WO2002004606A1 - Utilisation de compositions de verre bioactif pour la stimulation de la production d'osteoblaste - Google Patents

Utilisation de compositions de verre bioactif pour la stimulation de la production d'osteoblaste Download PDF

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Publication number
WO2002004606A1
WO2002004606A1 PCT/US2001/021801 US0121801W WO0204606A1 WO 2002004606 A1 WO2002004606 A1 WO 2002004606A1 US 0121801 W US0121801 W US 0121801W WO 0204606 A1 WO0204606 A1 WO 0204606A1
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Prior art keywords
bioactive glass
ppm
composition
extract
bone
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PCT/US2001/021801
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English (en)
Inventor
Larry L. Hench
Julia M. Polak
Ioannis D. Xynos
Lee D.K. Buttery
Jason Maroothynaden
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Imperial College Innovations
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Application filed by Imperial College Innovations filed Critical Imperial College Innovations
Priority to AU2001280507A priority Critical patent/AU2001280507A1/en
Priority to US10/332,731 priority patent/US20040009598A1/en
Priority to EP01958900A priority patent/EP1311656A4/fr
Priority to CA002414510A priority patent/CA2414510A1/fr
Publication of WO2002004606A1 publication Critical patent/WO2002004606A1/fr

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    • CCHEMISTRY; METALLURGY
    • C03GLASS; MINERAL OR SLAG WOOL
    • C03CCHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
    • C03C12/00Powdered glass; Bead compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02Inorganic materials
    • A61L27/10Ceramics or glasses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02Inorganic materials
    • CCHEMISTRY; METALLURGY
    • C03GLASS; MINERAL OR SLAG WOOL
    • C03CCHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
    • C03C3/00Glass compositions
    • C03C3/04Glass compositions containing silica
    • C03C3/076Glass compositions containing silica with 40% to 90% silica, by weight
    • C03C3/097Glass compositions containing silica with 40% to 90% silica, by weight containing phosphorus, niobium or tantalum
    • CCHEMISTRY; METALLURGY
    • C03GLASS; MINERAL OR SLAG WOOL
    • C03CCHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
    • C03C4/00Compositions for glass with special properties
    • C03C4/0007Compositions for glass with special properties for biologically-compatible glass
    • CCHEMISTRY; METALLURGY
    • C03GLASS; MINERAL OR SLAG WOOL
    • C03CCHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
    • C03C4/00Compositions for glass with special properties
    • C03C4/0007Compositions for glass with special properties for biologically-compatible glass
    • C03C4/0014Biodegradable glass
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0068General culture methods using substrates
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06Animal cells or tissues; Human cells or tissues
    • C12N5/0602Vertebrate cells
    • C12N5/0652Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0654Osteocytes, Osteoblasts, Odontocytes; Bones, Teeth
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/02Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00Supports or coatings for cell culture, characterised by material
    • C12N2533/10Mineral substrates
    • C12N2533/12Glass

Definitions

  • the present invention is generally in the area of methods for repair and reconstruction of bone, cartilage and enhancement of healing of other tissues.
  • Bone is a dense network of collagen protein fibers arranged in layers with crystals of hydrated and carbonated calcium phosphate between the fibers, where about 25% of the weight is calcium.
  • Living cells called osteocytes are arranged in lacunae throughout the bone. Very small blood vessels extend throughout the bone and supply the osteocytes with oxygen and nutrients.
  • the natural process for repairing bone defects involves having osteoclasts remove damaged bone, and then having osteoblast cells lay down new bone.
  • the osteoblasts repeatedly form layers, each consisting of a network of collagen fibers, which produce enzymes resulting in calcium and phosphorus deposition as crystalline hydroxy carbonate apatite until the defect is repaired.
  • Relatively small bone defects can be repaired using bone cements, pins, screws and other devices for mechanical stabilization.
  • Relatively large defects typically require that the missing bone be replaced with a biocompatible material that provides support and which can be immobilized.
  • Bone grafts are often necessary when bone fails to repair itself or when bone loss occurs through fracture or tumor. Bone grafts have to provide mechanical stability and be a source of osteogenesis. Bone grafting is described, for example, in Friedlaender, G. E., "Current Concepts Review: Bone Grafts," Journal of Bone and Joint Surgery, 69A(5), 786-790 (1987). Osteoinduction and osteoconduction are two mechanisms by which a graft may stimulate the growth of new bone.
  • osteoinduction inductive signals lead to the phenotypic conversion of progenitor cells to bone cells.
  • the implant provides a scaffold for bony ingrowth.
  • the bone remodeling cycle is a continuous event involving the resorption of pre-existing bone by osteoclasts and the formation of new bone by the work of osteoblasts.
  • Bony defects are commonly treated using grafts of organic and synthetic construction, typically autografts, allografts, and xenografts.
  • An autograft is tissue transplanted from one site to another in the patient. The benefits of using the patient's tissue are that the graft will not evoke a strong immune response and that the material may or may not be vascularized, which allows for speedy incorporation.
  • using an autograft requires a second surgery, which increases the risk of infection and introduces additional weakness at the harvest site. Further, bone available for grafting may be removed from a limited number of sites, for example the fibula, ribs and iliac crest.
  • An allograft is tissue taken from a different organism of the same species, and a xenograft from an organism of a different species.
  • tissue taken from a different organism of the same species, and a xenograft from an organism of a different species.
  • the latter types of tissue are readily available in larger quantities than autografts, but genetic differences between the donor and recipient may lead to graft rejection.
  • Synthetic materials have also been used, for example titanium and steel alloys, particularly those having a porous structure to allow cellular ingrowth to stabilize the implant, bone cements, alone or mixed with cells, sterilized bone, and polymeric or polymeric/hydroxyapatite implants. All have advantages and disadvantages, yet none provides a perfect replacement for the missing bone. Large defects are particularly difficult to treat.
  • One approach involves using tissue engineering to stimulate production of osteoblasts or bone tissue. It would be advantageous to provide new compositions and methods for stimulating osteoblast production.
  • the present invention provides such compositions and methods.
