WO2016154691A1 - Bioactive vitreous composition and use thereof for bone regeneration - Google Patents

Bioactive vitreous composition and use thereof for bone regeneration Download PDF

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WO2016154691A1
WO2016154691A1 PCT/BR2015/000186 BR2015000186W WO2016154691A1 WO 2016154691 A1 WO2016154691 A1 WO 2016154691A1 BR 2015000186 W BR2015000186 W BR 2015000186W WO 2016154691 A1 WO2016154691 A1 WO 2016154691A1
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mol
bone
bioactive
composition
glasses
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PCT/BR2015/000186
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French (fr)
Portuguese (pt)
Inventor
João Henrique LOPES
Celso Aparecido BERTRAN
Lucas Pereira Lopes DE SOUZA
Italo Odone MAZALI
José Angelo CAMILLI
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Universidade Estadual De Campinas - Unicamp
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Priority claimed from BR102015007042-0A external-priority patent/BR102015007042B1/en
Application filed by Universidade Estadual De Campinas - Unicamp filed Critical Universidade Estadual De Campinas - Unicamp
Publication of WO2016154691A1 publication Critical patent/WO2016154691A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • C—CHEMISTRY; METALLURGY
    • C03—GLASS; MINERAL OR SLAG WOOL
    • C03C—CHEMICAL 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
    • C03C3/00—Glass compositions
    • C03C3/04—Glass compositions containing silica
    • C03C3/062—Glass compositions containing silica with less than 40% silica by weight
    • C—CHEMISTRY; METALLURGY
    • C03—GLASS; MINERAL OR SLAG WOOL
    • C03C—CHEMICAL 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
    • C03C3/00—Glass compositions
    • C03C3/04—Glass compositions containing silica
    • C03C3/076—Glass compositions containing silica with 40% to 90% silica, by weight
    • C—CHEMISTRY; METALLURGY
    • C03—GLASS; MINERAL OR SLAG WOOL
    • C03C—CHEMICAL 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
    • C03C3/00—Glass compositions
    • C03C3/04—Glass compositions containing silica
    • C03C3/076—Glass compositions containing silica with 40% to 90% silica, by weight
    • C03C3/083—Glass compositions containing silica with 40% to 90% silica, by weight containing aluminium oxide or an iron compound
    • C03C3/085—Glass compositions containing silica with 40% to 90% silica, by weight containing aluminium oxide or an iron compound containing an oxide of a divalent metal
    • C03C3/087—Glass compositions containing silica with 40% to 90% silica, by weight containing aluminium oxide or an iron compound containing an oxide of a divalent metal containing calcium oxide, e.g. common sheet or container glass
    • C—CHEMISTRY; METALLURGY
    • C03—GLASS; MINERAL OR SLAG WOOL
    • C03C—CHEMICAL 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
    • C03C3/00—Glass compositions
    • C03C3/04—Glass compositions containing silica
    • C03C3/076—Glass compositions containing silica with 40% to 90% silica, by weight
    • C03C3/097—Glass compositions containing silica with 40% to 90% silica, by weight containing phosphorus, niobium or tantalum

Definitions

  • the present invention relates to a bioactive glassy composition comprising niobium oxide and its use for bone regeneration.
  • the present invention is in the field of Material Chemistry comprising bone tissue engineering scaffolds, osteoregenerative medicine and its application is directed to the filling of bone defects caused by disease or accident.
  • Bioglass has the advantage of stimulating osteogenesis, however, have the same disadvantage that is found in ceramics and glass, its fragility.
  • modifications in the structure of bioglass or its combination with other materials offered better biomechanical performance. In this context, obtaining glassy materials with better mechanical properties and bioactive properties is a major challenge for materials science.
  • Niobium has been used in titanium alloys for endosseous implants because of its excellent biocompatibility, superior corrosion resistance and fatigue. In glassy compositions, the presence of niobium in its oxide form (Nb20s) has exhibited similar behavior.
  • the addition of niobium oxide in phosphate glasses improves its chemical durability and the presence of niobium in niobium phosphate bioglass promotes significant improvements in the mechanical properties of this material and confers, also, modulus of elasticity close to the cortical bone for the phosphate glasses.
  • Nb 5+ replaces P 5+ in POP bonds in niobiophosphate glasses.
  • Nb and P there is a chemical similarity between the elements Nb and P with regard to the most common oxidation state (5+) and, consequently, the tendency of formation of analogous chemical compounds, eg Nb20s and P2O5.
  • niobium can positively influence apatite layer formation and regulate the genes that control the differentiation of cells involved in osteogenesis.
  • Nb5 + ions have been shown to reduce cytotoxicity, significantly promote calcification of normal human osteoblasts, and have the potential to promote alkaline phosphatase (ALP) activity, an important marker for the process of generation of New bone.
  • ALP alkaline phosphatase
  • the presence of niobium oxide improves biocompatibility and promotes bioactivity.
  • bioactive glass ion product to induce cell differentiation and proliferation is well described in the literature for silicon, calcium and niobium ions (Hench, L.L, Polak, JM, Xynos, ID, & Buttery, LDK (2000). Bioactive materials to control cell cycle Materials Research Innovations, 3 (6), 313-323 doi: Doi 10,1007 / S100190000055Hench, LL, Xynos, ID, Edgar, AJ, Buttery, L DK, Polak, JM, Zhong, JP, Chang, J.
  • bioactive niobophosphate glasses with better chemical durability compared to calcium phosphate glasses, resembling to the present invention in that it comprises a glassy niobium phosphate composition applied for osteostimulation.
  • the present invention differs from the technology described in the article in that the glassy compositions are based on silicate glasses. Unlike phosphate glasses, silicate glasses have been associated with increased osteogenesis and neovascularization. Thus in our invention it combines the positive effects of silicon and niobium ions to promote increased bioactivity.
  • the bio-glasses presented in this invention have a considerably lower Nb20s content ( ⁇ 5 mol%) compared to that presented by Carbonari's work (8 ⁇ x ⁇ 15 mol%).
  • the present invention differs from the technology described in the article in that the glassy matrix addressed by the article is phosphate belonging to P205-BaO-K20-Nb20s and the ND2O5 content is greater than 5 mol%.
  • the present invention differs from the document cited in that it comprises a distinct composition:
  • the vitreous matrix is composed mainly of silicate which, in critical concentration, is related to the increase of cell differentiation and proliferation.
  • the phosphate concentration related to the structural instability when in significant quantities, is low in the present invention
  • the glass matrix is composed mainly of the ref
  • knowing that the presence of phosphate is not required for bioactivity in glasses, the present invention has structural and application advantages over the mentioned article.
  • US20140271565A1 relates to a fluoroapatite ceramic glass, resembling the present invention in that it comprises a glass of similar composition ((32,3 or 31,5 ⁇ Si0 2 - (23,9 , 19.0, 11, 9, 6, 0 , or 0) dog-(2.9 or 2.3) -Na 2 O (5.0 or 5.1) 2 P 2 O5-0,2Nb oJ- MgO-SrO- K 2 O-A 2 O 3 -CaF 2) - in molar percentages.
  • the technology reported in US20140271565A1 has osteostimulating properties.
  • the present invention differs from the technology described in the patent in that it has a distinct composition and no crystal structure.
  • the system described in the technology is complex, comprising ten components.
  • the described system does not form glass, but in vitro ceramics (there is crystallinity).
  • crystallization is known to reduce bioactivity due to the entrapment of ions in the crystal
  • the technology reported in US20140271565A1 has limitations regarding osteostimulation.
  • a lower leaching rate can be expected for this composition and, consequently, a lower application potential.
  • the presence of MgO, SrO, K2O and CaF2 oxides is associated with different biological responses associated with each one.
  • ND2O5 both in niobium phosphate glasses and niobium silicate glasses, is known to promote structural changes that impart better chemical durability and biomechanical performance to the glass matrix.
  • changes may compromise bioactivity due to reduced solubility and, consequently, decreased availability of silicon and calcium ions, which, when released in a controlled manner, play an important role in gene regulation and activation in osteoprogenitor cells.
  • This problem is evident in the closest technologies reported in this topic.
  • prior knowledge of these aspects involving niobium-containing glasses led to the choice of glass compositions with reduced concentrations of Nb20s and phosphates according to the proposal of the present patent application.
  • the present invention relates to a bioactive glass composition comprising niobium oxide and its use for bone regeneration.
  • the bioactive glassy composition comprises the following components:
  • the bioactive glass composition preferably comprises 46.1% by weight. of S1O2, 26.9 ' mol% CaO, 24.4 mol% Na20, 3 mol% P2O5, and 1.3 mol% Nb20s
  • the bioactive glass composition has medical and dental application, such as bone filler biomaterials, for bone regeneration, bone tissue engineering scaffoids, bioactive coatings for bioinert metallic biomaterials, and in the treatment of dentin hypersensitivity.
  • Figure 1 shows the X-ray diffractograms of the bioactive glass compositions selected to exemplify the present invention.
  • the diffractogram for BG45S5 has been added for comparison only.
  • FIG. 2 shows DSC (Differential scanning calorimetry) curves for the bioactive glass compositions selected for exemplify the present invention, (a) BGPN1.3 and BGPN2.6 and (b) BGSN1, BGSN2.5 and BGSN5.
  • the DSC curve for BG45S5 has been added for comparison only.
  • Figure 3 shows the Raman spectra indicating the effects of niobium oxide on the vitreous structure (a) BGPN1.3 and BGPN2.6 and (b) BGSN1, BGSN2.5 and BGSN5.
  • the Raman spectrum for BG45S5 has been added for comparison only.
  • Figure 4 shows data obtained from nanoindentation tests for the effects of Nb20s on the mechanical properties of (a) hardness and (b) modulus of elasticity of Nb20s containing bioglass.
  • Figure 5 shows the solubility curves obtained by studying the pH variation in water as a function of immersion time.
