WO2009145630A1 - Osteoinductive nanocomposites - Google Patents
Osteoinductive nanocomposites Download PDFInfo
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- WO2009145630A1 WO2009145630A1 PCT/NL2009/050296 NL2009050296W WO2009145630A1 WO 2009145630 A1 WO2009145630 A1 WO 2009145630A1 NL 2009050296 W NL2009050296 W NL 2009050296W WO 2009145630 A1 WO2009145630 A1 WO 2009145630A1
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- calcium phosphate
- nanocrystals
- organic solvent
- composite material
- polymer
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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
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
Definitions
- the invention relates to porous osteoinductive nanocomposite materials and to methods of producing these materials.
- Autologous bone harvested from the patient's own bone is the gold standard bone substitute for repairing large bone defects.
- the amount of autologous bone harvestable from a patient is limited and the bone subtraction itself poses significant health risks and results in loss of structural integrity of the remaining bone.
- synthetic implants for instance in the form of scaffold materials, which allow attachment of bone cells and ingrowth of new bone tissue and subsequent deposition of new bone mineral.
- the synthetic materials may either be grafted ex vivo with bone cells prior to implantation or may be implanted as naked scaffolds that attract bone cells from the periphery to the site of the implant.
- Calcium phosphates such as hydroxyapatite (HA; the mineral phase of bone), biphasic calcium phosphate (BCP) and ⁇ - or ⁇ - tricalcium phosphate (TCP) are known to possess both osteoconductive (bioactive) as well as osteoinductive properties and provide very suitable scaffold materials.
- HA hydroxyapatite
- BCP biphasic calcium phosphate
- TCP tricalcium phosphate
- the bioactive nature of calcium phosphates allows them to function as a template for new bone formation by osteogenic cells through deposition of new mineral material at the scaffold's surface and is an important feature of the scaffold material.
- the osteoinductive nature of calcium phosphates is a qualitative feature, i.e.
- Bone induction is generally defined as the mechanism by which a mesenchymal tissue is induced to change its cellular structure to become osteogenic.
- Bone formation in scaffolding materials following ectopic implantation is generally a demonstration of osteoinduction of such scaffolding materials.
- porous calcium phosphates have been found to exhibit osteoinductivity.
- porous hydroxyapatite ceramic granules for instance, Yamasaki et at., in Biomaterials 13:308-312 (1992), describe the occurrence of heterotopic ossification (formation of new bone in tissue that does not normally ossify) around porous hydroxyapatite ceramic granules, but not around dense granules.
- the porous granules range in size from 200 to 600 ⁇ m, and have a continuous and interconnected microporosity of which the pores range in diameter from 2 to 10 ⁇ m.
- the present invention describes porous osteoinductive nanocomposites and the methods to make such porous osteoinductive nanocomposites.
- the said porous composites comprise, preferably consist of, biocompatible polymers and amorphous non- stoichiometric calcium phosphate nanocrystals; b. the said calcium phosphate nanocrystals are not heated or sintered at above 100°C; c. in said porous composites the content of said calcium phosphate nanocrystals is above 20% by weight; d. the said porous composites are porous with pores larger than 50 ⁇ m; e. the said porous composites have porosity over than 10%.
- the present invention provides a porous osteoinductive composite material comprising a biocompatible polymer, at least 20 wt.%, based on the weight of the total composition, of calcium phosphate nanocrystals, said composite having a porosity of at least 10% and having pores with a pore size of at least 50 ⁇ m.
- said calcium phosphate nanocrystals have needle-shaped or plate-like crystals having a width of about 5-200 nm, preferably about 10-150 nm.
- said calcium phosphate nanocrystals have needle-shaped or plate-like crystals of which the length is not particularly limiting.
- the present invention thus inter alia provides a porous osteoinductive nanocomposites and for the methods to prepare osteoinductive nanocomposites.
- the osteoinductive composites consist of biocompatible polymers and non-heated (or non- sintered), needle-shaped or plate-like calcium phosphate nanocrystals and the methods preferably comprise the steps of: a. adding phosphate to a calcium solution thereby evoking precipitation of calcium phosphate nanocrystals; b. washing the nanocrystals with water and suspending them in an organic solvent or getting dry calcium phosphate nanocrystals after evaporating organic solvent; c.