  • compositions comprising bioactive glass compositions or extracts thereof, which include ions in an appropriate concentration and ratio that they enhance osteoblast production, and methods of preparation and use thereof, are disclosed.
  • compositions can be included in implantable devices that are capable of inducing tissue formation at the implant site, for example as coatings and/or matrix materials.
  • implantable devices that are capable of inducing tissue formation at the implant site, for example as coatings and/or matrix materials.
  • examples of such devices include prosthetic implants, sutures, stents, screws, plates, tubes, and the like.
  • Aqueous extracts of the bioactive glass compositions which extracts are capable of stimulating osteoblast production, are also disclosed.
  • Such extracts can be formed by placing bioactive glass in an aqueous solution, allowing the glass to dissolve over a suitable period of time, for example one day or more, and filtering out the undissolved glass particles.
  • the solvent can also be evaporated to provide a solid material with osteoblast- stimulating properties.
  • the solutions can be prepared by mixing the correct ions in an appropriate concentration rather than by extraction from bioactive glass.
  • compositions can be used, for example, to induce local tissue formation from a progenitor cell in a mammal, for accelerating allograft repair in a mammal, for promoting in vivo integration of an implantable prosthetic device to enhance the bond strength between the prosthesis and the existing target tissue at the joining site, and for treating tissue degenerative conditions in a mammal.
  • compositions and methods for enhancing osteoblast production using the compositions include an osteoblast-stimulating bioactive glass or extract thereof with a ratio and/or concentration of ions that stimulates osteoblast proliferation, differentiation and/or function.
  • a major function of osteoblasts is the formation of new bone or other tissues, such as those involved in the process of membranous or endochondral bone formation. While not wishing to be bound to a particular theory, it is believed that exposure of human osteoblast cells to the ions results in up-regulation of certain cytokines, proteoglycans and/or other proteins such as growth factors that are implicated in the growth, differentiation and control of bone formation in humans.
  • Genes whose expression is enhanced by exposure to the bioactive glass solutions include c-jun and c-myc genes, which are implicated in the early events of cell proliferation and differentiation. In some cases, up-regulation is observed even after 48 hours post- exposure.
  • the genes shown to be upregulated by exposure to the bioactive glass or bioactive glass extract compositions of the invention are involved in: a) signaling to produce proteins responsible for cell binding, b) up-regulation of the osteoblast cell cycle, thus stimulating new cell development, c) enhancing collagen synthesis, and d) controlling apoptosis, thereby increasing the rate of the cell cycle.
  • Exposure to the compositions also increases expression of insulin-like growth factor-II (IGF-II), an abundant mitogenic molecule found in bone which stimulates chondrocyte activity and osteoblast proliferation and differentiation. It is believed to appear earlier in the bone regeneration cycle than bone morphogenic proteins (BMPs).
  • IGF-II insulin-like growth factor-I
  • biocompatible refers to a material that does not elicit detrimental effects associated with the body's various protective systems, such as cell and humoral-associated immune responses, e.g., inflammatory responses and foreign body fibrotic responses.
  • biocompatible also implies that no specific undesirable cytotoxic or systemic effects are caused by the material when it is implanted into the patient.
  • morphogenic activity “inducing activity” and “tissue inductive activity” alternatively refer to the ability of an agent to stimulate a target cell to undergo one or more cell divisions (proliferation) that can optionally lead to cell differentiation.
  • target cells are referred to generically herein as progenitor cells.
  • Cell proliferation is typically characterized by changes in cell cycle regulation and can be detected by a number of means which include measuring DNA synthesis or cellular growth.
  • Early stages of cell differentiation are typically characterized by changes in gene expression patterns relative to those of the progenitor cell, which can be indicative of a commitment towards a particular cell fate or cell type.
  • Later stages of cell differentiation can be characterized by changes in gene expression patterns, cell physiology and morphology. Any reproducible change in gene expression, cell physiology or morphology can be used to assess the initiation and extent of cell differentiation induced by the compositions described herein.
  • bioactive glass or bioactive glass extract compositions described herein when added to cells in culture, were observed to have the following effects:
  • An effective amount of bioactive glass or bioactive glass extract for stimulation of osteoblast production, or osteoblast proliferation, differentiation, function or a combination thereof, will be an amount which will provide at least one of the above-listed effects.
  • compositions include osteoblast-stimulating bioactive glass, preferably in the form of fibers, particles, preferably non-interlinked particles, extracts derived from the bioactive glass, and sols, gels or solids derived from the extracts.
  • the compositions can optionally include other therapeutic agents.
  • bioactive glass or “biologically active glass” mean an inorganic glass material having an oxide of silicon as its major component and which is capable of bonding with growing tissue when reacted with physiological fluids.
  • osteoblast-stimulating refers to bioactive glasses and aqueous extracts thereof with particular ratios and/or concentrations of ions which stimulate osteoblast proliferation, differentiation and/or function.
  • Bioactive glasses are well known to those skilled in the art, and are disclosed, for example, in An Introduction to Bioceramics. L. Hench and J. Wilson, eds. World Scientific, New Jersey (1993).
  • the glass includes a composition by approximate weight percent of between about 42 and 52% by weight of silicon dioxide (Si0 2 ), between about 15 and 25% by weight of sodium oxide (Na 2 0), between about 15 and 25% by weight calcium oxide (CaO), and between about 1 and 9% by weight phosphorus oxide (P 2 0 5 ), when the glass is melt- derived.
  • the glass includes between about 55 and 80% by weight of silicon dioxide (Si0 2 ), between about 0 and 9% by weight of sodium oxide (Na 2 0), between about 10 and 40% by weight calcium oxide (CaO), and between about 3 and 8% by weight phosphorus oxide (P 2 0 5 ), when the glass is sol gel-derived.
  • the oxides can be present as solid solutions or mixed oxides, or as mixtures of oxides.
  • the currently most preferred glass is 45S5 bioglass, which has a composition by weight percentage of approximately 45% Si0 2 ,
  • CaF 2 , B 2 0 3 , A1 2 0 3 , MgO, Ag 2 0, ZnO and K 2 0 can be included in the composition in addition to silicon, sodium, phosphorus and calcium oxides.