  • Figure 6 shows the cell viability data obtained by MTT assays in osteoblast cultures isolated from the calvaria of rats for times 1, 7 and 14 days of culture.
  • Figure 7 shows micrographs of the newly formed subperiosteal bone in the cortex adjacent to the implant in all groups after 28 postoperative days. Hematoxylin-Eosin Staining. 200x total increase.
  • Figure 8 shows the average area of subperiosteal bone formed in the cortex adjacent to the vitreous implant in all groups after 14 and 28 days of surgery.
  • Figure 9 shows the mean blood vessel density in the implant area in all groups after 28 postoperative days.
  • composition comprises the following molar percentages of the components:
  • P2O5 phosphorus pentoxide in amounts between 0.001 and 5, preferably 1.3 mol%
  • Nb206 niobium pentoxide in amounts between 0.001 and 5, preferably 1.3 mol%;
  • composition of the present invention is based on the oxides S1O2, CaO, Na2O, P2O5 and Nb2Os.
  • the presence of Nb2Os in amounts less than 5 mol% is an innovation compared to commercial bioglass.
  • Bio-glasses prepared with reduced amounts of Nb2Os promote changes in the vitreous network increasing solubility and consequently increasing the amount of silicon, calcium and niobium ions in the glass. middle. The presence of these ions increases cell viability through direct control of the genes that control the processes of cell differentiation and proliferation.
  • Nb20s in the glassy compositions allows modulating the mechanical properties, thermal stability and chemical durability of bioglass, expanding its applications in the field of biomaterials.
  • niobium is a strategic element for the country's economic development, since 98% of all known niobium reserves are located in Brazilian territory.
  • the present invention further relates to the use of the niobium oxide-based bioactive glass composition in the regeneration of bone tissue, the induction of blood vessel formation from existing vessels (positive feature for regeneration of any type of bactericidal, hemostatic agent, and drug delirium systems for controlled drug delivery and / or cell therapy.
  • the present invention relates to a vitreous series (relative to a series formed by different glass compositions containing niobium oxide) containing niobium oxide (Nb20s) with high bioactivity and osteostimulatory capacity.
  • Nb20s niobium oxide
  • Bioglass applications are They can be used to fill bone cavities caused by fractures, infections or cancer, to restore periodontal defects, facial reconstruction and osteotomies.
  • the material can be used in the treatment of gastric ulcers, skin wounds and burns as it has hemostatic and bactericidal properties. Due to its high bioactivity and rapid formation of hydroxyapatite from calcium and phosphorus precipitation, this material can be incorporated into the composition of toothpastes for the treatment of hypersensitivity, as it provides occlusion of dentinal canals.
  • the glassy compositions developed are completely biocompatible and have a partial dissolution of their surface, releasing ions, which in optimal concentrations have therapeutic action.
  • glassy compositions described in this invention may be exploited in composites for the preparation of porous secondary structures for tissue engineering (scaffolds), development of drug and / or cell-loaded devices for controlled release thereof. the treatment of cancers and focal infections and various other applications.
  • the methodology which is based on the conventional glass preparation processes produced was used, traditionally through the melting / cooling method. This method involves melting a mixture of the starting materials, followed by rapid cooling sufficient for glazing.
  • the chemical composition of the 45S5 bioglass (46.1 Si02 - 26.9 CaO - 24.4 Na20 - 2.6% P2O5 in mol%) was modified by replacing 1, 3 and 2.6% P2O5 with ND2O5 or the substitution of 2.5 and 5% of S1O2 by Nb20s, generating two series of glasses, (I) and (II), respectively.
  • Table 1 provides the nomenclature, composition, and network connectivity for all materials that were prepared to exemplify this invention. ,
  • CaCO3 and Na2CO3 were mixed with S1O2 and macerated in an agate grail for complete homogenization of the precursor materials. This mixture was then baked in a platinum crucible for the decarbonation step: heating at a speed of 5 ° C min 1 from room temperature to 500 ° C and employing a heating rate of 3 ° C min 1 to 950 ° C, which was held for 3 hours.
  • the oxide mixture obtained after the decarbonation step was homogenized and stored in plastic bottles in a desiccator until the preparation of the bioglass. B20s and / or P2O5 were added to the mix only moments before the oxide fusion process.
  • the fusion was performed in a Pt crucible using a Lindberg / Blue M 1700 ° C oven (Model BF51524C, Thermo Electron Corporation, Asheville, NC, USA) at 1400 ° C for 3 hours. During this time, the melt was carefully stirred twice to homogenize the mixture. After melting time the melt was poured into graphite (cylindrical shape) and annealed at 500 ° C for 12 hours to relieve stress and stress on the glass block structure.
  • a Lindberg / Blue M 1700 ° C oven Model BF51524C, Thermo Electron Corporation, Asheville, NC, USA
  • the obtained glass block was cut into discs 1 mm thick and 30 mm in diameter.
  • the discs were polished using silicon carbide at 220, 500, 1000 and 1500 mesh size and finally with 6pm polycrystalline diamond paste.
  • the powder fractions employed in this study were obtained by pouring the melt into water (frits method).
  • the obtained granules were milled in agate grains and selected with the help of sieves with granulometry 38 ⁇ ⁇ 53 ⁇ .
  • the diffractograms for Series I specimens confirm the non-crystalline nature of these materials by the absence of diffraction peaks, and only an amorphous halo (2 ⁇ -34 °) can be observed in the analysis region ( 10 ⁇ 2 ⁇ ⁇ 50). Such behavior is peculiar to short-range vitreous silicate materials.
  • Glazing has been characterized by its thermal properties, which provide information that is important to evaluate the effects of Nb20s addition on the microstructure of glazing.
  • Figure 2a-b shows the DSC results for series I and II glasses.
  • Table 3 shows all the thermal parameters extracted from the DSC curves for the glassy samples prepared to exemplify the glassy compositions described in this invention.
  • T g is not a defined temperature (commonly referred to as a temperature range) and may vary with the thermal history of the glass, it can be correlated with the degree of polymerization of the glass lattice.
  • T g can be attributed to structural changes that lead to an increase in the degree of polymerization of the vitreous network for BGNs.
  • Figure 3a-b shows the Raman spectra for the vitreous compositions belonging to series I and II and BG45S5. This spectrum can be divided into three regions: low frequencies (highlighted region), frequencies i ⁇
  • the low frequency region of the spectra exhibits some discrete peaks attributed to ring structures in the glass network (symmetrical mode of ring respiration, mainly involving oxygen movement, glassy silica network defects, or glass breathing modes). planar rings of three and four member rings). Although, a gradual increase in intensity is observed as a function of niobium oxide content, no absorption was observed at 220 or 593 cm 1 , confirming the absence of Nb-O-Nb bonds in the studied glasses.
  • the intermediate region of the frequency spectrum can be observed at a wide peak at about 630 crrr 1 for BG45S5, which has been attributed to the symmetrical deformation of Si-O-Si in Si0 4 three-membered rings, oxygen balance.
  • Figure 4 shows the pH curve profiles in deionized water and HEPES buffered solution for BG45S5 and BGNs of series I and II.
  • a marked increase in pH occurs within the first hour of immersion for all materials under study.
  • the variation in pH is dependent on the amount of leached cation we can verify that the materials BGSN1 and BGPN1 .3 are more soluble than BG45S5.
  • So Nb-modified bioglass can be sorted for solubility with BGSN1 -BGPN1 .3>BG45S5>BGP2.6>BGSN2.5> BGSN5.
  • Figure 6 shows the result for the cell viability study for BGN's for times 1, 7 and 14 days. According to the results obtained, a tendency of increasing the number of cells with time was observed in all cultures, confirming the cell viability for all studied glasses. After 1 day, the osteoblasts adhered and proliferated on the surface of the BGNs bioglass presenting, however, a lower rate when compared to the control. Between the groups it is possible to verify a difference between the materials BGSN2.5 and BGPN2.6, which presented a higher cell viability compared to BG45S5. After 7 days of cultivation, a continuous growth in the number of osteoblasts adhered to the surface of all samples can be observed, however, showed a lower degree in relation to the control.

Abstract

The present invention relates to a bioactive vitreous composition comprising niobium oxide, and to the use thereof for bone regeneration. The present invention pertains to the field of the chemistry of scaffold-comprising materials for bone tissue engineering and osteoregenerative medicine, and is aimed at correcting bone defects caused by diseases or accidents. The present application relates to a bioactive vitreous composition (bioglass) comprising from 40 to 55 mol% SiO2, from 23 to 33 mol% CaO, from 20 to 30 mol% Na2O, from 0.001 to 5 mol% P2O5 and from 0.001 to 5 mol% Nb2O5. This composition has medical and odontological uses as bone filling material, as scaffold for bone tissue engineering, for bioactive coatings and for the treatment of dentin hypersensitivity.

Description

COMPOSIÇÃO VÍTREA BIOATIVA E SEU USO PARA REGENERAÇÃO  BIOACTIVE VITREA COMPOSITION AND ITS USE FOR REGENERATION
ÓSSEA BONE
CAMPO DA INVENÇÃO FIELD OF INVENTION
[001] A presente invenção refere-se a uma composição vítrea bioativa que compreende óxido de nióbio e seu uso para regeneração óssea.  The present invention relates to a bioactive glassy composition comprising niobium oxide and its use for bone regeneration.
[002] A presente invenção se insere no campo da Química de Materiais compreendendo scaffolds para engenharia tecidual óssea, medicina osteoregenerativa e têm a sua aplicação direcionada no preenchimento de defeitos ósseos causados por doenças ou acidentes.  [002] The present invention is in the field of Material Chemistry comprising bone tissue engineering scaffolds, osteoregenerative medicine and its application is directed to the filling of bone defects caused by disease or accident.