- said calcium phosphate nanocrystals are present in said material in an amount of at least 20 wt.%, preferably at least 40 wt.%; In a preferred embodiment of a material of the present invention, said porosity is 30 to 70% and wherein said pore size is 100 to 1000 ⁇ m.
- the present invention provides a method for preparing an osteoinductive composite material, comprising the steps of: a) adding phosphate to a calcium solution thereby evoking precipitation of calcium phosphate nanocrystals; b) washing the calcium phosphate nanocrystals with water and either suspending the nanocrystals in an organic solvent to provide a suspension of calcium phosphate nanocrystals and/or drying said calcium phosphate nanocrystals by evaporating said organic solvent to provide powder of dried calcium phosphate nanocrystals; c) providing a polymer in the form of a polymer solution wherein said polymer is dissolved in an organic solvent capable of dissolving said polymer or providing a meltable polymer in the form of a dry powder; d) mixing the calcium phosphate nanocrystals of step b) with the polymer provided in step c), in order to provide a composite mixture, preferably said mixing is performed by rotational mixing, preferably using beads, to provide a composite material mixture
- the material may also be moulded after setting of the composite, for instance by milling or by cutting, into a desired shape.
- the moulded composite of the present invention may take any shape desirable.
- the calcium phosphate nanocrystals are prepared using a calcium solution comprising not more than 0.5M of Ca, and a phosphate solution comprising not more than 0.5M of P at a reaction rate equivalent to the production of 1 gram of nanocrystals per minute.
- the dry calcium phosphate nanocrystals are obtained through dehydration with organic agents, such as acetone and ethanol.
- step c) is dissolved in the same organic solvent as used for the calcium phosphate in step b).
- said porogenic agent is in the form of particles selected from the group consisting of salts (NaCl, KCl, CaCb, sodium tartrate, sodium citrate and the like), biocompatible mono- and disaccharides (glucose, fructose, dextrose, maltose, lactose, sucrose), polysaccharides (starch, alginate, pectin) and water soluble proteins (gelatine, agarose), more preferably wherein said porogenic agent is NaCl.
- salts NaCl, KCl, CaCb, sodium tartrate, sodium citrate and the like
- biocompatible mono- and disaccharides glucose, fructose, dextrose, maltose, lactose, sucrose
- polysaccharides starch, alginate, pectin
- water soluble proteins gelatine, agarose
- the organic solvent is chosen from the group consisting of ethanol, ethyl formate, hexafluoro-2-propanol (HFIP), cyclic ethers (i.e. tetrahydrofuran (THF), and 2,5-dimethylfuran (DMF)), acetone, acetates of C2 to C5 alcohol (such as ethyl acetate and butyl acetate), glyme or dimethoxyethane (i.e.
- butanone dipropyleneglycol methyl ether
- lactones such as ⁇ -valerolactone, ⁇ -valerolactone, b- butyrolactone, g-butyrolactone
- 1,4-dioxane 1,3-dioxolane
- ethylene carbonate dimethylcarbonate, diethylcarbonate
- benzene toluene
- benzyl alcohol p-xylene
- N-methyl-2- pyrrolidone dimethylformamide
- chloroform i.e.
- trichloromethane methyl trichloride
- DCM 1,2-dichloromethane
- morpholine dimethylsulfoxide (DMSO)
- DMSO dimethylsulfoxide
- HFAS hexafluoroacetone sesquihydrate
- anisole i.e. methoxybenzene
- the organic solvent is acetone.
- hydroxymethyl cellulose carboxymethyl cellulose, hydroxypropylmethyl cellulose
- chitosan alginate, collagen, chitin, glycogen, starch, keratins, polypepetides or combinations or mixtures thereof.
- the polymer is chosen from PLA, PCL or copolymers thereof.
- the calcium phosphate is in the form of amorphous non- stoichiometric calcium phosphate nano-crystals with Ca/P ratio of 1.0-2.0, preferably 1.50 to 1.67 and more preferably 1.67.
- a method of the present invention as described above for preparing a material according to the present invention as described above.