  • the preferred range for B 2 0 3 is between 0 and 10% by weight.
  • the preferred range for K 2 0 is between 0 and 8% by weight.
  • the preferred range for MgO is between 0 and 5% by weight.
  • A1 2 0 3 is between 0 and 1.5% by weight.
  • the preferred range for CaF 2 is between 0 and 12.5 % by weight.
  • the preferred range for Ag 2 0 and ZnO is between 0 and 2% by weight.
  • Particulate, non-interlinked bioactive glass is preferred. That is, the glass is in the form of small, discrete particles, rather than a fused matrix of particles or a mesh or fabric
  • the discrete particles of the present invention can tend to cling together because of electrostatic or other forces but are still considered to be non-interlinked.
  • Useful ranges of particle sizes are less than about 1200 microns, typically between 1 and 1000 microns.
  • the particle size range depends on the intended application. In one embodiment, the size range of the particles is about 100 to about 800 microns. In a preferred aspect of the invention, the size range of the particles is about 300 to about 700 microns.
  • the particle size is preferably less than about 90 microns; more preferably, less than about 20 microns; even more preferably, less than about 5 microns, and ideally, less than about 3 microns, as measured by SEM or laser light scattering techniques.
  • Highly porous bioactive glass can also be used, particularly in tissue engineering applications where the high porosity can be useful in matrix materials for cell culture.
  • Highly porous bioactive glass has a relatively fast degradation rate and high surface area, in comparison to non-porous bioactive glass compositions.
  • the pore size is between about 0 and 500 ⁇ m, preferably between about 50 and 500 ⁇ m, more preferably between 100 and 400 ⁇ m.
  • the degree of porosity of the glass is between about 0 and 85 %, preferably between about 30 and 80 %, and more preferably between about 40 and 60 %.
  • Porous bioactive glass can be prepared, for example, by incorporating a leachable substance into the bioactive glass composition, and leaching the substance out of the glass.
  • Suitable leachable substances are well known to those of skill in the art and include, for example, sodium chloride and other water-soluble salts.
  • the particle size of the leachable substance is roughly the size of the resulting pore.
  • the relative amount and size of the leachable substance gives rise to the degree of porosity.
  • porosity can be achieved using sintering and/or by controlling the treatment cycle of glass gels to control the pores and interpores of the material.
  • the glass composition can be prepared in several ways, to provide melt-derived glass, sol-gel derived glass, and sintered glass particles.
  • the sintered particles can be in sol-gel derived, or pre-reacted melt derived form.
  • Sol-gel derived glass is generally prepared by synthesizing an inorganic network by mixing metal alkoxides in solution, followed by hydrolysis, gelation, and low temperature (around 200-900 C C) firing to produce a glass.
  • Sol-gel derived glasses produced this way are known to have an initial high specific surface area compared with either melt-derived glass or porous melt-derived glass.
  • Melt derived glass is generally prepared by mixing grains of oxides or carbonates, melting and homogenizing the mixtures at high temperatures, typically between about 1250 and 1400 °C. The molten glass can be fritted and milled to produce a small particulate material.
  • the glass composition is preferably melt-derived. In each preparation, it is preferred to use reagent grade glass and/or chemicals, especially since the glass and/or chemicals are used to prepare materials which ultimately can be administered to a patient.
  • a melt-derived glass composition can be prepared, for example, by preparing an admixture of the individual metal oxides and other components used to prepare the glass composition, blending the admixture, melting the admixture, and cooling the mixture.
  • the melting temperature is determined in large part by the glass composition, and ranges, for example, from about 900-1500°C, preferably between about 1250 and 1450°C.
  • the melt is preferably mixed, for example, by oxygen bubbling, to ensure a thorough homogenation of the individual components.
  • the mixture can be cooled, for example by casting the molten admixture into a suitable liquid such as deionized water, to produce a glass frit.
  • Porosity can be introduced by grinding the glass into a powder, admixing the powder with a foaming agent, and hot pressing the mixture under vacuum and elevated temperature.
  • the particle size of the glass powder is between about 2 and 70 ⁇ m, the vacuum is preferably less than 50 MPa, and the hot pressing is preferably performed at a temperature above 400 °C, preferably between about 400 and 500 °C.
  • Suitable foaming agents include compounds which evolve carbon dioxide and/or water at elevated temperatures, for example metal hydroxides, metal carbonates, and peroxides such as hydrogen peroxide.
  • Preferred metal carbonates are sodium bicarbonate, sodium carbonate and calcium carbonate.
  • the foaming agents are preferably added in a range of between about 1-5, more preferably 2-3 percent by weight of the glass powder.
  • the preparation of melt-derived porous glass is described, for example, in U.S. Patent No. 5,648,301 to Ducheyne and El Ghannam.
  • Glass can be sintered using known methodology.
  • an aqueous slurry of the glass powder and a foaming agent with a suitable binder, such as polyvinyl alcohol, is formed.
  • the slurry is then poured into a mold, allowed to dry, and sintered at high temperatures.
  • These temperature can range, depending on the glass composition and foaming agent used, between about 450 and 1000°C, more preferably between about 550 and 800°C.
  • the glass composition can include a material which can be preferably leached out of the glass composition, and in doing so, provide the composition with high porosity.
  • a material which can be preferably leached out of the glass composition can be mixed with or melted into the glass, and subsequently leached out.
  • the resulting voids have roughly the same size as the particle that was leached out.
  • the size of the pores and degree of porosity depends on the amount of added material relative to the amount of glass.
  • the leached material constituted about 80% of the glass
  • the glass would be approximately 80% porous when the material was leached out.
  • Osteoblast-stimulating compositions derived from aqueous or other extracts of bioactive glass, and/or solutions including the same ions at the same concentration ranges can be used in the methods described herein.
  • the extracts can be formed by placing an osteoblast-stimulating bioactive glass in an aqueous solution, allowing the glass to dissolve over a suitable period of time, and filtering out the un-dissolved glass particles.
