants such as melatonin; and/or at least a substance
  • the bone cement described above has shown to possess good cohesive characteristics and adheres easily to the surrounding bone tissue; the said properties can be further increased with the addition of phospholipids. It is also possible to add an appropriate quantity of ions Cu ++ to increase the stability of the brushite at neutral pH.
  • the said process comprises at least a passage a) wherein an appropriate quantity of a solid phase, at least comprising an efficient quantity of a mixture of at least two calcium phosphate salts in powder, is put in contact/made to react, in appropriate conditions, with an efficient quantity of a liquid phase constituted of a fluid gel, substantially neutral, comprising at least an efficient quantity of a low molecular weight chitosan, eventually a medium molecular weight chitosan, or of one of its derivatives, mixed with an efficient quantity of at least one stabilizing or neutralizing substance.
  • the said solid phase is preferably obtained by mixing intimately the two following calcium phosphate salts: ⁇ -tri-calcium phosphate (Ca 3 (P0 4 ) 2 , ⁇ -TCP acronym), preferably with a degree of purity ⁇ 94%, better still ⁇ 96%; and calcium phosphate monobasic monohydrate (Ca (H 2 P0 4 ) 2 - H 2 0, MCPM acronym), preferably with a degree of purity ⁇ 96%, better still ⁇ 98%.
  • ⁇ -tri-calcium phosphate Ca 3 (P0 4 ) 2 , ⁇ -TCP acronym
  • Ca 3 (P0 4 ) 2 , ⁇ -TCP acronym calcium phosphate monobasic monohydrate
  • Ca (H 2 P0 4 ) 2 - H 2 0, MCPM acronym calcium phosphate monobasic monohydrate
  • the said two calcium phosphate salts are mixed between them, with methods and equipment known in the background art, in a molar relation of about 1:1, better still, of 1:1.
  • the granulometry of the powders can be modulated/classified, for example, through grinding and appropriate sieving, depending on the mechanical properties and on the degree of macroporosities and interconnection that wants to be conferred to the final cement.
  • the granulometry of the powders is maintained below 50 ⁇ , better still, ⁇ 40 ⁇ , better still, ⁇ 35 ym.
  • the said liquid phase consists, preferably, of a fluid gel, buffered at a pH value close to neutrality and stable at room temperature, obtained by mixing appropriately a chitosan, or a phosphate chitosan, having a molecular weight comprised between 1 KDa and 10 KDa and with a degree of deacetylation comprised between 75% and 85%, with an efficient quantity of ⁇ -glycerol phosphate disodium salt ( (H0CH 2 ) 2 CHOPO (ONa) 2 ⁇ xH 2 0, ⁇ -GP acronym) , in the presence of an appropriate quantity of HC1.
  • ⁇ -glycerol phosphate disodium salt (H0CH 2 ) 2 CHOPO (ONa) 2 ⁇ xH 2 0, ⁇ -GP acronym)
  • the chitosan is present in a concentration of about 0,865% in g/100 ml of gel and the ⁇ -GP is present in a concentration of about 32,464% in g/100 ml of gel.
  • the said solid phase (molar mixture 1:1 of ⁇ -TCP and MCPM powders) is mixed at room temperature with the said liquid phase (neutral gel) in a solid (g) /liquid (ml) relation 3:1, to give a cement constituted of brushite.
  • the paste obtained results easily modellable and homogeneous and completely sets in a period of time comprised between about 10 min and about 25 min; preferably, between about 15 min and about 20 min, forming a preformed brushite cement..
  • the desired/necessary macro microporous structure interconnected is obtained by submitting the paste described above to a granulation process to give granules of one or more than one dimensional categories and to a subsequent compaction process during the setting reaction, that is, before it reaches the end.
  • the granules of cement in the setting phase represent the structural unit that allows to custom-made obtain and module the final architecture of the scaffold/cement since their dimensions can be appropriately varied on the basis of the type of product that wants to be realized.
  • the subsequent compaction process of the granules is preferably carried out through isotropic compression sufficient to determine a partial compenetration of the granules, which are welded one with the other once the completion of the setting reaction is obtained.
  • the granules are compacted in a consequential manner so as to form, at the end of the setting, a single cylindrical structure but with macroporosities centrally more evident.
  • the compaction described above takes place through the use of appropriate punches for the sequential compressing machine.
  • the paste is granulated, obtaining granules of two dimensional classes in differentiated times.
  • the first granulated, of average greater dimensions is precompacted forming the simil- spongy core of the scaffold and, subsequently, the second granulated,, finer, is organized and compacted on it, forming the so-called simil-cortical shell, in analogy with the composition of the bone.
  • the pre-formed scaffold results therefore structured in two regions with different porosities, and.
  • the central core is a region with greater average porosity to simulate the spongy bone and be able to concentrate and optimize the processes that lead to the bone regeneration
  • the perypheral shell is a region with minor average porosity to simulate the compact bone and be able to support the physiological load to which it is actually subject to.
  • the said solid phase further comprises an efficient quantity of at least one porogenous substance, in powder, intimately mixed with the said at least two calcium sulfate salts.
  • the said porogenous substance is selected from those described before.
  • the said porogenous substance is preferably represented by a calcium phosphate salt, better still, calcium sulfate hemihydrate (CaS0 4 .1/2H 2 0, CSH acronym) .