- the present invention provides an osteoinductive composite according to the present invention as described above, produced by the methods according to the present invention as described above.
- the present invention provides the use of the osteoinductive composite material according to the present invention as described above for the induction of bone formation in a living organism.
- the present invention provides the use of the osteoinductive composite material according to the present invention as described above as an implant material alone or combined with growth factors or/and cells for the production of autologous bone in a non-osseous site.
- the present invention provides the use of the osteoinductive composite material according to the present invention as described above for the production of a medical implant or device alone or combined with growth factors or/and cells.
- Uses of the invention are particularly beneficial in dental surgery and/or for the reconstruction of bone
- amorphous non- stoichiometric calcium phosphate nanocrystals is used to refer to non- hydroxyl apatite (HA) materials, which are typically sintered (heated) materials wherein the crystals are aligned, in stead of the random crystals obtained in amorphous crystals.
- HA hydroxyl apatite
- the calcium phosphate is obtained preferably through precipitation at temperatures below 100°C, preferably below 80°C.
- the composite then has as a feature that it exhibits high mechanical strength, it is bioactive, bone bonding, and may show resorption of the CaP part in vivo.
- One of said methods for the production of the nanocomposite of the present invention may comprise the steps of: a.
- phosphate to a calcium solution thereby evoking precipitation of nano- scaled amorphous non- stoichiometric calcium phosphate crystals, optionally washing calcium phosphate crystals, preferably with distilled water, optionally filter or sieve to selected size range; b. suspending them in an organic solvent; c. adding a polymer (previously dissolved in an organic solvent); d. mixing the components, preferably by rotational mixing using beads; e. adding porogenic agents to the composites and uniformly mix; f. optionally moulding the composite material; g. evaporation of the organic solvent; and h. leaching the porogenic agents in water.
- the amorphous non- stoichiometric calcium phosphate crystals can suitably be dried through vacuum filtration in order to get a cake of calcium phosphate crystals.
- the cake of calcium phosphate crystals can be dehydrated by washing the cake with an organic solvent (preferably at least 10 times).
- the polymer is preferably chosen from the group consisting of polyesters, polylactic acid or polylactide (PLA), polyglycolide (PGA), copolymers of PLA and PGA, polycaprolactone (PCL) and copolymers based on PCL, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylee oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), poly (methyl vinyl ether), poly(maleic anhydride), polyvinyl alcohol, and copolymers, terpolymers, natural polymers such as celluloses (i.e.
- the calcium phosphate is in the form of amorphous non- stoichiometric nano-crystals with Ca/P ratio of 1.0 to 2.0 preferably with a Ca/P ratio of 1.67.
- the calcium phosphate is not a hydroxyapatite, with which is meant that produced by heating, i.e. that it is not a sintered (heated to >900°C) calcium phosphate and also not a calcined (heated to between 100-900°C) calcium phosphate, and that the crustal structure is 58phous.
- the crystals of the calcium phosphate preferably have a width of about 5-200 nm, more preferably about 10-150 nm.
- the length of the crystals is not particularly limited.
- the content in apatite of said composite is higher than 20% (by weight of the composite), more preferably higher than 40% (by weight of the composite).
- the invention comprises an osteoinductive composite material produced by the methods according to the invention.
- the material of the present invention is characterized in that it exhibits osteoinductive capacity, meaning that when a culture of osteoblastic cells is exposed to the material, the cells will express alkaline phosphatase activity and form bone apatite.
- a further part of the invention is the use of said osteoinductive composite material for the induction of bone formation ectopically in a living organism.
- the osteoinductive composite material according to the invention is used as an implant material alone or combined with growth factors or/and cells for the production of autologous bone in a non-osseous site. In such a way the osteoinductive composite material according to the invention can be used for the production of a medical implant or device alone or combined with growth factors or/and cells.
- One of the areas where such an osteoinductive composite material can be applied is the field of dentistry.
- Fig. 1 Measurement of calcium phosphate nanocrystals.
- Fig. 2 Left, composite porous particles. Right, BSEM image showing the distribution of apatite nanocrystals in the polymer
- FIG. 3 Overview of the stained sections after 12 weeks implantation. As it can be seen, the bone formation occurred only in 40CaP composites. The arrows indicate the formed bone.