FUNDAMENTOS DA INVENÇÃO BACKGROUND OF THE INVENTION
[003] Um biomateria! ideal requer compatibilidade bioquímica e biomecânica adequada. Os biovidros possuem a vantagem de estimular a osteogênese, porém, apresentam a mesma desvantagem que é encontrada nas cerâmicas e vidros, a sua fragilidade. Por outro lado, modificações na estrutura dos biovidros ou a sua combinação com outros materiais ofereceram um meihor desempenho biomecânico. Neste contexto, a obtenção de materiais vítreos com melhores propriedades mecânicas e propriedades bioativas é um grande desafio para a ciência dos materiais.  [003] A biomaterial! ideal requires adequate biochemical and biomechanical compatibility. Bioglass has the advantage of stimulating osteogenesis, however, have the same disadvantage that is found in ceramics and glass, its fragility. On the other hand, modifications in the structure of bioglass or its combination with other materials offered better biomechanical performance. In this context, obtaining glassy materials with better mechanical properties and bioactive properties is a major challenge for materials science.
[004] O nióbio tem sido usado em ligas de titânio para implantes endósseos em virtude de sua excelente biocompatibilidade, resistência à corrosão e a fadiga superiores. Em composições vítreas, a presença do nióbio em sua forma de óxido (Nb20s), tem exibido comportamento similar. Sabe-se que a adição de óxido de nióbio em vidros fosfatos melhora sua durabilidade química e que a presença de nióbio em biovidros de nióbiofosfatos promove significativas melhorias nas propriedades mecânicas deste material e confere, ainda, módulo de elasticidade próximo ao do osso cortical para os vidros fosfatos. Niobium has been used in titanium alloys for endosseous implants because of its excellent biocompatibility, superior corrosion resistance and fatigue. In glassy compositions, the presence of niobium in its oxide form (Nb20s) has exhibited similar behavior. The addition of niobium oxide in phosphate glasses improves its chemical durability and the presence of niobium in niobium phosphate bioglass promotes significant improvements in the mechanical properties of this material and confers, also, modulus of elasticity close to the cortical bone for the phosphate glasses.
[005] Do ponto de vista estrutural, há a indicação que o Nb5+ substitui P5+ nas ligações P-O-P em vidros nióbiofosfatos. De fato, observa-se uma semelhança química entre os elementos Nb e P no que diz respeito ao estado de oxidação mais comum (5+) e, consequentemente na tendência de formação de compostos químicos análogos, por exemplo, Nb20s e P2O5. Estas considerações tornam o Nb20s interessante para substituir o P2O5 no biovidro 45S5. From a structural point of view, there is an indication that Nb 5+ replaces P 5+ in POP bonds in niobiophosphate glasses. In fact, there is a chemical similarity between the elements Nb and P with regard to the most common oxidation state (5+) and, consequently, the tendency of formation of analogous chemical compounds, eg Nb20s and P2O5. These considerations make Nb20s interesting to replace P2O5 in the 45S5 bioglass.
[006] Com relação à bioatividade, o comportamento do nióbio em composições vítreas para fins biomédicos tem sido pouco explorado. No entanto, o nióbio pode influenciar positivamente a formação da camada de apatíta e regular os genes que controlam a diferenciação das células envolvidas na osteogênese.  With respect to bioactivity, the behavior of niobium in vitreous compositions for biomedical purposes has been little explored. However, niobium can positively influence apatite layer formation and regulate the genes that control the differentiation of cells involved in osteogenesis.
[007] Do ponto de vista de bicompatibilidade, íons Nb5+ tem apontado citotoxicidade reduzida, promoção significativa da calcificação de osteoblastos humanos normais, além de apresentar potencial de promover a atividade de fosfatase alcalina (ALP), um marcador importante para o processo de geração de osso novo. Além disso, a presença do óxido do nióbio melhora a biocompatilidade e promove a bioatividade.  From the standpoint of bicompatibility, Nb5 + ions have been shown to reduce cytotoxicity, significantly promote calcification of normal human osteoblasts, and have the potential to promote alkaline phosphatase (ALP) activity, an important marker for the process of generation of New bone. In addition, the presence of niobium oxide improves biocompatibility and promotes bioactivity.
[008] Alguns documentos do Estado da Técnica que apresentam ensinamentos próximos à presente invenção são citados abaixo:  [008] Some prior art documents providing teachings close to the present invention are cited below:
[009] O documento "Apatite-forming ability of niobium oxide gels in a simulated body fluid" publicado na revista Journal of Ceramic Society of Japan 109: 929-933 (2001) refere-se a géis de óxido nióbio com potencial aplicação para a formação de apatíta, assemeíhando-se à presente invenção peto fato de compreender um material à base de nióbio, aplicado a processos de osteoestimulação. Nb entanto, a presente invenção difere-se da tecnologia descrita no artigo pêlo fato do nosso material possuir uma estrutura vítrea derivada do sistema Si02-CaO-Na20-P20s-Nb205 o que pode potencializar a regeneração óssea peia lixiviação de íons da matriz, que em concentrações crítica, podem ter efeitos sobre a regulação de genes envolvidos no processo de biomineralização. O emprego do produto iônico de vidros bioativos para indução da diferenciação e proliferação celular é bem descrito na literatura para íons silício, cálcio e nióbio (Hench, L. L, Polak, J. M., Xynos, I. D., & Buttery, L. D. K. (2000). Bioactive materiais to control cell cycle. Materials Research ínnovations, 3(6), 313-323. doi: Doi 10.1007/S100190000055Hench, L.L, Xynos, I. D., Edgar, A. J., Buttery, L D. K., Polak, J. M., Zhong, J. P., . . . Chang, J. (2002). Gene activating glasses Journal of Inorganic Materials, 17(5), 897-909. Obata, A., Takahashi, Y., Miyajima, T., Ueda, K., Narushima, T., & Kasuga, T. (2012). Effects of niobium ions released from calcium phosphate invert glasses containing Nb205 on osteoblast-like cell functions. ACS Appl Mater Interfaces, 4(10), 5684-5690. doi: 10.1021/am301614aXynos, I. D., Edgar, A. J., Buttery, L. D., Hench, L. L, & Polak, J. M. (2000a). lonic products of bioactive glass dissolution increase proliferation of human osteoblasts and induce insulin-like growth factor II mRNA expression and protein synthesis. Biochemical and Biophysical Research Communications, 276(2), 461-465. doi: 10.1006/bbrc.2000.3503Xynos, I. D., Edgar, A. J., Buttery, L. D. K,, Hench, L. L., & Polak, J. M. (2001a). Gene-expression profiling of human osteoblasts following treatment with the ionic products of Bioglass (R) 45S5 dissolution. Journal of Biomedical Materiais Research, 55(2), 151-157. Xynos, I. D., Edgar, A. J., Buttery, L. D. K., Hench, L. L, & Polak, J. M. (2001 b). Gene-expression profiling of human osteoblasts following treatment with the ionic products of Bioglass® 45S5 dissolution. Journal of Biomedical Materials Research, 55(2), 151 -157. doi: 10.1002/1097-4636(200105)55:2<15 : :aid-jbm1001 >3.0.co;2-dXynos, I . D., Hukkanen, M. V., Batten, J. J., Buttery, L. D., Hench, L. L, & Polak, J. M. (2000b). Bioglass 45S5 stimulates osteoblast tumover and enhances bone formation In vitro: implications and appfications for bone tissue engineering. Calcified Tissue International, 67(4), 321-329.) . [009] The document "Apatite-forming ability of niobium oxide gels in a simulated body fluid" published in the Journal of Ceramic Society of Japan 109: 929-933 (2001) refers to niobium oxide gels with potential application. for the formation of apatite, resembling the present invention is that it comprises a niobium-based material applied to osteostimulation processes. However, the present invention differs from the technology described in the article in that our material has a glass structure derived from the Si02-CaO-Na20-P20s-Nb205 system which can enhance bone regeneration by matrix ion leaching. at critical concentrations, they may have effects on the regulation of genes involved in the biomineralization process. The use of the bioactive glass ion product to induce cell differentiation and proliferation is well described in the literature for silicon, calcium and niobium ions (Hench, L.L, Polak, JM, Xynos, ID, & Buttery, LDK (2000). Bioactive materials to control cell cycle Materials Research Innovations, 3 (6), 313-323 doi: Doi 10,1007 / S100190000055Hench, LL, Xynos, ID, Edgar, AJ, Buttery, L DK, Polak, JM, Zhong, JP, Chang, J. (2002) Gene activating glasses Journal of Inorganic Materials, 17 (5), 897-909 Obata, A., Takahashi, Y., Miyajima, T., Ueda, K., Narushima, T., & Kasuga, T. (2012) Effects of niobium ions released from calcium phosphate invert glasses containing Nb205 on osteoblast-like cell functions ACS Appl Mater Interfaces, 4 (10), 5684-5690 doi: 10.1021 / am301614aXynos , ID, Edgar, AJ, Buttery, LD, Hench, L.L, & Polak, JM (2000a) .onic products of bioactive glass dissolution increase proliferation of human osteoblasts and induce insulin-like growth factor II m RNA expression and protein synthesis. Biochemical and Biophysical Research Communications, 276 (2), 461-465. doi: 10.1006 / bbrc.2000.3503Xynos, ID, Edgar, AJ, Buttery, LDK, Hench, LL, & Polak, JM (2001a). Gene-expression profiling of human osteoblasts following treatment with the ionic products of Bioglass (R) 45S5 dissolution. Journal of Biomedical Materials Research, 55 (2), 151-157. Xynos, ID, Edgar, AJ, Buttery, LDK, Hench, L.L, & Polak, JM (2001b). Gene-expression profiling of human osteoblasts following treatment with the ionic products of Bioglass® 45S5 dissolution. Journal of Biomedical Materials Research, 55 (2), 151-157. doi: 10,1002 / 1097-4636 (200105) 55: 2-15:: aid-jbm1001>3.0c; 2-dXynos, I. D., Hukkanen, MV, Batten, JJ, Buttery, LD, Hench, L.L, & Polak, JM (2000b). Bioglass 45S5 stimulates osteoblast tumover and bone formation enhancements In vitro: implications and applications for bone tissue engineering. Calcified Tissue International, 67 (4), 321-329.).