  • the said solid phase consists of a mixture of: ⁇ -tri-calcium phosphate ( ⁇ -TCP), preferably with a degree of purity ⁇ 94%, better still ⁇ 96%; calcium phosphate monobasic monohydrate (MCP ) , preferably with a degree of purity ⁇ 96%, better still ⁇ 98%; and calcium sulfate hemihydrate (CSH) with a degree of purity ⁇ 95%, better still > 97%.
  • ⁇ -TCP ⁇ -tri-calcium phosphate
  • MCP calcium phosphate monobasic monohydrate
  • CSH calcium sulfate hemihydrate
  • the said three salts are mixed among them, with methods and equipments known in the background art, in a molar relation, respectively, of about 1:1:2, better still, of.1:1:2.
  • the said liquid phase consists, preferably, of a fluid gel, buffered with a pH value close to neutrality and stable at room temperature, obtained by mixing appropriately a chitosan, or a phosphate chitosan, having a molecular weight comprised between 1 KDa and 10 KDa and with a degree of deacetylation comprised between 75% and 85%, with an efficient quantity of ⁇ -glycerol phosphate dihydrate disodium salt ( (HOCH 2 ) 2 CHOPO (ONa) 2 ⁇ xH 2 0, ⁇ -GP acronym), in the presence of an appropriate quantity of HCl.
  • a fluid gel buffered with a pH value close to neutrality and stable at room temperature, obtained by mixing appropriately a chitosan, or a phosphate chitosan, having a molecular weight comprised between 1 KDa and 10 KDa and with a degree of deacetylation comprised between 75% and 85%, with an efficient quantity of ⁇ -
  • the chitosan is present in a concentration of about 0,865% in g/100 ml of gel and the ⁇ -GP is present in a concentration of about 32,464% in g/100 ml of gel.
  • the said solid phase (molar mixture 1:1:2 of ⁇ -TCP, MCPM, and CSH powders) is mixed at room temperature with the said liquid phase (neutral gel) in a solid (g) /liquid (ml) relation 2:1, to give a cement constituted of brushite and by calcium sulfate dihydrate.
  • the paste obtained results initially fluid and, therefore, directly injectable in the bone cavity/defect to be filled.
  • the acquisition of the final macro/microporous structure interconnected takes place spontaneously: the paste, initially fluid and injectable after a short time (as a rule, some minutes), expands, occupying totally the space wherein it is confined and it is structured porous both inside and on the surface.
  • the said liquid phase described in precedence consisting of a fluid gel, buffered at a pH value close to neutrality and stable at room temperature, is preferably prepared through the process comprising the following passages:
  • the said process further comprises the following passage:
  • K 2 HPO 4 in powder in a quantity sufficient to take and to maintain the pH of the gel at about 7, preferably at 7.
  • K 2 HP0 4 has demonstrated useful also as porogenous .
  • the addition of K2HPO4 has advantageously demonstrated useful also for stabilizing the gel of chitosan, for modifying the rheology of the final product, conferring to it a greater granulability, and for improving the mechanical properties of it, for example the resistance to compression.
  • a quantity of at least one retardant/plasticizer is added to the neutral gel of the present invention.
  • the said retardant /plasticizer is preferably represented by a citrate, such as sodium citrate.
  • sodium citrate at 28% V/V in a concentration comprised between 0,3 M and 2 M; preferably, between 0.5 M and 1,75 ; better still of about 0,5 .
  • an appropriate quantity of at least one antioxidant is added to the neutral gel of the present invention.
  • an appropriate quantity of melatonin that has revealed particularly indicated for protecting the chitosan from the degradation , radio inducted during the sterilization with gamma rays (preferably at 25 Kgy) .
  • the calcium phosphate bone cement according to the present invention has shown to be able to answer advantageously the needs of osteotransductivity ( osteoinductivity and osteoconductivity) , re-absorption and mechanical properties already highlighted in precedence. It is therefore presented as a product advantageously capable of supporting the functions of the lacking bone tissue, without substituting it in a permanent manner, that is osteointegrable .
  • the calcium phosphate bone cement according to the present invention has demonstrated particularly useful and, above all, versatile to fill all types of bone cavities, defects and/or discontinuities, either under the form of injectable paste in the place of the defect, or under the form of pre-formed bone substitute to be modelled and adapted custom-made to the place of the defect itself.
  • the cement of the present invention advantageously finds application on orthopaedic surgery for obtaining constructs to be implanted in even medium-big bone defects, as competitive rival of the present ceramic cements (much more expensive) .
  • the injectable version it is advantageously presented as filler that allows a quick recovery of the posture and mobility and the pain relief of radicular compression in mini-invasive surgery operations of the vertebral column, such as, for example, preventive cifoplasty, vertebroplasty and/or chiroplasty of the fractures of osteoporosis and/or for the prosthetic stabilization in orthopaedic surgery. Thanks to the characteristics of malleability and modellability of the cement of the invention it is also possible to obtain also custom made bone substitutes in orthopaedic and maxillofacial surgery and for crane facial bone defects.
  • the said cement can also be engineered appropriately so as to be used as medicated cement for releasing pharmaceuticals (anti-tumorals, painkillers, antiinflammatories, anti-osteoporosis drugs); they can also be loaded with growing factors for increasing bone regeneration and/or with contrast agents for producing molecular imaging.
  • pharmaceuticals anti-tumorals, painkillers, antiinflammatories, anti-osteoporosis drugs