- FIG. 4 Left, bone induction in 40CaP after 12 weeks of intramuscular implantation. Right, fluorescent image showing that bone formation started between 6 and 9 weeks after implantation (C, calcein). DETAILED DESCRIPTION OF THE INVENTION
- a calcium phosphate material or calcium phosphate composite in aspects of the present invention may be based on any calcium phosphate (CaP), such as a CaP obtained by precipitation from an aqueous solution at low temperature (e.g. 20-80°C) or by a high temperature (thermal) process (but preferably not higher than 100°C.
- CaP calcium phosphate
- Highly preferred calcium phosphates are the calcium orthophosphates.
- the term "calcium orthophosphate” as used herein refers to a family of compounds, each of which contains a calcium cation, Ca 2+ , and a phosphate anion, PO4 3 .
- calcium orthophosphates including monocalcium orthophosphate (monobasic), dicalcium orthophosphate (dibasic), tricalcium orthophosphate (tribasic), and hydroxyapatite (penta calcium triphosphate).
- calcium pyrophosphates e.g., dicalcium diphosphate (Ca2P2 ⁇ 7, synonym: calcium pyrophosphate), calcium pyrophosphate dihydrate (CPPD, Ca2P2 ⁇ 7.2H2 ⁇ ). and calcium dihydrogen diphosphate (CaH2P2 ⁇ 7; synonyms: acid calcium pyrophosphate, monocalcium dihydrogen pyrophosphate)), and polyphosphate ((CaP2 ⁇ e)n, n> 2; synonyms: calcium metaphosphates, calcium polymetaphosphates), and combinations of the various phosphates.
- Ca2P2 ⁇ 7 dicalcium diphosphate
- CPPD calcium pyrophosphate dihydrate
- Ca2P2 ⁇ 7.2H2 ⁇ calcium dihydrogen diphosphate
- CaH2P2 ⁇ 7 synonyms: acid calcium pyrophosphate, monocalcium dihydrogen pyrophosphate
- polyphosphate ((CaP2 ⁇ e)n, n> 2; synonyms: calcium metaphosphates,
- Non-lJmiiing examples of the calcium phosphate compound that may be used in aspects of the invention are:
- MCPA monocalcium phosphate anhydrous
- the calcium phosphates used in methods of the present invention are nanocrystals and are preferably obtained by precipitation from a solution comprising suitable calcium and phosphate sources.
- suitable calcium source is Ca(NOs) 2 -4H 2 O.
- a suitable phosphate source is (NH 4 ) 2 HPO 4 .
- ammonia may be used.
- calcium phosphates nanocrystals may be obtained by other methods, such as by milling and/or sieving of calcium phosphates microparticles. However, the preparation of calcium phosphates nanocrystals by precipitation is most preferred.
- the calcium phosphates particularly in case they are derived from natural sources, may be calcined prior to use as used in most of the applications.
- Preparation of osteoinductive material of the invention which preferably used as an implant in living tissue should mimic the way by which living organs produce mineralized tissues, the calcium phosphate is therefore preferably not sintered or heated.
- the osteoinductive material is preferably both sufficiently compatible and sufficiently biodegradable for use as an implant in living tissue.
- the calcium phosphate on which the osteoinductive material is based is preferably (bio)resorbable, meaning that it exhibits chemical dissolution and cell-mediated resorption when placed in a mammalian body.
- An osteoinductive material according to the invention is preferably based on any calcium phosphates having Ca/P ration of 1.0-2.0 or combinations thereof.
- An osteoinductive material according to the invention is most preferably based on a calcium phosphate having Ca/P ratio of 1.50 to 1.67.
- Synthetic polymers provide for very suitable organic scaffold materials. Advantages of such polymers include the ability to tailor mechanical properties and degradation kinetics to suit various applications. Synthetic polymers are also attractive because they can be fabricated into various shapes with desired pore morphologic features conducive to tissue in-growth. Furthermore, polymers can be designed with chemical functional groups that can induce tissue in-growth. Numerous synthetic polymers can be used to prepare synthetic polymer-comprising scaffolds useful in methods of the invention. They may be obtained from sources such as Sigma Chemical Co., St. Louis, Mo., Polysciences, Warrenton, Pa., Aldrich, Milwaukee, Wis., Fluka, Ronkonkoma, N. Y., and BioRad, Richmond, Calif.