[0010] O documento "Desenvolvimento de vidros niobofosfato bioattvos" publicado na tese de doutorado de Marcelo José Carbonari (2003), refere-se a composições de vidros niobofosfatos bioativos de melhor durabilidade química em relação a vidros de fosfato de cálcio, assemelhando-se à presente invenção pelo fato de compreender uma composição vítrea de fosfato e nióbio aplicada para osteoestimulação. No entanto, a presente invenção difere-se da tecnologia descrita no artigo pelo fato das composições vítreas serem baseadas em vidros silicatos. Ao contrário dos vidros fosfatos, os vidros silicatos tem sido associado a um aumento da osteogênese e neovascularização. Assim em nossa invenção combina os efeitos positivos dos íons silício e nióbio para promover o aumento da bioatividade. Além disso, os biovidros apresentados nesta invenção possuem um teor de Nb20s consideravelmente menor (< 5 % em mol), comparado ao apresentado pelo trabalho de Carbonari (8<x<15 % em mol).  The document "Development of bioattvos niobophosphate glasses" published in the doctoral thesis of Marcelo José Carbonari (2003), refers to bioactive niobophosphate glasses compositions with better chemical durability compared to calcium phosphate glasses, resembling to the present invention in that it comprises a glassy niobium phosphate composition applied for osteostimulation. However, the present invention differs from the technology described in the article in that the glassy compositions are based on silicate glasses. Unlike phosphate glasses, silicate glasses have been associated with increased osteogenesis and neovascularization. Thus in our invention it combines the positive effects of silicon and niobium ions to promote increased bioactivity. In addition, the bio-glasses presented in this invention have a considerably lower Nb20s content (<5 mol%) compared to that presented by Carbonari's work (8 <x <15 mol%).
[0011]0 documento "Resposta do tecido subcutâneo de camundongos à implantação de um novo biovidro à base de óxido de nióbio" publicado na revista Matéria 16: 574-582 (2011) refere-se a um biovidro à base de óxido de nióbio, assemelhando-se à presente invenção pelo fato de compreender um material vítreo de nióbio com características oesteoestimulantes. No entanto, a presente invenção difere-se da tecnologia descrita no artigo pelo fato da matriz vítrea abordada pelo artigo ser fosfato pertencente ao P205-BaO-K20-Nb20s e o teor de ND2O5 ser maiores que 5% em mol. [0011] The document "Mouse subcutaneous tissue response to implantation of a new niobium oxide-based bioglass" published in the journal Matter 16: 574-582 (2011) refers to a niobium oxide-based bioglass, resembling the present invention in that it comprises a glassy niobium material with western stimulating characteristics. However, the present invention differs from the technology described in the article in that the glassy matrix addressed by the article is phosphate belonging to P205-BaO-K20-Nb20s and the ND2O5 content is greater than 5 mol%.
[0012]O documento "Effects of Niobium lons Released from Calcium Phosphate Invert Glasses Containing Nb2Os on Osteoblast-Like Celi Functions" publicado na revista Applied Materials & Interfaces 4: 5684-5690 (2012) refere- se a vidro de fosfato, cálcio e nióbio com função osteoestimulante, assemelhando-se à presente invenção pelo fato de compreender um vidro de composição similar (60CaO-(10-x)-Na2O-30P2O5-xNb2O5 (mol %, x = 0-10%). No entanto, a presente invenção difere-se do documento citado pelo fato compreender composição distinta. Na invenção proposta a matriz vítrea é composta majoritariamente por silicato, o qual, em concentração crítica, está relacionado ao aumento da diferenciação e da proliferação celular. Além disso, a concentração de fosfatos, relacionados à instabilidade estrutural quando em significativas quantidades, é baixa na presente invenção. Em contrapartida, no artigo descrito a matriz vítrea é composta majoritariamente pelas referidas espécies químicas. Adicionalmente, sabendo-se que, a presença do fosfato não é requerida para a bioatividade em vidros, a presente invenção detém vantagens estruturais e de aplicação em relação ao artigo mencionado. [0012] The document "Effects of Niobium lons Released from Calcium Phosphate Invert Glasses Containing Nb 2 Osteoblast-Like Celi Functions" published in Applied Materials & Interfaces 4: 5684-5690 (2012) refers to phosphate glass, calcium and niobium with osteostimulating function, resembling the present invention in that it comprises a glass of similar composition (60CaO- (10-x) -Na2O-30P2O 5 -xNb2O5 (mol%, x = 0-10%). However, the present invention differs from the document cited in that it comprises a distinct composition: In the proposed invention the vitreous matrix is composed mainly of silicate which, in critical concentration, is related to the increase of cell differentiation and proliferation. the phosphate concentration, related to the structural instability when in significant quantities, is low in the present invention In contrast, in the described article the glass matrix is composed mainly of the ref In addition, knowing that the presence of phosphate is not required for bioactivity in glasses, the present invention has structural and application advantages over the mentioned article.
[0013]O documento de patente US20140271565A1 refere-s4 a um vidro cerâmico de fluoroapatita, assemelhando-se à presente invenção pelo fato de compreender um vidro de composição similar ((32,3 ou 31 ,5}Si02-(23,9; 19,0; 11,9; 6,0 ou 0)CaO-(2,9 ou 2,3)-Na2O-(5,0 ou 5,1)P2O5-0,2Nb2oJ-MgO-SrO- K20-AÍ203-CaF2) - em porcentagens molares. Além disso, a tecnologia relatada em US20140271565A1 detém propriedades osteoestimulantes. No entanto, a presente invenção difere-se da tecnologia descrita na patente pelo fato de apresentar uma composição distinta e de não apresentar uma estrutura cristalina. O sistema descrito na tecnologia é complexo, compreendendo dez componentes. Além disso, o sistema descrito não forma vidro, e sim vitro- cerâmica (há cristalinidade). Sabendo-se que a cristalização proporciona redução da bioatividade em virtude do aprisionamento dos íons no cristal, a tecnologia relatada em US20140271565A1 apresenta limitações no que se refere à osteoestimulação. Assim, pode ser esperado uma menor taxa de lixiviação para essa composição e, consequentemente, menor potencial de aplicação. A presença dos óxidos MgO, SrO, K2O e CaF2 está associada a diferentes respostas biológicas associadas com cada um. US20140271565A1 relates to a fluoroapatite ceramic glass, resembling the present invention in that it comprises a glass of similar composition ((32,3 or 31,5} Si0 2 - (23,9 , 19.0, 11, 9, 6, 0 , or 0) dog-(2.9 or 2.3) -Na 2 O (5.0 or 5.1) 2 P 2 O5-0,2Nb oJ- MgO-SrO- K 2 O-A 2 O 3 -CaF 2) - in molar percentages. In addition, the technology reported in US20140271565A1 has osteostimulating properties. However, the present invention differs from the technology described in the patent in that it has a distinct composition and no crystal structure. The system described in the technology is complex, comprising ten components. In addition, the described system does not form glass, but in vitro ceramics (there is crystallinity). As crystallization is known to reduce bioactivity due to the entrapment of ions in the crystal, the technology reported in US20140271565A1 has limitations regarding osteostimulation. Thus, a lower leaching rate can be expected for this composition and, consequently, a lower application potential. The presence of MgO, SrO, K2O and CaF2 oxides is associated with different biological responses associated with each one.
[0014]Sabe-se que o ND2O5, tanto em vidros nióbio fosfatos quanto em vidros nióbio silicatos, promove mudanças estruturais que conferem uma melhor durabilidade química e desempenho biomecânico à matriz vítrea. Todavia, tais mudanças podem comprometer a bioatividade devido à redução da solubilidade e, consequentemente, uma diminuição da disponibilidade dos íons silício e cálcio, os quais, quando liberados de forma controlada, desempenham um papel importante na regulação e ativação de genes em células osteoprogenitoras. A referida problemática é evidente nas tecnologias mais próximas relatadas nesse tópico. Dessa maneira, o conhecimento prévio desses aspectos envolvendo vidros contendo nióbio proporcionou a escolha de composições vítreas com concentrações reduzidas de Nb20s e fosfatos conforme a proposta do presente pedido de patente. BREVE DESCRIÇÃO DA INVENÇÃO ND2O5, both in niobium phosphate glasses and niobium silicate glasses, is known to promote structural changes that impart better chemical durability and biomechanical performance to the glass matrix. However, such changes may compromise bioactivity due to reduced solubility and, consequently, decreased availability of silicon and calcium ions, which, when released in a controlled manner, play an important role in gene regulation and activation in osteoprogenitor cells. This problem is evident in the closest technologies reported in this topic. Thus, prior knowledge of these aspects involving niobium-containing glasses led to the choice of glass compositions with reduced concentrations of Nb20s and phosphates according to the proposal of the present patent application. BRIEF DESCRIPTION OF THE INVENTION
[0015] A presente invenção refere-se a uma composição vítrea bioativa que compreende óxido de nióbio e seu uso para regeneração óssea.  The present invention relates to a bioactive glass composition comprising niobium oxide and its use for bone regeneration.
[0016] A composição vítrea bioativa compreende os seguintes componentes:  The bioactive glassy composition comprises the following components:
- S1O2 em quantidades entre 40 e 55 %mol;  - S1O2 in amounts between 40 and 55 mol%;
- CaO em quantidades entre 23 e 33 %mol;  - CaO in amounts between 23 and 33 mol%;
- Na20 em quantidades entre 20 e 30 %mol;  - Na20 in amounts between 20 and 30 mol%;
- P2O5 em quantidades entre 0,001 e 5 %mol; e  - P2O5 in amounts between 0.001 and 5 mol%; and
- NbaOs em quantidades entre 0,001 e 5 %mol.  - NbaOs in amounts between 0.001 and 5 mol%.