  • the solvent can be evaporated to provide a sol, gel or solid material with osteoblast-stimulating properties.
  • the compositions can be used in situations where osteoblast production is desired, for example solutions used for cell culture, and buffer solutions.
  • the extract may be incorporated into hydrogels or other aqueous based biocompatible carriers for delivery to specific sites in the body.
  • hydrogels or other aqueous based biocompatible carriers for delivery to specific sites in the body.
  • the molecular weight and/or water content of polymers or other materials utilized as carriers may be used to control the rate of release of the ionic bioactive glass extracts.
  • the concentration of ions in aqueous osteoblast-enhancing solutions is as follows: Si - 1 ppm to 100 ppm
  • the osteoblast-enhancing solutions will also contain sodium ions.
  • the amount will depend on the environment in which the solution is used and the amount of time of reaction of the initial glass composition.
  • aqueous solutions can be dried, for example by spray drying or by drying in vacuo, to provide an antibacterial composition.
  • the compositions can be incorporated into other solutions used in cell culture or other tissue engineering applications, such as cell culture media.
  • cell culture media there are many types of cell culture media, each of which are essentially isotonic with the cells to be cultured. These include Dulbecco's minimal essential media, Hank's balanced salt solution, and others.
  • the compositions described herein can be added to any of these solutions to enhance osteoblast proliferation, differentiation and/or function in the cell culture media.
  • the cell culture media including the compositions described herein are also useful for other cell types, including fibroblasts, chondroblasts and other cells with a phenotype similar to osteoblasts.
  • compositions can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms such as tablets, pills, powders, liquid solutions or suspensions, suppositories, and injectable and infusible solutions.
  • the preferred form depends on the intended mode of administration and therapeutic application and can be selected by one skilled in the art.
  • Modes of administration can include oral, parenteral, subcutaneous, intravenous, intralesional or topical administration, or direct injection into a bony defect or an adjacent tissue locus.
  • the pharmaceutical compositions will be administered in the vicinity of the treatment site in need of tissue regeneration or repair.
  • compositions can, for example, be placed into sterile, isotonic formulations with or without co-factors which stimulate uptake or stability. Solutions including the ions at appropriate concentrations and/or ratios can be lyophilized, stored under refrigeration and reconstituted prior to administration with sterile Water-For-Injection (USP).
  • the compositions can include conventional pharmaceutically acceptable carriers well known in the art (see for example Remington's Pharmaceutical Sciences. 16th Edition, 1980, Mac Publishing Company). Such pharmaceutically acceptable carriers can include other medicinal agents, carriers, genetic carriers, adjuvants, excipients, etc., such as human serum albumin or plasma preparations.
  • the compositions are preferably in the form of a unit dose and will usually be administered as a dose regimen that depends on the particular tissue treatment.
  • compositions can also be administered, for example, in microspheres, liposomes, other microparticulate delivery systems, polymers or sustained release formulations placed in, near, or otherwise in communication with affected tissues or the bloodstream bathing those tissues.
  • Liposomes containing the compositions described herein can be prepared by well-known methods (See, e.g., DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. U.S.A., 82, pp. 3688-92 (1985); Hwang et al., Proc. Natl. Acad. Sci. U.S.A., 77, pp. 4030-34 (1980); U.S. Pat. Nos. 4,485,045 and 4,544,545). Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about
  • the proportion of cholesterol is selected to control the optimal rate of release.
  • Dosing of the compositions can be via a single dose, sequential dosing, or continuous release.
  • the formulations can include other therapeutic agents such as antibiotics, antivirals, healing promotion agents, anti-inflammatory agents, immunosuppressants, growth factors, anti- metabolites, cell adhesion molecules (CAMs), bone morphogenic proteins (BMPs), vascularizing agents, anti-coagulants, and topical anesthetics/analgesics.
  • antibiotics antibiotics, antivirals, healing promotion agents, anti-inflammatory agents, immunosuppressants, growth factors, anti- metabolites, cell adhesion molecules (CAMs), bone morphogenic proteins (BMPs), vascularizing agents, anti-coagulants, and topical anesthetics/analgesics.
  • Suitable growth factors include platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic f ⁇ broblast growth factor (FGF), insulin-like growth factors (IGF-I and IGF-II), endothelial derived growth supplement (EDGS), keratinocyte growth factor (KGF), osteogenin, skeletal growth factor (SGF), osteoblast-derived(BDGFs), retinoids, growth hormone (GH), bone morphogenic proteins (BMPs), tissue growth factor-beta (TGF- ⁇ ), CBFA-1 and transferrin.
  • PDGF platelet-derived growth factor
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • FGF basic f ⁇ broblast growth factor
  • IGF-I and IGF-II insulin-like growth factors
  • EDGS endothelial derived growth supplement
  • KGF keratinocyte growth factor
  • SGF skeletal growth factor
  • Devices can be prepared which include the compositions described herein, for example, dispersed in an implantable or extracorporeal biocompatible carrier material that functions as a suitable delivery or support system for the composition.
  • sustained release carriers include semi-permeable polymer matrices in the form of shaped articles such as suppositories or capsules.
  • Implantable or microcapsular sustained release matrices include polylactides (U.S. Pat. No. 3,773,319; EP 058 481), copolymers of L-glutamic acid and ethyl-L-glutamate (Sidman et al., Biopolymers, 22, pp.
  • the carrier includes a biocompatible matrix made up of particles or porous materials.
  • the pores are preferably of a dimension to permit progenitor cell migration and subsequent differentiation and proliferation.
  • Various matrices known in the art can be employed (see, e.g., U.S. Pat. Nos. 4,975,526; 5,162,114; 5,171,574 and PCT WO 91/18558).
  • the matrix can be formed, for example, by close packing particulate material into a shape spanning the particular tissue or bone defect to be treated.
  • a biocompatible, preferably biodegradable material can be structured to serve as a temporary scaffold and substrate for recruiting migratory progenitor cells, and as a base for their subsequent anchoring and proliferation.