- Representative synthetic polymers include alkyl cellulose, cellulose esters, cellulose ethers, hydroxyalkyl celluloses, nitrocelluloses, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyalkylenes, polyamides, polyanhydrides, polycarbonates, polyesters, polyglycolides, polymers of acrylic and methacrylic esters, polyorthoesters, polyphosphazenes, polysiloxanes, polyurethanes, polyvinyl alcohols, polyvinyl esters, polyvinyl ethers, polyvinyl halides, polyvinylpyrrolidone, and blends and copolymers of the above.
- the scaffold may comprise both oligomers and polymers of the above.
- these broad classes of polymers include poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly (methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly (ethylene oxide), poly (ethylene terephthalate), poly (vinyl alcohols), poly(vinyl acetate), poly(vinyl chloride), polystyrene, polyurethane, poly(lactic acid), poly(butyric acid), poly(valeric acid), poly[lactide-co-glycolide], poly(fum
- the polymers used in scaffolds may be non-biodegradable.
- preferred non-biodegradable polymers include ethylene vinyl acetate, poly(meth)acrylic acid, polyamides, and copolymers and mixtures thereof.
- Polymers used in scaffolds may also be biodegradable.
- the rate of degradation of the biodegradable scaffolds is determined by factors such as configurational structure, copolymer ratio, crystallinity, molecular weight, morphology, stresses, amount of residual monomer, porosity and site of implantation. The skilled person will be able to choose the combination of factors and characteristics such that the rate of degradation is optimized.
- biodegradable polymers include synthetic polymers such as polyesters, polyanhydrides, poly(ortho)esters, polyurethanes, siloxane-based polyurethanes, poly(butyric acid), tyrosine-based polycarbonates, and natural polymers and polymers derived therefrom such as albumin, alginate, casein, chitin, chitosan, collagen, dextran, elastin, proteoglycans, gelatin and other hydrophilic proteins, glutin, zein and other prolamines and hydrophobic proteins, starch and other polysaccharides including cellulose and derivatives thereof (e.g.
- the foregoing materials may be used alone, as physical mixtures (blends), or as a co-polymer.
- the most preferred polymers are polyesters, polyanhydrides, polystyrenes and blends thereof.
- the polyesters and polyanhydrides are advantageous due to their ease of degradation by hydrolysis of ester linkage, degradation products being resorbed through the metabolic pathways of the body in some cases and because of their potential to tailor the structure to alter degradation rates.
- Some disadvantages of these polymers in prior art tissue engineering applications are their release of acidic degradation products and its effect on the regenerating tissue. By using a method of the present invention, this disadvantage is essentially overcome.
- the mechanical properties of the biodegradable material are preferably selected such that early degradation, i.e. degradation prior to sufficient regeneration of the desired tissue, and concomitant loss of mechanical strength is prevented.
- Preferred biodegradable polyesters are for instance poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly(glycolic-co-lactic acid) (PGLA), poly(dioxanone), poly(caprolactone) (PCL), poly(3-hydroxybutyrate) (PHB), poly(3-hydroxyvalerate) (PHV), poly(lactide-co-caprolactone) (PLCL), poly(valerolactone) (PVL), poly(tartronic acid), poly( ⁇ -malonic acid), poly(propylene fumarate) (PPF) (preferably photo cross-linkable), poly(ethylene glycol)/poly(lactic acid) (PELA) block copolymer, poly(L-lactic acid- ⁇ -caprolactone) copolymer, and poly(lactide)-poly(ethylene glycol) copolymers.