[0017] Mais especificamente, a composição vítrea bioativa compreende preferencialmente 46,1 %mo! de S1O2, 26,9' %mol de CaO, 24,4 %mol de Na20, ,3 %mol de P2O5, e 1 ,3 %mol de Nb20s More specifically, the bioactive glass composition preferably comprises 46.1% by weight. of S1O2, 26.9 ' mol% CaO, 24.4 mol% Na20, 3 mol% P2O5, and 1.3 mol% Nb20s
[0018] Além disso, a composição vítrea bioativa tem aplicação médica e odontológica, como biomateriais de preenchimento ósseos, para regeneração óssea, scaffoids para engenharia de tecido ósseo, revestimentos bioativos para biomateriais metálicos bioinertes e no tratamento de hipersensibilidade dentinária  In addition, the bioactive glass composition has medical and dental application, such as bone filler biomaterials, for bone regeneration, bone tissue engineering scaffoids, bioactive coatings for bioinert metallic biomaterials, and in the treatment of dentin hypersensitivity.
BREVE DESCRIÇÃO DAS FIGURAS  BRIEF DESCRIPTION OF THE FIGURES
[0019]A Figura 1 mostra os difratogramas de raios X referentes às composições vítreas bioativas selecionadas para exemplificar a presente invenção. O difratograma para o BG45S5 foi adicionado somente a título de comparação.  Figure 1 shows the X-ray diffractograms of the bioactive glass compositions selected to exemplify the present invention. The diffractogram for BG45S5 has been added for comparison only.
[0020]A Figura 2 mostra as curvas de DSC (Differential scanning calorimetry) para às composições vítreas bioativas selecionadas para exemplificar a presente invenção, (a) BGPN1.3 e BGPN2.6 e (b) BGSN1 , BGSN2.5 e BGSN5. A curva de DSC para o BG45S5 foi adicionada somente a título de comparação. [0020] Figure 2 shows DSC (Differential scanning calorimetry) curves for the bioactive glass compositions selected for exemplify the present invention, (a) BGPN1.3 and BGPN2.6 and (b) BGSN1, BGSN2.5 and BGSN5. The DSC curve for BG45S5 has been added for comparison only.
[0021] A Figura 3 mostra os espectros Raman indicando os efeitos do óxido de nióbio sobre a estrutura vítrea (a) BGPN1.3 e BGPN2.6 e (b) BGSN1 , BGSN2.5 e BGSN5. O espectro Raman para o BG45S5 foi adicionado somente a título de comparação.  Figure 3 shows the Raman spectra indicating the effects of niobium oxide on the vitreous structure (a) BGPN1.3 and BGPN2.6 and (b) BGSN1, BGSN2.5 and BGSN5. The Raman spectrum for BG45S5 has been added for comparison only.
[0022]A Figura 4 mostra os dados obtidos dos ensaios de nanoindentação para os efeitos do Nb20s sobre as propriedades mecânicas de (a) dureza e (b) módulo de elasticidade dos biovidros contendo Nb20s.  Figure 4 shows data obtained from nanoindentation tests for the effects of Nb20s on the mechanical properties of (a) hardness and (b) modulus of elasticity of Nb20s containing bioglass.
[0023]A Figura 5 mostra as curvas de solubilidade obtidas pelo estudo da variação de pH em água em função do tempo de imersão.  [0023] Figure 5 shows the solubility curves obtained by studying the pH variation in water as a function of immersion time.
[0024jA Figura 6 mostra os dados de viabilidade celular obtidos pelos ensaios de MTT em culturas de osteoblastos isolados da calvaria de ratos para os tempos de 1 , 7 e 14 dias de cultura.  Figure 6 shows the cell viability data obtained by MTT assays in osteoblast cultures isolated from the calvaria of rats for times 1, 7 and 14 days of culture.
[0025]A Figura 7 mostra micrografias do osso subperiostal neoformado na cortical adjacente ao implante em todos os grupos após 28 dias pós- cirúrgicos. Coloração Hematoxilina-Eosina. Aumento total de 200x.  Figure 7 shows micrographs of the newly formed subperiosteal bone in the cortex adjacent to the implant in all groups after 28 postoperative days. Hematoxylin-Eosin Staining. 200x total increase.
[0026JA Figura 8 mostra área média de osso subperiostal formado na cortical adjacente ao implante vítreo em todos os grupos após 14 e 28 dias de cirurgia.  Figure 8 shows the average area of subperiosteal bone formed in the cortex adjacent to the vitreous implant in all groups after 14 and 28 days of surgery.
[0027]A Figura 9 mostra a densidade média de vasos sanguíneos na área de implante em todos os grupos após 28 dias pós- operatórios.  Figure 9 shows the mean blood vessel density in the implant area in all groups after 28 postoperative days.
DESCRIÇÃO DETALHADA DA INVENÇÃO [0028]A presente invenção refere-se a uma composição vítrea bioativa que compreende os seguintes componentes: DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a bioactive glassy composition comprising the following components:
- S1O2 (sílica);  - S1O2 (silica);
- CaO (óxido de cálcio);  - CaO (calcium oxide);
- Na20 (óxido de sódio);  - Na20 (sodium oxide);
- P2O5 (Pentóxido de fósforo);  - P2O5 (Phosphorus Pentoxide);
- Nb20õ (Pentóxido de nióbio);  - Nb206 (niobium pentoxide);
[0029] Mais especificamente, a composição acima compreende as seguintes porcentagens molares dos componentes:  More specifically, the above composition comprises the following molar percentages of the components:
- S1O2 (sílica) em quantidades entre 40 e 55, preferencialmente 46,1 - S1O2 (silica) in amounts between 40 and 55, preferably 46.1
%mol; % mol;
- CaO (óxido de cálcio) em quantidades entre 23 e 33, preferencialmente 26,9 %mol;  - CaO (calcium oxide) in amounts between 23 and 33, preferably 26.9 mol%;
- Na2O (óxido de sódio) em quantidades entre 20 e 30, preferencialmente 24,4 %mol;  Na 2 O (sodium oxide) in amounts between 20 and 30, preferably 24.4 mol%;
- P2O5 (pentóxido de fósforo) em quantidades entre 0,001 e 5, preferencialmente 1 ,3 %mol;  P2O5 (phosphorus pentoxide) in amounts between 0.001 and 5, preferably 1.3 mol%;
- Nb2Oõ (pentóxido de nióbio) em quantidades entre 0,001 e 5, preferencialmente 1 ,3 %mol;  - Nb206 (niobium pentoxide) in amounts between 0.001 and 5, preferably 1.3 mol%;
[0030]A composição da presente invenção é baseada nos óxidos S1O2, CaO, Na2O, P2O5 e Nb2Os. A presença do Nb2Os em quantidades menores que 5% em mol é uma inovação quando comparado com biovidros comerciais.  The composition of the present invention is based on the oxides S1O2, CaO, Na2O, P2O5 and Nb2Os. The presence of Nb2Os in amounts less than 5 mol% is an innovation compared to commercial bioglass.
[0031 ] Os biovidros preparados com quantidades reduzidas de Nb2Os promove modificações na rede vítrea aumentando a solubilidade e, consequentemente, aumentando a quantidade dos íons silício, cálcio e nióbio no meio. A presença destes íons aumenta a viabilidade celular, através do controle direto dos genes que controlam os processos de diferenciação e proliferação celular. Bio-glasses prepared with reduced amounts of Nb2Os promote changes in the vitreous network increasing solubility and consequently increasing the amount of silicon, calcium and niobium ions in the glass. middle. The presence of these ions increases cell viability through direct control of the genes that control the processes of cell differentiation and proliferation.
[0032]Os ensaios in vivo confirmam que a presença do b20s induz uma maior formação de tecido ósseo e também a angiogênese comparados a biovidros sem a presença deste óxido (Nb20s), o que é de extrema importância para o processo de biomineralização.  In vivo assays confirm that the presence of b20s induces a greater formation of bone tissue and also angiogenesis compared to bioglass without the presence of this oxide (Nb20s), which is extremely important for the biomineralization process.
[0033]Além disso, a presença do Nb20s nas composições vítreas permite modular as propriedades mecânicas, estabilidade térmica e a durabilidade química dos biovidros ampliando suas aplicações no campo de biomateriais.  In addition, the presence of Nb20s in the glassy compositions allows modulating the mechanical properties, thermal stability and chemical durability of bioglass, expanding its applications in the field of biomaterials.
[0034] Vale ressaltar que o nióbio é um elemento estratégico para o desenvolvimento económico do país, uma vez que 98 % de todas as reservas de nióbio conhecidas estão localizadas em território brasileiro.  It is noteworthy that niobium is a strategic element for the country's economic development, since 98% of all known niobium reserves are located in Brazilian territory.
[0035]A presente invenção refere-se, ainda ao uso da composição vítrea bioativa à base de óxido de nióbio na regeneração de tecido ósseo, na indução da formação de vasos sanguíneos a partir de vasos existentes (característica positiva para regeneração de qualquer tipo de tecido), como bactericida, agente hemostático e em sistemas de drug delívery para liberação controlada de fármacos e/ou terapia celular.  The present invention further relates to the use of the niobium oxide-based bioactive glass composition in the regeneration of bone tissue, the induction of blood vessel formation from existing vessels (positive feature for regeneration of any type of bactericidal, hemostatic agent, and drug delirium systems for controlled drug delivery and / or cell therapy.
[0036] Mais especificamente a presente invenção refere-se a uma série vítrea (relativo a uma série formada por diferentes composições vítreas contendo óxido de nióbio) contendo óxido de nióbio (Nb20s) com elevada bioatividade e capacidade osteoestimuladora. Em concentrações adequadas em composições vítreas, o Nb20s promove um aumento da solubilidade, melhora as propriedades mecânicas e é eficiente para estimulação óssea. As aplicações dos biovidros são variadas, podendo ser usadas para preenchimento de cavidades nos ossos causadas por fraturas, infecções ou câncer, para a restauração de defeitos periodontais, reconstruções faciais e de osteotomias. More specifically the present invention relates to a vitreous series (relative to a series formed by different glass compositions containing niobium oxide) containing niobium oxide (Nb20s) with high bioactivity and osteostimulatory capacity. At appropriate concentrations in glassy compositions, Nb20s promotes increased solubility, improves mechanical properties and is efficient for bone stimulation. Bioglass applications are They can be used to fill bone cavities caused by fractures, infections or cancer, to restore periodontal defects, facial reconstruction and osteotomies.