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Surgery (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Composite Materials (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne un ciment osseux à base de phosphate de calcium tamponné avec un pH physiologique, présentant des macroporosités et des microporosités, reliées entre elles, de réabsorption in vivo prévisible et/ou programmable et présentant des propriétés mécaniques intéressantes, un procédé pour sa préparation et ses utilisations pour combler des cavités, des défauts ou des discontinuités osseux.
EP10807669A 2009-12-17 2010-12-09 Ciment osseux à base de phosphate de calcium, procédé pour sa préparation et utilisations associées Withdrawn EP2512536A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITPI2009A000159A IT1396984B1 (it) 2009-12-17 2009-12-17 Un cemento osseo calciofosfato, procedimento per la sua preparazione e suoi usi
PCT/IB2010/055697 WO2011073860A1 (fr) 2009-12-17 2010-12-09 Ciment osseux à base de phosphate de calcium, procédé pour sa préparation et utilisations associées

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EP2512536A1 true EP2512536A1 (fr) 2012-10-24

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EP (1) EP2512536A1 (fr)
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NL2007850C2 (en) * 2011-11-24 2013-05-27 Stichting Katholieke Univ Injectable calcium phosphate cement comprising glucono-delta-lactone.
CN107296977B (zh) * 2012-01-31 2021-03-23 托莱多大学 可注射的、生物可降解的骨接合剂及其制造和使用方法
CN103656753B (zh) * 2013-12-04 2015-04-22 上海纳米技术及应用国家工程研究中心有限公司 磷酸钙系中性骨水泥及其制备方法
CN105327395B (zh) * 2015-11-19 2018-07-13 上海纳米技术及应用国家工程研究中心有限公司 一种酸性羟基磷灰石催化固化骨水泥的制备方法
CN108635624B (zh) * 2018-04-25 2022-01-04 武汉理工大学 一种抗溃散型可注射的磷酸镁基骨水泥
CN109939261B (zh) * 2019-04-24 2021-06-11 东南大学 一种可调控磷酸钙骨水泥注射性的固化液及其制备方法和应用
CN110960726A (zh) * 2019-11-22 2020-04-07 同济大学 含白磷钙矿的硼硅酸盐生物玻璃基骨水泥制备方法及应用
CN112107732A (zh) * 2020-09-18 2020-12-22 成都理工大学 抗冲刷型高矿化活性复合骨水泥及其制备方法

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US20030158302A1 (en) * 1999-12-09 2003-08-21 Cyric Chaput Mineral-polymer hybrid composition
EP1945233B1 (fr) * 2005-10-21 2017-03-29 Ada Foundation Systemes precurseurs de ciment a deux phases pour reparer des os

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WO2011073860A1 (fr) 2011-06-23
ITPI20090159A1 (it) 2011-06-18
IT1396984B1 (it) 2012-12-20

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