- PGA poly(glycolic acid)
- PLA poly(lactic acid)
- PGLA poly(glycolic-co
- Preferred biodegradable poly anhydrides are for instance poly[l,6-bis(carboxyphenoxy)hexane], poly(fumaric-co-sebacic)acid or P(FA:SA), and such polyanhydrides may be used in the form of copolymers with polyimides or poly(anhydrides-co-imides) such as poly-[trimellitylimidoglycine-co-bis(carboxyphenoxy)hexane], poly[pyromellitylimidoalanine-co-l,6-bis(carboph-enoxy)-hexane], poly[sebacic acid-co-l,6-bis(p-carboxyphenoxy)hexane] or P(SA:CPH) and poly[sebacic acid-co-l,3-bis(p-carboxyphenoxy)propane] or P(SA:CPP).
- Poly(anhydride-co-imides) have significantly improved mechanical properties over polyanhydrides, particularly compressive
- biocompatible materials are biocompatible materials that are accepted by the tissue surface.
- the broad term biocompatible includes also nontoxicity, noncarcinogenity, chemical inertness, and stability of the material in the living body.
- Examplary biocompatible materials are titanium, alumina, zirconia, stainless steel, cobalt and alloys thereof and ceramic materials derived thereform such as ZrO2 and/or AI2O3.
- ceramic materials derived thereform such as ZrO2 and/or AI2O3.
- Almost all metallic implants and ceramics are bioinert, meaning that a dense fibrous tissue of variable thickness will encapsulate the scaffold, which prevents proper distribution of stresses and may cause loosening of the implant. Therefore, in specific applications bioactive materials are preferably used. Such materials result in the formation of an interfacial bond between the scaffold and the surrounding tissue.
- CaP calcium phosphate matrices
- HA hydroxyapatite
- CaP sintered hydroxyapatite and bioactive glasses or ceramics, such as 45S5 Bioglass® (US Biomaterials Corp, USA), and apatite- and wollastonite-containing glass- ceramic (glass-ceramic A-W), that form bone-like apatite on their surfaces in the living body and thereby bond to the living bone, exhibit high bioactivity and biocompatibility and are therefore also very suitable for use in the present invention.
- Hydroxyapatite has the advantage that it is osteoconductive, which term refers to the materials ability to guide bone formation and bond to bone.
- a subclass of calcium phosphates which comprise specific arrangements of surface microporosity and micro-architecture have been described as being osteoinductive, which term refers to the materials ability to induce bone cell growth.
- Very suitable matrix materials are the combined materials such as osteoinductive hydroxyapatite/tricalcium phosphate (HA/TCP) matrices, preferably biphasic calcium phosphate (BCP).
- H/TCP osteoinductive hydroxyapatite/tricalcium phosphate
- BCP biphasic calcium phosphate
- inorganic and ceramic materials are in principle brittle and hence primarily find their application in non-load bearing functions.
- Such materials may be combined with polymers in order to produce a composite with mechanical properties analogous to bone and a bioactive character.
- suitable composite materials are for instance hydroxyapatite coatings on titanium-based implants, layered double hydroxide nanocomposites, HA reinforced with high- density polyethylene, plasma sprayed HA/Zr ⁇ 2 composite coatings, oxide ceramics with calcium phosphate coatings, glass hydroxyapatite coatings on titanium, and polydimethylsiloxane (PDMS)-Ti ⁇ 2 hybrid optionally treated with hot water.
- PDMS polydimethylsiloxane
- All of the above scaffold materials may be used in different forms such as in the form of blocks, foams, sponges, granules, cements, implant coatings, composite components and may for instance be combined organic/inorganic materials or ceramics and may be from various origins, natural, biological or synthetic.
- the various forms may for instance be obtained by extrusion, injection moulding, solvent casting, particular leaching methods, compression moulding and rapid prototyping such as 3D Printing, Multi-phase Jet Solidification, and Fused Deposition Modeling (FDM) of the materials.
- a suitable cement may for instance be used as a injectable (bone) scaffold material and may upon hardening and vascularization later be loaded with the cells.
- a cement may for instance comprise hydroxyapatite (HA) nanocrystals in combination with a curable polymer.
- the scaffold will generally be implanted by surgery.
- the surgical procedures to implant the scaffold may be similar to the procedures that are normally used by the skilled surgeon when implanting other types of scaffolds.
- the nanocomposite of the present invention may be porous or dense, but is preferably porous.