[0037] Processado na forma de pó o material pode ser usado no tratamento de úlceras gástricas, feridas de pele e queimaduras, uma vez que apresenta propriedades hemostáticas e bactericidas. Devido a sua alta bioatividade e rápida formação de hídroxiapatita a partir da precipitação do cálcio e fósforo esse material pode ser incorporado a composição de cremes dentais para o tratamento de hipersensibilidade, por propiciar a oclusão dos canalículos dentinários.  Processed in powder form the material can be used in the treatment of gastric ulcers, skin wounds and burns as it has hemostatic and bactericidal properties. Due to its high bioactivity and rapid formation of hydroxyapatite from calcium and phosphorus precipitation, this material can be incorporated into the composition of toothpastes for the treatment of hypersensitivity, as it provides occlusion of dentinal canals.
[0038] As composições vítreas desenvolvidas são completamente biocompatíveis e apresentam uma dissolução parcial de sua superfície, liberando íons, os quais em concentrações ótimas possuem ação terapêutica.  The glassy compositions developed are completely biocompatible and have a partial dissolution of their surface, releasing ions, which in optimal concentrations have therapeutic action.
[0039]Além disso, as composições vítreas descritas nesta invenção podem ser exploradas em compósitos para o preparo de estruturas secundárias porosas para a engenharia de tecidos (scaffolds), desenvolvimento de dispositivos carregados com fármacos e/ou células para uma liberação controlada dos mesmos para o tratamento de cânceres e infecções focais e diversas outras aplicações.  Furthermore, the glassy compositions described in this invention may be exploited in composites for the preparation of porous secondary structures for tissue engineering (scaffolds), development of drug and / or cell-loaded devices for controlled release thereof. the treatment of cancers and focal infections and various other applications.
EXEMPLOS EXAMPLES
[0040]Todos os resultados foram confrontados com o biovidro 45S5 Bioglass® a título de comparação, em razão de sua elevada bioatividade e por ser um produto comercial.  All results were compared with the 45S5 Bioglass® bio glass by way of comparison because of its high bioactivity and because it is a commercial product.
[0041 ] Para obtenção das composições vítreas foi utilizada a metodologia que se baseia nos processos de preparação de vidros convencionais produzidos, tradicionalmente, através do método de fusão/resfriamento. Esse método envolve a fusão de uma mistura dos materiais de partida, seguido de um resfriamento rápido suficiente para vitrificação. In order to obtain the glass compositions, the methodology which is based on the conventional glass preparation processes produced was used, traditionally through the melting / cooling method. This method involves melting a mixture of the starting materials, followed by rapid cooling sufficient for glazing.
[0042]A composição química do biovidro 45S5 (46,1 Si02 - 26,9 CaO - 24,4 Na20 - 2,6% P2O5 em % molar) foi modificada pela substituição de 1 ,3 e 2,6% de P2O5 por ND2O5 ou pela substituição de , 2,5, e 5% de S1O2 por Nb20s, gerando duas séries de vidros, (I) e (II), respectivamente.  The chemical composition of the 45S5 bioglass (46.1 Si02 - 26.9 CaO - 24.4 Na20 - 2.6% P2O5 in mol%) was modified by replacing 1, 3 and 2.6% P2O5 with ND2O5 or the substitution of 2.5 and 5% of S1O2 by Nb20s, generating two series of glasses, (I) and (II), respectively.
[0043]A nomenclatura dos biovidros das séries I e II foi baseada nas variações introduzidas na composição química do biovidro 45S5. Deste modo, a seguinte norma foi adotada: BG (Bioglass) + símbolo do óxido removido + símbolo do óxido incrementado + a quantidade em porcentagem em mol. Para exemplificar, BGSN5, significando que o S1O2 foi substituído por Nb20s na quantidade de 5% em moi. Além disso, a nomenclatura simplificada BGNs será empregada para se referir a todas as amostras modificadas por ND2O5.  The nomenclature of series I and II bio-glasses was based on the variations introduced in the chemical composition of the 45S5 bio-glass. Thus, the following standard was adopted: BG (Bioglass) + symbol of removed oxide + symbol of increased oxide + quantity in mol percentage. For example, BGSN5, meaning that S1O2 was replaced by Nb20s in the amount of 5% moi. In addition, the simplified nomenclature BGNs will be employed to refer to all ND2O5 modified samples.
[0044]A Tabela 1 traz a nomenclatura, composição e conectividade de rede para todos os materiais que foram preparados para exemplificar essa invenção. ,  Table 1 provides the nomenclature, composition, and network connectivity for all materials that were prepared to exemplify this invention. ,
Tabela 1. Nomenclatura, composição química para os diferentes materiais vítreos preparados. \ Table 1. Nomenclature, chemical composition for the different prepared glass materials. \
Composição química (% molj  Chemical composition (% mol)
Vidros Glasses
Figure imgf000014_0001
Figure imgf000014_0001
BG45S5 46 o —— — -~ — ^ Õ ~ BG45S5 46 o —— - - ~ - ^ Õ ~
Série Series
BGPN1.3 26,90 ' 24,40 ' 1,30 BGPN1.3 26.90 '24 .40 ' 1.30
BGPN2.6 26,90 ~~ 24,40 " 0.00 Série II BGPN2.6 26.90 ~~ 24.40 " 0.00 Series II
BGSN1 45, 10 26,90 24,40 2,60 1,00 BGSN1 45, 10 26.90 24.40 2.60 1.00
BGSN2.5 43,60 26,90 24,40 2,60 2,50BGSN2.5 43.60 26.90 24.40 2.60 2.50
BGSN5 41, 10 26, 90 24,40 2,60 5,00 BGSN5 41, 10 26, 90 24.40 2.60 5.00
[0045]Todos os reagentes precursores empregados no preparo dos vidros neste trabalho e suas características estão expostos na Tabela 2.  All precursor reagents employed in glass preparation in this work and their characteristics are set forth in Table 2.
Tabela 2. Características de todos os reagentes precursores dos materiais vítreos preparados. Table 2. Characteristics of all precursor reagents of prepared glassy materials.
Reagente Precursor Fornecedor Pureza  Precursor Reagent Supplier Purity
S1O2 S O2 Sigma-Aldrich 99,8% S1O2 S O2 Sigma-Aldrich 99.8%
CaO CaC03 Merck >99,5%CaO CaC0 3 Merck> 99.5%
Na20 Na2COJa> Sigma-Aldrich 99,00%Na 2 0 Na 2 COJ a > Sigma-Aldrich 99.00%
P2O5 P2O5 Sigma-Aldrich 99,99%P2O5 P2O5 Sigma-Aldrich 99.99%
NbaOs Nb2Os CBMMW >99%NbaOs Nb 2 O s CBMMW> 99%
(a)0 ND2Õ5 de grau ótico foi doado pela^ompanhia Brasileira de Metalurgia e (a) The optical grade ND2Õ5 was donated by the Brazilian Metallurgy and
Mineração (CBMM).  Mining (CBMM).
[0046] Previamente à fusão, CaC03 e Na2C03 foram misturados ao S1O2 e macerados em um graal de ágata para a homogeneização completa dos materiais precursores. Em seguida, essa mistura foi levada ao forno em cadinho de platina para a etapa de descarbonatação: aquecimento a uma velocidade de 5 °C min 1 da temperatura ambiente a 500 °C e empregando uma taxa de aquecimento de 3 °C min 1 até 950 °C, a qual foi mantida por 3 horas. A mistura dos óxidos obtida após a etapa de descarbonatação foi homogeneizada e armazenada em frascos plásticos em dessecador até o momento do preparo do biovidro. O b20s e/ou P2O5 foram acrescentados à mistura somente momentos antes do processo de fusão dos óxidos. A fusão foi realizada em cadinho de Pt, empregando um forno Lindberg/Blue M 1700 °C (modelo BF51524C, Thermo Electron Corporation, Asheville, NC, USA) a 1400 °C por 3 horas. Durante esse período, o fundido foi cuidadosamente agitado por duas vezes para homogeneização da mistura. Terminado o tempo de fusão o fundido foi vertido em forma de grafite (formato cilíndrico) e recozido a 500 °C por 12 horas para aliviar as tensões e estresse na estrutura do bloco de vidro. Prior to fusion, CaCO3 and Na2CO3 were mixed with S1O2 and macerated in an agate grail for complete homogenization of the precursor materials. This mixture was then baked in a platinum crucible for the decarbonation step: heating at a speed of 5 ° C min 1 from room temperature to 500 ° C and employing a heating rate of 3 ° C min 1 to 950 ° C, which was held for 3 hours. The oxide mixture obtained after the decarbonation step was homogenized and stored in plastic bottles in a desiccator until the preparation of the bioglass. B20s and / or P2O5 were added to the mix only moments before the oxide fusion process. The fusion was performed in a Pt crucible using a Lindberg / Blue M 1700 ° C oven (Model BF51524C, Thermo Electron Corporation, Asheville, NC, USA) at 1400 ° C for 3 hours. During this time, the melt was carefully stirred twice to homogenize the mixture. After melting time the melt was poured into graphite (cylindrical shape) and annealed at 500 ° C for 12 hours to relieve stress and stress on the glass block structure.
[0047] O bloco de vidro obtido foi cortado em discos de 1 mm de espessura e 30 mm de diâmetro. Os discos foram polidos utilizando-se carbeto de silício nas granulometrias de 220, 500, 1000 e 1500 mesh e finalmente com pasta de diamante policristalina 6pm.  The obtained glass block was cut into discs 1 mm thick and 30 mm in diameter. The discs were polished using silicon carbide at 220, 500, 1000 and 1500 mesh size and finally with 6pm polycrystalline diamond paste.