  • Useful matrix materials include, for example, collagen; hydrogels; homopolymers or copolymers of glycolic acid, lactic acid, and butyric acid, including derivatives thereof; and ceramics, such as hydroxyapatite, tricalcium phosphate and other calcium phosphates.
  • the bioactive glass or bioactive glass extracts of the invention may be used with, incorporated into or encapsulated within matrix carrier materials, such as hydrogels, to enable the release of the ions from the glass or extract in a controlled fashion. This release of the ions preferably will be controlled over time and may be a sustained release formulation.
  • Various therapeutic agents as described above, can be adsorbed onto or dispersed within the carrier material, and will also be released over time at the implantation site as the matrix material is slowly absorbed.
  • Implantable prosthetic devices including the compositions described herein can also be prepared.
  • Such prosthetic implant can be selected for a particular treatment by the skilled practitioner, and can include materials such as metals and/or ceramics.
  • the compositions can be moldable or machinable.
  • prosthetic devices include hip devices, screws, rods, cages for spine fusion, stents, plates, sheets, pins, valves, sutures, tubes and the like.
  • the composition is disposed as a coating on prosthetic implants.
  • the coating is present in an amount sufficient to promote enhanced tissue growth into the surface of the implant.
  • the amount of the composition sufficient to promote enhanced tissue growth can be determined empirically by those of skill in the art using appropriate bioassays.
  • animal studies are performed to optimize the concentration of the composition components before a similar prosthetic device is used in the human patient.
  • Such prosthetic devices will be useful for repairing orthopedic defects, injuries or anomalies in the treated mammal.
  • In vivo integration of implantable prosthetic devices into target tissue can be performed, for example, by providing the composition on a surface of a prosthetic device, and implanting the device in a mammal at a locus where the target tissue and the surface of the prosthetic device are maintained at least partially in contact for a time sufficient to permit enhanced tissue growth between the target tissue and the device.
  • compositions and devices disclosed herein will permit the physician to treat a variety of tissue injuries, tissue degenerative or disease conditions and disorders that can be ameliorated or remedied by localized, stimulated tissue regeneration or repair.
  • the compositions and devices of the invention may be used to treat osteoblast- related tissue degenerative conditions.
  • the devices can be used to induce local tissue formation from a progenitor cell in a mammal by implanting the device at a locus accessible to at least one progenitor cell of the mammal.
  • the devices can be used alone or in combination with other therapies for tissue repair and regeneration.
  • the devices can also be implanted in or surrounding a joint for use in cartilage and soft tissue repair, or in or surrounding nervous system-associated tissue for use in neural regeneration and repair.
  • the tissue specificity of the particular composition will determine the cell types or tissues that will be amenable to such treatments and can be selected by one skilled in the art.
  • the ability to enhance tissue regeneration by administering the compositions described herein is thus not believed to be limited to any particular cell-type or tissue.
  • the compositions and methods disclosed herein can be practiced to enhance new tissue inductive functions as they are discovered in the future.
  • the compositions and devices will permit the physician to obtain predictable bone and/or cartilage formation.
  • the compositions and devices can be used to treat more efficiently and/or effectively all of the injuries, anomalies and disorders that have been described in the prior art of osteogenic devices.
  • the devices can also include a matrix including allogeneic bone.
  • a matrix including allogeneic bone can also be implanted at a site in need of bone replacement to accelerate allograft repair and incorporation in a mammal.
  • the devices can also be used in cartilage repair, for example, following joint injury or in osteoarthritis treatment. The ability to enhance cartilage-inducing activity by administering the compositions described herein can permit faster or more extensive tissue repair and replacement.
  • compositions and devices described herein will be useful in treating certain congenital diseases and developmental abnormalities of cartilage, bone and other tissues.
  • heritable conditions including congenital bone diseases, for which use of the morphogenic compositions and devices described herein will be useful include osteogenesis imperfecta, the Hurler and Marfan syndromes, and several disorders of epiphyseal and metaphyseal growth centers such as is presented in hypophosphatasia, a deficiency in alkaline phosphatase enzymatic activity.
  • Inflammatory joint diseases can also benefit from the compositions and devices described herein. These include infectious, non-infectious, rheumatoid and psoriatic arthritis, bursitis, ulcerative colitis, regional enteritis, Whipple's disease, and ankylosing spondylitis (also called Marie Strumpell or Bechterew's disease); the so-called "collagen diseases” such as systemic lupus erythematosus (SLE), progressive systemic sclerosis (scleroderma), polymyositis (dermatomyositis), necrotizing vasculitides, Sjogren's syndrome (sicca syndrome), rheumatic fever, amyloidosis, thrombotic thrombocytopenic purpura and relapsing polychondritis.
  • Heritable disorders of connective tissue include
  • Marfan's syndrome homocystinuria, Ehlers-Danlos syndrome, osteogenesis imperfecta, alkaptonuria, pseudoxanthoma elasticum, cutis laxa, Hurler's syndrome, and myositis ossif ⁇ cans progressiva.
  • the compounds are used to fill voids, including voids created during medical procedures.
  • the hollowed-out tooth can be filled with a composition including bioactive glass. This will help prevent bacterial infection until the tooth is ultimately filled.
  • bioactive glass-containing compositions can be used to fill the pockets that can develop between the teeth and gums.
  • the compositions can also be used to fill voids, for example those present in aneurysms, and those formed surgically, such as removal of a spleen, ovary, gall bladder, or tumor.
  • compositions at enhancing bone and/or tissue growth can be demonstrated using conventional bioassays.
  • useful bioassays are described in U.S. Pat. No. 5,344,654 to Rueger et al. Feline and Rabbit Models
  • the procedure is as follows: Sixteen adult cats each weighing less than 10 lbs. undergo unilateral preparation of a 1 cm bone defect in the right femur through a lateral surgical approach. In other experiments, a 2 cm bone defect can be created. The femur is immediately internally fixed by lateral placement of an 8-hole plate to preserve the exact dimensions of the defect.