- the composite material is macroporous, with pore size ranging from 10-1000 ⁇ m, preferably of 50-500 ⁇ m, more preferably 3-400 ⁇ m.
- the total porosity may for instance range from 10 to 90%, preferably from 30 to 70%. Porosity can be achieved by the composite itself, but also by adding a porogenic compound when manufacturing the composite.
- the effective amount that can be comprised in a calcium phosphate material before it becomes toxic depends in many cases on the rate of release and thus on the stability of the calcium phosphate matrix in the body. Less stable calcium phosphate matrices will degrade more rapidly, releasing larger amounts of trace elements per unit of time and can hold lower effective amounts of trace elements than do more stable matrices.
- An advantage in the case of ceramics, comprising ratios of compounds with different stability, is that the stability of the ceramic can be varied by varying the amounts of the various compounds. This allows for adjustment of the desired release-rates of trace elements from the calcium phosphate material.
- the glass balls loading volume represented 1/3 of the whole volume of the ball mill chamber.
- the rotation speed of the system was 12 rpm. After evaporation of acetone and leaching of NaCl with distilled water porous bodies were obtained.
- SBF simulated body fluid
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CA2729449A CA2729449A1 (en) | 2008-05-27 | 2009-05-27 | Osteoinductive nanocomposites |
US12/994,933 US9272071B2 (en) | 2008-05-27 | 2009-05-27 | Osteoinductive nanocomposites |
EP09755087A EP2296720B1 (en) | 2008-05-27 | 2009-05-27 | Osteoinductive nanocomposites |
AU2009251989A AU2009251989B2 (en) | 2008-05-27 | 2009-05-27 | Osteoinductive nanocomposites |
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EP08157009A EP2127689A1 (en) | 2008-05-27 | 2008-05-27 | Novel homogenous osteoinductive nanocomposites |
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DE102010036039A1 (en) * | 2010-08-31 | 2012-03-01 | Gottfried Wilhelm Leibniz Universität Hannover | Coating for medical implants and coated medical implants |
EP3354665B9 (en) | 2011-06-02 | 2022-08-03 | Massachusetts Institute of Technology | Modified alginates for cell encapsulation and cell therapy |
BR102012004682A2 (en) * | 2012-03-01 | 2013-10-22 | Bioactive Biomateriais Ltda | BIO-RESORVABLE AND BIOACTIVE THREE-DIMENSIVE POROS MATERIAL AND THE OBTAINING PROCESS |
RU2531377C2 (en) * | 2012-12-14 | 2014-10-20 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Method for preparing calcium pyrophosphate porous ceramics |
NL2011195C2 (en) | 2013-07-18 | 2015-01-21 | Xpand Biotechnology B V | Method for producing an osteoinductive calcium phosphate and products thus obtained. |
CN112999429B (en) | 2014-08-01 | 2022-07-22 | 麻省理工学院 | Modified alginates for anti-fibrotic materials and uses |
US10238507B2 (en) | 2015-01-12 | 2019-03-26 | Surgentec, Llc | Bone graft delivery system and method for using same |
WO2016140626A1 (en) * | 2015-03-04 | 2016-09-09 | Agency For Science, Technology And Research | Composite material for drug delivery |
RU2018120104A (en) | 2015-11-01 | 2019-12-02 | Массачусетс Инститьют Оф Текнолоджи | MODIFIED ALGINATES AS ANTI-FIBROUS MATERIALS AND THEIR APPLICATION |
KR102558416B1 (en) * | 2015-11-01 | 2023-07-24 | 메사추세츠 인스티튜트 오브 테크놀로지 | Substances with improved properties |
CN107261214A (en) * | 2017-06-08 | 2017-10-20 | 暨南大学 | A kind of bone renovating material of the acetate containing agarose and preparation method thereof |
US11318231B2 (en) | 2017-11-06 | 2022-05-03 | Massachusetts Institute Of Technology | Anti-inflammatory coatings to improve biocompatibility of neurological implants |
US11116647B2 (en) | 2018-04-13 | 2021-09-14 | Surgentec, Llc | Bone graft delivery system and method for using same |