[0048]As frações pó empregadas neste estudo foram obtidas pelo vertimento do fundido em água (método fritas). Os grânulos obtidos foram moídos em graal de ágata e selecionado com auxílio de peneiras a granulometria 38 < φ < 53μηη.  The powder fractions employed in this study were obtained by pouring the melt into water (frits method). The obtained granules were milled in agate grains and selected with the help of sieves with granulometry 38 <φ <53μηη.
[0049]Os difratogramas de raios X para os biovidros das séries I e II e vidros usados para comparação são mostrados na Figura 1.  [0049] X-ray diffractograms for Series I and II bio-glasses and glasses used for comparison are shown in Figure 1.
[0050] Os difratogramas para os corpos de provas das séries I e confirmam a natureza não-cristalina desses materiais pela ausência de picos de difração, sendo possível observar apenas a ocorrência de um halo amorfo (2Θ -34°) na região de análise (10 < 2Θ < 50). Tal comportamento é peculiar de materiais silicatos vítreos com ordenamento a curto alcance.  The diffractograms for Series I specimens confirm the non-crystalline nature of these materials by the absence of diffraction peaks, and only an amorphous halo (2Θ -34 °) can be observed in the analysis region ( 10 <2Θ <50). Such behavior is peculiar to short-range vitreous silicate materials.
[0051] Os vidros foram caracterizados por suas propriedades térmicas, as quais fornecem informações que são importantes para avaliar os efeitos da adição de Nb20s sobre a microestrutura dos vidros. A Figura 2a-b mostra os resultados obtidos por DSC para os vidros das séries I e II. A Tabela 3 apresenta todos os parâmetros térmicos extraídos das curvas de DSC para as amostras vítreas preparadas para exemplificar as composições vítreas descritas nesta presente invenção. [0051] Glazing has been characterized by its thermal properties, which provide information that is important to evaluate the effects of Nb20s addition on the microstructure of glazing. Figure 2a-b shows the DSC results for series I and II glasses. Table 3 shows all the thermal parameters extracted from the DSC curves for the glassy samples prepared to exemplify the glassy compositions described in this invention.
[0052] Conforme pode ser observado, as temperaturas relacionadas com os eventos térmicos Tg, Tx e Tc foram deslocados para temperaturas superiores com o acréscimo de óxido de nióbio (Nb20s). Este comportamento é um indicativo de modificações estruturais relacionadas a uma melhoria nas propriedades mecânicas e estabilidade química descrita para vidros contendo Nb205. Embora a Tg não seja uma temperatura definida (comumente referida como uma faixa de temperatura) e possa sofrer variações com a história térmica do vidro, ela pode ser correlacionada com o grau de polimerização da rede vítrea. Logo, o aumento da Tg observado pode ser atribuído a mudanças estruturais que conduzem a um aumento do grau de polimerização da rede vítrea para os BGNs. Tabela 3. Compilação dos dados térmicos obtidos via DSC: temperatura de transição vítrea Tg, temperatura de início de cristalização Tx, estabilidade vítrea ΔΤΧ9 (Τχ - Tg), temperatura de cristalização Tc e a variação de entalpia envolvendo o processo de cristalização (ΔΗσ). As can be seen, temperatures related to thermal events T g , T x and T c were shifted to higher temperatures with the addition of niobium oxide (Nb20s). This behavior is indicative of structural modifications related to an improvement in mechanical properties and chemical stability described for glasses containing Nb205. Although T g is not a defined temperature (commonly referred to as a temperature range) and may vary with the thermal history of the glass, it can be correlated with the degree of polymerization of the glass lattice. Thus, the observed increase in T g can be attributed to structural changes that lead to an increase in the degree of polymerization of the vitreous network for BGNs. Table 3. Compilation of thermal data obtained via DSC: glass transition temperature T g , crystallization initiation temperature Tx, glass stability ΔΤ Χ9 (Τχ - T g ), crystallization temperature T c and the enthalpy variation involving the process of crystallization (ΔΗ σ ).
Propriedades Térmicas Thermal Properties
Vidros Glasses
Figure imgf000017_0001
Figure imgf000017_0001
(°C) (°C) (Tx - Tg) (°C) mJ mg-1 (° C) (° C) (Tx - Tg) (° C) mJ mg -1
BG45S5 539,9 ±0,4 676 ±1 136 ±1 698 ±5 -267 ±6BG45S5 539.9 ± 0.4 676 ± 1 136 ± 1 698 ± 5 -267 ± 6
Série I Series I
BGPN1.3 545,6 ±0,8 695 ±5 149 ±6 730 ±3 -301 ±1 BGPN2.6 552 ±3 685 ±4 133 ±7 715 ±5 -313 ±2 Série II BGPN1.3 545.6 ± 0.8 695 ± 5 149 ± 6 730 ± 3 -301 ± 1 BGPN2.6 552 ± 3 685 ± 4 133 ± 7 715 ± 5 -313 ± 2 Series II
BGSN1 546,4 ±0,1 739 ±5 ' 193 ±5 788,0 ±0,1 -304 ±6 BGSN1 546.4 ± 0.1 739 ± 5 '193 ± 5 788.0 ± 0.1 -304 ± 6
BGSN2.S 556,4 ±0,8 761 ±4 205 ±5 835 ±3 -307 ±5BGSN2.S 556.4 ± 0.8 761 ± 4 205 ± 5 835 ± 3 -307 ± 5
BGSN5 568 ±2 757 ±2 189 ±4 797 ±3 -314 ±1 BGSN5 568 ± 2 757 ± 2 189 ± 4 797 ± 3 -314 ± 1
[0053]A Figura 3a-b mostra os espectros Raman para as composições vítreas pertencentes às séries I e II e o BG45S5. Este espectro pode ser dividido em três regiões: baixas frequências (região em destaque), frequências i ·  Figure 3a-b shows the Raman spectra for the vitreous compositions belonging to series I and II and BG45S5. This spectrum can be divided into three regions: low frequencies (highlighted region), frequencies i ·
intermediárias (560-790 cm 1) e região em maiores números de onda (800-1100 cm 1). intermediate (560-790 cm 1 ) and region in higher wavelengths (800-1100 cm 1 ).
[0054]A região de baixa frequência os espectros exibem alguns picos discretos atribuídos a estruturas de anel na rede de vidro (modo simétrico da respiração do anel, envolvendo principalmente o movimento de oxigénio, defeitos na rede de sílica vítrea ou os modos de respiração de anéis planares de três e quatro anéis membros). Embora, observa-se um aumento gradual da intensidade como uma função do conteúdo de óxido de nióbio, nenhuma absorção foi observada em 220 ou 593 cm 1, confirmando a ausência de ligações Nb-O-Nb nos vidros estudados. A região intermédia do espectro de frequência pode ser observado um pico largo a cerca de 630 crrr1 para o BG45S5, que tem sido atribuída ao modo de deformação simétrica de Si-O-Si em anéis de três membros de Si04, balanço do oxigénio BO {bridiging oxygen) na unidade estrutural que contém oxigénio NBO e deformação angular do oxigénio. Para os biovidros contendo Nb2Os pode ser observado um deslocamento para maior frequência (~ 650 cm"1), o que é atribuído ao modo vibracional para Si-O-Si ligações acoplado flexão modos de vibrações das ligações Nb-O no octaedro NbOe com baixo grau de distorção e sem NBO (non-bridiging oxygen). Além disso, pode-se observar uma banda intensa em 800 cm 1 e 810 cnr para os biovidros contendo Nb205, as quais estão relacionadas a presença dos octaedros NbCte com diferentes graus de distorção ligados em cadeias (Nb-O- Si). Tais absorções tendem a ofuscar os modos de vibração Si-O, devido à maior polarizabilidade e consequente seção de espalhamento das ligações Nb-O. Em frequências superiores, aparece uma banda complexa na faixa de 800-1 100 cnr 1 com dois máximos bem definidos e um ombro para maiores energias. Essa banda carrega toda informação estrutural dos vidros silicatos, e ela é composta pela sobreposição dos modos de estiramento das espécies de sílica e estiramento das espécies fosfatos. Os deslocamentos Raman em 864, 906, 944 e 1086 cnr1 estão associados ao modo de estiramento simétrico da ligação Si- O das espécies SÍQ°, SÍQ , SÍQ2 e ssQ3, respectivamente. A presença do fósforo é evidenciada pelo estiramento da ligação P-0 em 906 e 1008 cm"1. The low frequency region of the spectra exhibits some discrete peaks attributed to ring structures in the glass network (symmetrical mode of ring respiration, mainly involving oxygen movement, glassy silica network defects, or glass breathing modes). planar rings of three and four member rings). Although, a gradual increase in intensity is observed as a function of niobium oxide content, no absorption was observed at 220 or 593 cm 1 , confirming the absence of Nb-O-Nb bonds in the studied glasses. The intermediate region of the frequency spectrum can be observed at a wide peak at about 630 crrr 1 for BG45S5, which has been attributed to the symmetrical deformation of Si-O-Si in Si0 4 three-membered rings, oxygen balance. BO (bridiging oxygen) in the NBO oxygen-containing structural unit and angular oxygen deformation. For Nb2Os-containing bio-glasses, a higher frequency shift (~ 650 cm- 1 ) can be observed, which is attributed to the vibrational mode for Si-O-Si couplings coupled to flexural vibration modes of Nb-O couplings in the octahedron. Low distortion NbOe and no non-bridiging oxygen (NBO). In addition, an intense band at 800 cm 1 and 810 cnr can be observed for Nb205 containing bio-glasses, which are related to the presence of NbCte octahedra with varying degrees of chain-linked distortion (Nb-O-Si). Such absorptions tend to overshadow the Si-O vibration modes due to the higher polarizability and consequent scattering section of the Nb-O bonds. At higher frequencies, a complex band appears in the 800-1 100 cm 1 range with two well-defined highs and one shoulder for higher energies. This band carries all the structural information of the silicate glasses, and it is composed by overlapping modes of stretching of silica species and stretching of phosphate species. The Raman offsets at 864, 906, 944 and 1086 cm -1 are associated with the symmetric stretch mode of the SiO bond of the SIC, SIC, SIC 2 and ssQ 3 species, respectively. The presence of phosphorus is evidenced by the stretching of the P-0 bond at 906 and 1008 cm -1 .