  • group I is a negative control group which undergoes the same plate fixation with implants of 4M guamdine-HCl-treated (inactivated) cat demineralized bone matrix powder (GuHCl-DBM) (360 mg);
  • group II is a positive control group implanted with biologically active demineralized bone matrix powder (DBM) (360 mg); and groups III and IV undergo a procedure identical to groups I-II, with the addition of the compositions to be evaluated.
  • the group I GuHCl-DMB negative-control implants should generally exhibit no bone growth at four weeks, less than 10% at eight and 12 weeks, and about 16% (+/-10%) at 16 weeks.
  • the group II DMB positive-control implants should generally exhibit about 15-20% repair at four weeks, 35% at eight weeks, 50% (+/-10%) at 12 weeks and 70% (+/-12%) by 16 weeks.
  • Excised test and normal femurs can be immediately studied by bone densitometry, or wrapped in two layers of saline-soaked towels, placed into sealed plastic bags, and stored at -20 °C. until further study. Bone repair strength, load-to-failure, and work-to-failure are tested by loading to failure on a specially designed steel 4-point bending jig attached to an Instron testing machine to quantitate bone strength, stiffness, energy absorbed and deformation to failure. The study of test femurs and normal femurs yields the bone strength (load) in pounds and work-to-failure in joules. Normal femurs exhibit a strength of 96 (+/-12) pounds.
  • the bones are immediately sliced into two longitudinal sections at the defect site, weighed, and the volume measured. One-half is fixed for standard calcified bone histomorphometrics with fluorescent stain incorporation evaluation, and one-half is fixed for decalcified hemotoxylin/eosin stain histology preparation.
  • the marrow cavity of the 1.5 cm ulnar defect is packed with activated osteogenic protein in rabbit bone powder in the presence or absence of a MPSF.
  • the bones are allografted in an intercalary fashion. Negative control ulnae are not healed by eight weeks and reveal the classic "ivory" appearance.
  • a modified version of the Sampath and Reddi rat ectopic implant assay (see above) is disclosed in PCT WO 95/16035.
  • the modified assay monitors tendon and ligament-like tissue formation.
  • This tendon/ligament-like tissue assay can be used to identify compositions that stimulate tendon/ligament-like tissue formation in a particular treatment site.
  • the assay can also be used to optimize concentrations and treatment schedules for therapeutic tissue repair regimens.
  • the above experimental procedure can be modified within the skill of the art in a number of ways to be useful in determining whether a device is capable of inducing tendon and/or ligament-like tissue in vivo. It can be used to test various ion concentrations and/or ratios, and to produce an in vivo dose response curve useful in determining effective relative concentrations and/or ratios of ions in the bioactive glasses or extracts thereof.
  • Implants are fixed in Bouins Solution, embedded in paraffin, and cut into 6-8 ⁇ m sections. Staining with toluidine blue or hemotoxylin/eosin demonstrates clearly the ultimate development of endochondral bone. Twelve-day implants are usually sufficient to determine whether the implants contain newly-induced bone.
  • Biological markers Alkaline phosphatase (AP)activity can be used as a marker for osteogenesis.
  • the enzyme activity can be determined spectrophotometrically after homogenization of the implant. The activity peaks at 9-10 days in vivo and thereafter slowly declines. Implants showing no bone development by histology have little or no alkaline phosphatase activity under these assay conditions.
  • the assay is useful for quantification and obtaining an estimate of bone formation quickly after the implants are removed from the rat. Alternatively, the amount of bone formation can be determined by measuring the calcium content of the implant.
  • Gene expression patterns that correlate with endochondral bone or other types of tissue formation can also be monitored by quantitating mRNA levels using procedures known to those of skill in the art such as Northern Blot analysis.
  • Such developmental gene expression markers can be used to determine progression through tissue differentiation pathways after osteogenic protein/MPSF treatments. These markers include osteoblastic-related matrix proteins such as procollagen a 2 L), procollagen (I), procollagen a
  • compositions described herein can be assessed using these assays. It is anticipated that the efficacy of any of the compositions described herein can be characterized using these assays.
  • Various compositions, dose-response curves, naturally-derived or synthetic matrices, and any other desired variations on the device components can be tested using the procedures essentially as described.
  • the following are examples which illustrate the compositions and devices described herein, and methods used to characterize them. These examples should not be construed as limiting; the examples are included for purposes of illustration and the present invention is limited only by the claims.
  • Example 1 The effect of the ionic dissolution products of Bioglass D 45S5 on human primary osteoblasts
  • Bioglass 45S5 is a bioactive glass ceramic material which resorbs initially by selective leaching of at least silicon, calcium and phosphorus ions followed by network dissolution mediated by surface re-polymerization.
  • the ionic dissolution products of Bioglass 45 S5 stimulate gene transcription in human primary osteoblasts, as demonstrated using cDNA micro-array and real time PCR methodologies.
  • the ionic dissolution products of Bioglass 45S5 can increase IGF-II availability in cells and tissues in two ways: i) by inducing the transcription of the growth factor and its carrier protein and ii) by regulating the dissociation of this factor from its binding protein resulting in an increase of free-active IGF-11, as determined by EIA.
  • Free IGF-II increases the cell proliferation observed in cultures stimulated with the ionic dissolution products of Bioglass 45S5.
  • the data demonstrate that the biomaterials described herein are useful not only for structural support, but also, through their resorption, for stimulating the intrinsic cellular pathways for bone growth, repair and regeneration.
  • Osteoblasts were isolated from trabecular bone of femoral heads taken during total hip arthroplasty using the method described by Beresford et al (Beresford et al., Metab. BoneDis. andRel. Res., 5:229-234 (1984)). Cultures were grown in DMEM (Dulbecco's modified Eagle's medium) supplemented with 10% fetal bovine serum (FBS), 2 mM L- glutamine, 50 U/ml penicillin G, 50 ⁇ g/ml streptomycin B and 0.3 ⁇ g/ml amphotericin B (complete medium) at 37°C, in 95%) air humidity and 5% C0 2 .