US10687828B2 (en) | 2018-04-13 | 2020-06-23 | Surgentec, Llc | Bone graft delivery system and method for using same |
GB202111039D0 (en) * | 2021-07-30 | 2021-09-15 | Promimic Ab | Materials and methods |
CN114668891B (en) * | 2021-11-30 | 2022-10-25 | 北京工业大学 | Phosphate-mediated apatite self-assembly method and application thereof |
CN114569732B (en) * | 2022-01-24 | 2023-09-01 | 国家纳米科学中心 | Nanometer medicine and its prepn and application |
CN114870092B (en) * | 2022-05-20 | 2023-08-22 | 广州骊贝生物科技有限公司 | Bone substitute complex, preparation method and application thereof |
CN115006609A (en) * | 2022-05-24 | 2022-09-06 | 曹建中 | Degradable material suitable for pre-operation preparation of fracture internal fixation and preparation method and application thereof |
CN115040690B (en) * | 2022-07-14 | 2023-09-19 | 滨州医学院 | Conductive porous bone tissue engineering scaffold, preparation method and application |
CN115845129A (en) * | 2022-12-06 | 2023-03-28 | 浙江大学 | Manufacturing process of large-size myocardial patch |
CN116446176A (en) * | 2022-12-23 | 2023-07-18 | 威高集团有限公司 | Functional carbon fiber for orthopedic implant, preparation method thereof, composite material for implant comprising functional carbon fiber and preparation method of composite material |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020115742A1 (en) * | 2001-02-22 | 2002-08-22 | Trieu Hai H. | Bioactive nanocomposites and methods for their use |
US20030180344A1 (en) * | 2002-02-05 | 2003-09-25 | Cambridge Scientific, Inc. | Bioresorbable osteoconductive compositions for bone regeneration |
EP1520593A1 (en) * | 2003-09-30 | 2005-04-06 | ADC Advanced Dental Care GmbH & CO KG | Method for producing bone substitution material |
US20070156238A1 (en) * | 2005-12-29 | 2007-07-05 | Industrial Technology Research Institute | Multi-layered matrix, method of tissue repair using the same, and multi-layered implant prepared thereof |
WO2007103372A2 (en) * | 2006-03-06 | 2007-09-13 | Nano Orthopedics, Llc | Plga/hydroxyapatite composite biomaterial and method of making the same |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1106861C (en) * | 2000-05-19 | 2003-04-30 | 清华大学 | Preparation method of nanometer phase calcium-phosphorus salt/collagen/polylactic acid bone composite material |
US6616742B2 (en) * | 2001-08-30 | 2003-09-09 | Cana Lab Corporation | Process for preparing a paste from calcium phosphate cement |
-
2008
- 2008-05-27 EP EP08157009A patent/EP2127689A1/en not_active Withdrawn
-
2009
- 2009-05-27 US US12/994,933 patent/US9272071B2/en active Active
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020115742A1 (en) * | 2001-02-22 | 2002-08-22 | Trieu Hai H. | Bioactive nanocomposites and methods for their use |
US20030180344A1 (en) * | 2002-02-05 | 2003-09-25 | Cambridge Scientific, Inc. | Bioresorbable osteoconductive compositions for bone regeneration |
EP1520593A1 (en) * | 2003-09-30 | 2005-04-06 | ADC Advanced Dental Care GmbH & CO KG | Method for producing bone substitution material |
US20070156238A1 (en) * | 2005-12-29 | 2007-07-05 | Industrial Technology Research Institute | Multi-layered matrix, method of tissue repair using the same, and multi-layered implant prepared thereof |
WO2007103372A2 (en) * | 2006-03-06 | 2007-09-13 | Nano Orthopedics, Llc | Plga/hydroxyapatite composite biomaterial and method of making the same |
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US20110111004A1 (en) | 2011-05-12 |
EP2296720A1 (en) | 2011-03-23 |
AU2009251989A1 (en) | 2009-12-03 |
EP2127689A1 (en) | 2009-12-02 |
US9272071B2 (en) | 2016-03-01 |
CA2729449A1 (en) | 2009-12-03 |
EP2296720B1 (en) | 2013-04-03 |
AU2009251989B2 (en) | 2014-02-20 |
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