[0055]A Figura 4 mostra os perfis das curvas de pH em água deionizada e em solução tamponada de HEPES para BG45S5 e para os BGNs das séries l e II. Como observado, um acentuado aumento no pH ocorre na primeira hora de imersão para todos os materiais em estudo. Tendo em vista, que a variação no pH é dependente da quantidade de cátion lixiviado podemos verificar que os materiais BGSN1 e BGPN1 .3 se mostram mais solúveis que o BG45S5. De forma que os biovidros modificados com Nb podem ser ordenados quanto a solubilidade com BGSN1 -BGPN1 .3 > BG45S5 > BGP2.6 > BGSN2.5 > BGSN5. Esse resultado indica que a presença do Nb20s substituindo o S1O2 ou P2O5 em até 1 % e 1 ,3%, respectivamente, aumenta a solubilidade em relação ao BG45S5. [0056]Os módulos de elasticidade determinados para os vidros BG45S5, BGPN1.3, BGPN2.6, BGSN1 , BGSN2.5 e BGSN5 foram 62 ±2, 72,8 ±0,2, 100 ±2, 14 ±1 , 84 ±1 e 53 ±2 GPa, respectivamente (Figura 5a). Os valores de dureza vickers determinados para os vidros BG45S5, BGPN1 .3, BGPN2.6, BGSN1 , BGSN2.5 e BGSN5 foram 5,1 ±0,3, 5,9 ±10, 7,3 ±0,2, 2,4 ±0,2, 5,8 ±0,6 e 4,9 ±0,3 GPa, respectivamente (Figura 5b). [0055] Figure 4 shows the pH curve profiles in deionized water and HEPES buffered solution for BG45S5 and BGNs of series I and II. As noted, a marked increase in pH occurs within the first hour of immersion for all materials under study. Given that the variation in pH is dependent on the amount of leached cation we can verify that the materials BGSN1 and BGPN1 .3 are more soluble than BG45S5. So Nb-modified bioglass can be sorted for solubility with BGSN1 -BGPN1 .3>BG45S5>BGP2.6>BGSN2.5> BGSN5. This result indicates that the presence of Nb20s replacing S1O2 or P2O5 by up to 1% and 1, 3%, respectively, increases solubility relative to BG45S5. The modulus of elasticity determined for the glasses BG45S5, BGPN1.3, BGPN2.6, BGSN1, BGSN2.5 and BGSN5 were 62 ± 2, 72.8 ± 0.2, 100 ± 2, 14 ± 1, 84 ± 1 and 53 ± 2 GPa, respectively (Figure 5a). The vickers hardness values determined for the BG45S5, BGPN1.3, BGPN2.6, BGSN1, BGSN2.5 and BGSN5 glasses were 5.1 ± 0.3, 5.9 ± 10, 7.3 ± 0.2, 2 , 4 ± 0.2, 5.8 ± 0.6 and 4.9 ± 0.3 GPa, respectively (Figure 5b).
[0057]A Figura 6 mostra o resultado para o estudo de viabilidade celular para os BGN's para os tempos de 1 , 7 e 14 dias. De acordo com os resultados obtidos foi observada uma tendência de aumento do número de células com o tempo em todas as culturas, confirmando a viabilidade celular para todos os vidros estudados. Após 1 dia, os osteoblastos aderiram e proliferaram na superfície dos biovidros BGNs apresentando, porém, uma taxa menor quando comparado ao controle. Entre os grupos é possível verificar uma diferença entre os materiais BGSN2.5 e BGPN2.6, os quais apresentaram uma maior viabilidade celular comparado ao BG45S5. Após 7 dias de cultivo, pode ser observado um contínuo crescimento no número de osteoblastos aderidos na superfície de todas as amostras, no entanto, apresentaram um grau menor em relação ao controle. Entre as amostras de mesmo tempo de cultura, não foi possível notar uma diferença entre os BGNs comparados ao BG45S5, exceto o BGPN2.6, o qual mostrou uma viabilidade celular significativamente superior. Similar comportamento para os biovidros pode ser observado após 14 dias de cultura. O crescimento celular para o biovidro BGNP2.6 foi estatisticamente similar ao controle (positivo).  [0057] Figure 6 shows the result for the cell viability study for BGN's for times 1, 7 and 14 days. According to the results obtained, a tendency of increasing the number of cells with time was observed in all cultures, confirming the cell viability for all studied glasses. After 1 day, the osteoblasts adhered and proliferated on the surface of the BGNs bioglass presenting, however, a lower rate when compared to the control. Between the groups it is possible to verify a difference between the materials BGSN2.5 and BGPN2.6, which presented a higher cell viability compared to BG45S5. After 7 days of cultivation, a continuous growth in the number of osteoblasts adhered to the surface of all samples can be observed, however, showed a lower degree in relation to the control. Among the samples from the same culture time, it was not possible to notice a difference between BGNs compared to BG45S5, except BGPN2.6, which showed significantly higher cell viability. Similar behavior for bioglass can be observed after 14 days of culture. Cell growth for BGNP2.6 bioglass was statistically similar to (positive) control.
[0058]A presença do implante de vidro estimulou a formação de um calo ósseo na cortical ao redor do implante em todas as composições estudadas. Em nenhum dos grupos foram observados sinais significativos de inflamação ou rejeição ao material, com degeneração óssea ou presença de infiltrado inflamatório significativo (Figura 7). [0058] The presence of the glass implant stimulated the formation of cortical bone callus around the implant in all compositions studied. In None of the groups showed significant signs of inflammation or material rejection, bone degeneration or significant inflammatory infiltrate (Figure 7).
[0059]A parte da cortical que estava em contato com o vidro apresentou trabéculas bem mais compactas depois do 28° dia após implante, exceto para o grupo BGSN1 (Figura 8). Além disso, a presença de uma lâmina óssea é nítida ao redor do implante em todos os grupos, demonstrando a capacidade osteocondutiva de todos os materiais testados.  The part of the cortical that was in contact with the glass had much more compact trabeculae after the 28th day after implantation, except for the BGSN1 group (Figure 8). In addition, the presence of a bone blade is clear around the implant in all groups, demonstrating the osteoconductive capacity of all materials tested.
[0060]A análise de cortes transversais dos músculos (Figura 9) contendo o vidro na forma de pó misturado à cola de fibrina, marcados por técnica imunohistoquímica, revelou que vários vasos sanguíneos estavam presentes na região do implante, principalmente na cápsula fibrosa que os circundava, não havendo diferenças significativas entre os grupos, o que demonstra que os vidros com nióbio em sua composição, assim como o BG45S5 também são capazes de estimular a angiogênese.  Analysis of cross sections of the muscles (Figure 9) containing the glass in the form of powder mixed with the fibrin glue, marked by immunohistochemistry technique, revealed that several blood vessels were present in the implant region, mainly in the fibrous capsule. surrounding, with no significant differences between the groups, which shows that glasses with niobium in its composition, as well as BG45S5 are also able to stimulate angiogenesis.
[0061 ]Tanto após 14 quanto após 28 dias havia de 10 a 18 vasos sanguíneos por mm2 na área do implante em todos os grupos, não havendo diferença significativa entre eles [F(3,20) = 1 ,137, p=0,358, ω= 0,13]. Both after 14 and after 28 days there were 10 to 18 blood vessels per mm 2 in the implant area in all groups, with no significant difference between them [F (3,20) = 1,137, p = 0.358 , ω = 0.13].

Claims

REIVINDICAÇÕES
1 . Composição vítrea bioativa caracterizada por compreender os seguintes componentes:  1 . Bioactive glassy composition comprising the following components:
- S1O2 em quantidades entre 40 e 55 %mol;  - S1O2 in amounts between 40 and 55 mol%;
- CaO em quantidades entre 23 e 33 %mol;  - CaO in amounts between 23 and 33 mol%;
- Na20 em quantidades entre 20 e 30 %mol;  - Na20 in amounts between 20 and 30 mol%;
- P2O5 em quantidades entre 0,001 e 5 %mol; e  - P2O5 in amounts between 0.001 and 5 mol%; and
- Nb20õ em quantidades entre 0,001 e 5 %mol.  - Nb206 in amounts between 0.001 and 5 mol%.
2. Composição, de acordo com a reivindicação 1 , caracterizada por compreender preferencialmente 46,1 %mol de SÍO2, 26,9 %mol de CaO, 24,4 %mol de Na20, 1 ,3 %mol de P205, e 1 ,3 %mol de Nb2Os. 2. Composition according to claim 1, comprising preferably 46.1 mol% SiO2, 26.9 mol% CaO, 24.4 mol% Na20, 1, 3 mol% of P 2 0 5, and 1.3 mol% Nb 2 Os.
3. Uso da composição vítrea bioativa conforme descrito nas reivindicações 1 e 2 caracterizado por possuir aplicação médica e odontológica, como biomateriais de preenchimento ósseos, para regeneração óssea, scaffoids para engenharia de tecido ósseo, revestimentos bioativos para biomateriais metálicos bioinertes e no tratamento de hipersensibilidade dentinária.  Use of the bioactive glass composition as described in claims 1 and 2 characterized in that it has medical and dental application such as bone filler biomaterials for bone regeneration, bone tissue engineering scaffoids, bioactive coatings for bioinert metallic biomaterials and in the treatment of hypersensitivity. dentin
PCT/BR2015/000186 2015-03-30 2015-12-15 Bioactive vitreous composition and use thereof for bone regeneration WO2016154691A1 (en)

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