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • 2 mM L- glutamine 50 U/ml penicillin G
  • 50 ⁇ g/ml streptomycin B 50 ⁇ g/ml streptomycin B
  • a solution containing the ionic dissolution products of Bioglass 45S5 was prepared by incubating 1 g of Bioglass 45S5 particulate (710-300 ⁇ m in diameter, US Biomaterials Corp, USA) in 100 ml DMEM for 24 hours at 37°C. The particulates were removed by filtration through a 0.20 ⁇ m filter (Sartorius, UK) and the collected medium was supplemented as described above for the complete medium. The elemental content of this solution in calcium (Ca), silicon (Si), phosphorus (P) and sodium (Na) ions was determined by ICP analysis.
  • RNA integrity was assessed by elecfrophoresis on a denaturing agarose/formaldehyde/EtBr gel to verify that the RNA was intact.
  • PCR System (Life Technologies, UK), according to manufacturer's protocol. Each reaction tube contained 1 ⁇ g of DNAse free total RNA in a total volume of 20 ⁇ l containing Ix cDNA Synthesis Buffer, 5mM DTT, 40 U RNASEOUT, ImM dNTP Mix, 15U THERMOSCRTPT RT and 2.5 ⁇ M oligo (dT) 12 . 18 primer. RT reaction was carried out at 50 °C for 60 min and terminated by incubating at 85 °C for 5 min. Finally 2U of RNase H was added to each reaction and the reaction mixture was incubated for a further 20 min. at 37°C. PCR primers and TaqMan probes for IGF-II were designed using Primer Express
  • the human IGF-II cDNA sequence was obtained from GenBank (accession number S77035). The following forward and reverse primers were used 5'-GTGCTACCCCCGCCAAGT-3' (located on exon four, anneals between residues 584 and 601) and 5'-CTGCTTCCAGGTGTCATATTGGA-3' (located on exon 5, anneals between residues 696 and 674).
  • GenBank accession number S77035
  • the following forward and reverse primers were used 5'-GTGCTACCCCCGCCAAGT-3' (located on exon four, anneals between residues 584 and 601) and 5'-CTGCTTCCAGGTGTCATATTGGA-3' (located on exon 5, anneals between residues 696 and 674).
  • the TaqMan probe sequence was 5-
  • CTCCGACCGTGCTTCCGGACAACT-3' (spans exon 4-exon 5 boundary, anneals between residues 623 and 646) and was labeled with the reporter fluorescent dye FAM (6- carboxyfluorescein), at the 5' end and the fluorescent dye quencher TAMRA (6-carboxy- tetramethyl-rhodamine) at the 3' end.
  • FAM fluorescent dye
  • TAMRA fluorescent dye quencher
  • each reaction mixture was subjected to PCR in a total volume of 25 ⁇ l containing lx TaqMan Universal Master Mix (PE Biosystems, UK), 300 nM forward primer, 300 nM reverse primer and 50 nM probe, TaqMan lx 18s ribosomal RNA endogenous control reagent (VIC fluorescent labeled probe and appropriate primers) was added in each reaction tube and served as internal amplification control. Each sample was run in quadruplicate. DNA amplification was carried out on the PE-ABI 7700 sequence detection system for the test samples, standards and no template controls using the sequence detector V 1.6 program.
  • Cycling parameters were: 50°C for 5min, 95°C for 10 min followed by 40 cycles of a two-stage temperature profile of 95°C for 15s and 60°C for 1 min. Data points collected following primer extension were analyzed at the end of thermal cycling. A threshold value was determined as 10 S.D. above the mean of the background fluorescence emission for all wells between cycles 1 and 15. The cycle number at which the fluorescence signal from a positive sample crosses this threshold was recorded.
  • mRNA transcripts for the IGF-II receptor was relatively unaffected by the stimulus.
  • the analysis identified 60 mRNA species that were upregulated greater than twofold in the treated cultures compared to the untreated control (Table 1). Only five genes were identified as down- regulated, including E-16 amino acid transporter, c-jun terminal kinase 2, polycystin precursor, Sp2 protein and proteasome inhibitor HP131 subunit.
  • Taqman real time PCR was used to confirm induction of IGF-II mRNA expression demonstrated by cDNA microarray analysis. Expression and induction of IGF-II followed the same pattern in all four donor osteoblast cell lines examined.
  • Free IGF-II represents the fraction of the molecule, which is not bound to IGF binding proteins (IGFBPs) and hence represents the active form of IGFII.
  • IGFBPs IGF binding proteins
  • the ionic dissolution products of Bioglass 45S5 were shown to statistically increase the concentration of free IGF-II by approximately 70%.
  • Osteoblast proliferation was increased 50.2% (P ⁇ 0.001) over control, following four days of stimulation with the ionic dissolution products of Bioglass 45S5.
  • the stimulatory effect on cell proliferation observed is believed to be mediated by IGF-II, which has been described as a potent mitogenic, growth factor for osteoblasts. Effects of stimulation of cells by ionic dissolution products
  • Bioglass 45 S5 resorbs initially by selective leaching of Si, Ca, and P ions followed by network dissolution mediated by surface re-polymerization.
  • IGF-II is an anabolic peptide of the insulin family and constitutes the most abundant growth factor in bone (Mohan et al., 1988, Bautista et al., 1990). It is produced locally by bone cells and is considered to exert mostly paracrine or autocrine effects. Nonetheless, differences in IGF-II expression occur and can significantly impact bone cell function in various physiological and pathological conditions. In vitro studies using osteoblasts of various animal sources have shown that IGF-II is a potent inducer of osteoblast proliferation and collagen synthesis.
  • IGFBPs IGE binding proteins
  • IGF-II m-RNA expression represents a true difference in IGF-II protein synthesis and IGF-II availability.
  • IGF-II bioavailability at the local level is regulated through IGFBPs limited proteolysis by several proteases resulting in IGF-II release in its free 'active' form. These include members of the metalloproteinase family, such as MMP I and 2 and cathepsin-D (Conover et al., 1994), some of which were found to be transcriptionally induced in the system described in this example. This effect was correlated with a statistically significant increase of free-active IGF-II in cells stimulated with the ionic dissolution products of Bioglass 45S5.
  • the ionic dissolution products of Bioglass 45S5 can increase the availability of IGF-II in cells and tissues in two ways, (i) by inducing the transcription of the growth factor and its carrier protein and (ii) by regulating the dissociation of this factor from its binding protein.
  • One of the direct effects of free IGF-II is the observed increase in cell proliferation.
  • the ionic dissolution products of Bioglass 45 S5 induce the bioavailability of IGF-II, IGFBP3, MMP2, MMP14, TIMP1, TIMP2, procollagen a2,
  • the ionic dissolution products of Bioglass were found to upregulate genes, at a rate greater than twofold in human osteoblasts, such as CD44 antigen hemotopoietic form precursor, MAP kinase-activated protein kinase 2, integrin beta 1, RCL growth-related c-myc-responsive gene, defender against cell death 1 (DAD-1), cyclin Dl, MMP14, CDKN1A, IGF-II, MMP2, TTMP1, decorin, TMP-2, extracellular signal- regulated kinase 1, cyclin K, ADP-ribosylation factor 1, MAP kinase p38, nuclear factor 1 (NFI), vascular endothelial growth factor precursor (VEGF), among others. It is believed that the upregulation of these genes by bioactive glass or glass extracts as taught herein contributes, directly or indirectly, to the stimulation of osteoblast proliferation, differentiation and/or function.

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Abstract

L'invention concerne des compositions renfermant des compositions de verre bioactif ou des extraits correspondants qui contiennent des ions dans une concentration et un taux adéquats leur permettant d'améliorer la production d'ostéoblaste, ainsi que des méthodes de préparation et d'utilisation correspondantes. On peut incorporer lesdites compositions dans des dispositifs implantables qui peuvent induire la formation tissulaire dans des autogreffes, allogreffes et xénogreffes, par exemple des revêtements et/ou des matières à matrice. Des exemples de tels dispositifs englobent des prothèses, des sutures, des stents, des vis, des plaques, des tubes et similaire. Cette invention concerne également des extraits aqueux de compositions de verre bioactif qui peuvent stimuler la production d'ostéoblaste. On peut utiliser ces compositions, par exemple, pour induire la formation tissulaire locale à partir d'une cellule souche chez un mammifère, afin d'accélérer la réparation de l'allogreffe chez ledit mammifère, de promouvoir l'intégration in vivo d'un appareil prothétique implantable de manière à améliorer la force d'adhésion entre la prothèse et les tissus cibles existants au niveau du site d'accolement, et de traiter des conditions tissulaires dégénératives.
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WO2004071542A1 (fr) * 2003-02-14 2004-08-26 The North West London Hospitals Nhs Trust Materiau bioactif pour une utilisation dans une vascularisation de simulation
WO2007072065A2 (fr) * 2005-12-23 2007-06-28 Advanced Bio-Technologies, Inc. Composition de silicone
WO2009080749A1 (fr) * 2007-12-21 2009-07-02 Bone Therapeutics S.A. Cellules de formation d'os humain dans le traitement de maladies rhumatismales inflammatoires
WO2014195864A1 (fr) 2013-06-03 2014-12-11 Universite Blaise Pascal-Clermont-Ferrand Ii Implant a porosite controlee comprenant une matrice revetue d'un verre bioactif ou d'un materiau hybride
WO2016051326A1 (fr) 2014-09-29 2016-04-07 Universite Blaise Pascal-Clermont-Ferrand Ii Implant a porosite variable en un materiau hybride
FR3088550A1 (fr) 2018-11-15 2020-05-22 Universite Clermont Auvergne Implant a porosite controlee en un materiau hybride dope en nutriment osteoinducteur
US11896612B2 (en) 2019-03-29 2024-02-13 Board Of Trustees Of Michigan State University Resurrection of antibiotics that MRSA resists by silver-doped bioactive glass-ceramic particles

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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

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071542A1 (fr) * 2003-02-14 2004-08-26 The North West London Hospitals Nhs Trust Materiau bioactif pour une utilisation dans une vascularisation de simulation
WO2007072065A2 (fr) * 2005-12-23 2007-06-28 Advanced Bio-Technologies, Inc. Composition de silicone
WO2007072065A3 (fr) * 2005-12-23 2007-10-04 Advanced Bio Technologies Inc Composition de silicone
WO2009080749A1 (fr) * 2007-12-21 2009-07-02 Bone Therapeutics S.A. Cellules de formation d'os humain dans le traitement de maladies rhumatismales inflammatoires
US20100272696A1 (en) * 2007-12-21 2010-10-28 Bone Therapeutics S.A. Human Bone-Forming Cells In The Treatment of Inflammatory Rheumatic Diseases
WO2014195864A1 (fr) 2013-06-03 2014-12-11 Universite Blaise Pascal-Clermont-Ferrand Ii Implant a porosite controlee comprenant une matrice revetue d'un verre bioactif ou d'un materiau hybride
WO2014195862A1 (fr) 2013-06-03 2014-12-11 Universite Blaise Pascal-Clermont-Ferrand Ii Implant en un materiau composite a porosite controlee
WO2014195863A1 (fr) 2013-06-03 2014-12-11 Universite Blaise Pascal-Clermont-Ferrand Ii Implant a porosite controlee en un materiau hybride
WO2016051326A1 (fr) 2014-09-29 2016-04-07 Universite Blaise Pascal-Clermont-Ferrand Ii Implant a porosite variable en un materiau hybride
FR3088550A1 (fr) 2018-11-15 2020-05-22 Universite Clermont Auvergne Implant a porosite controlee en un materiau hybride dope en nutriment osteoinducteur
WO2020099588A1 (fr) 2018-11-15 2020-05-22 Universite Clermont Auvergne Implant a porosite controlee en un materiau hybride dope en nutriment osteoinducteur
US11896612B2 (en) 2019-03-29 2024-02-13 Board Of Trustees Of Michigan State University Resurrection of antibiotics that MRSA resists by silver-doped bioactive glass-ceramic particles

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