WO2023051559A1 - 一种医用生物活性玻璃及其制备方法和应用 - Google Patents

一种医用生物活性玻璃及其制备方法和应用 Download PDF

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WO2023051559A1
WO2023051559A1 PCT/CN2022/121906 CN2022121906W WO2023051559A1 WO 2023051559 A1 WO2023051559 A1 WO 2023051559A1 CN 2022121906 W CN2022121906 W CN 2022121906W WO 2023051559 A1 WO2023051559 A1 WO 2023051559A1
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bioactive glass
medical
glass
metal oxide
fluoride
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PCT/CN2022/121906
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English (en)
French (fr)
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陈晓婧
陈敏慜
邱喜丽
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中南大学
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Priority to GBGB2405920.6A priority Critical patent/GB202405920D0/en
Priority to CN202280066099.8A priority patent/CN118119572A/zh
Publication of WO2023051559A1 publication Critical patent/WO2023051559A1/zh

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/50—Preparations specially adapted for dental root treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/70—Preparations for dentistry comprising inorganic additives
    • A61K6/71—Fillers
    • A61K6/74—Fillers comprising phosphorus-containing compounds
    • A61K6/75—Apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
    • A61K6/831—Preparations for artificial teeth, for filling teeth or for capping teeth comprising non-metallic elements or compounds thereof, e.g. carbon
    • A61K6/838—Phosphorus compounds, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • C03C3/11—Glass compositions containing silica with 40% to 90% silica, by weight containing halogen or nitrogen
    • 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
    • C03C3/11—Glass compositions containing silica with 40% to 90% silica, by weight containing halogen or nitrogen
    • C03C3/112—Glass compositions containing silica with 40% to 90% silica, by weight containing halogen or nitrogen containing fluorine
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the application belongs to the technical field of biomedical materials, and in particular relates to medical bioactive glass and its preparation method and application.
  • Bioactive glass is a class of inorganic non-metallic materials that can repair, replace and regenerate body tissues, and can form bonds between tissues and materials.
  • the first bioactive glass, 45S5 was discovered by Hench in 1969 and is a silicate glass composed of basic components such as SiO 2 , Na 2 O, CaO and P 2 O 5 .
  • Bioactive glass can degrade in body fluids, release active ions (Ca 2+ , Si 4+ , PO 4 3-, etc.), and generate hydroxyapatite (HAP, Ca 5 (PO 4 ) 3 OH), can form an intimate bond with the host bone, induce bone regeneration, promote gene expression of osteoblasts, increase DNA synthesis, stimulate angiogenesis, and accelerate the repair of soft and hard tissues.
  • the degradation products of bioactive glass can promote the production of growth factors, promote the proliferation of cells, enhance the gene expression of osteoblasts and the growth of bone tissue, and it is the only one that can not only bond with bone tissue, but also bond with soft tissue. Connected artificial biomaterials.
  • bioactive glass The physicochemical properties and biological functions of bioactive glass can be adjusted through its composition, structure and morphology, so as to meet different clinical needs.
  • introduction of different chemical elements can regulate the structure and function or endow glass with special properties. For example, adding strontium and chlorine to bioactive glass can accelerate the degradation of bioactive glass and improve its biological activity; adding zinc, Magnesium, cobalt, fluorine, etc. can make the glass antibacterial; adding strontium and fluorine can enhance the bone-forming effect of bioactive glass, etc.
  • the study also found that by changing the network formers in the glass (such as SiO 2 , connected to other network formers through bridge oxygen ions) and network modifiers (such as Na 2 O, CaO, etc., by breaking the bridge oxygen and network former elements Oxygen bridging bonds between the oxides that generate non-bridging oxygen ions) can change the network connectivity of the glass (that is, the average number of bridging oxygen bonds in each glass skeleton unit), and then regulate the degradation rate of the material to Meet different application requirements. For example, reducing the ratio of network formers and network modifiers in glass can change the structure of the glass from a three-dimensional network structure to a chain structure, thereby reducing the stability of the glass, improving its degradability, and forming bioactive glass, and vice versa.
  • network formers in the glass such as SiO 2 , connected to other network formers through bridge oxygen ions
  • network modifiers such as Na 2 O, CaO, etc.
  • the research results show that when the network connectivity of the bioactive glass is 1.9-2, it has good biological activity, that is, the ability to degrade and generate apatite-like. When the network connectivity of bioactive glass is greater than 2.6, it has almost no biological activity.
  • bioactive glasses composed of SiO 2 -Na 2 O-CaO-P 2 O 5 could only detect a small amount of mineralized hydroxyapatite formation after soaking in simulated body fluid for 24 hours, and degraded This will cause a rapid increase in the pH of the solution.
  • bioactive glass as a remineralizing toothpaste additive or desensitizing agent, the desired mineralization effect cannot be achieved quickly, efficiently and controllably.
  • too high pH will damage cells and tissues, and when bioactive glass is used as a bone graft material, the material will degrade too quickly, and the degradation rate will not be in harmony with the bone repair and reconstruction rate.
  • the purpose of this application is to provide a medical bioactive glass and its preparation method and application.
  • the medical bioactive glass can be used in dentistry and orthopedics.
  • This application firstly provides a medical bioactive glass, which includes the following raw materials: SiO 2 , P 2 O 5 , metal chloride or its crystalline hydrate, and a network modifier; the network modifier includes an alkali metal oxide or/ and alkaline earth metal oxides; the network connectivity NC of the medical bioactive glass is 1.5-3.35; wherein the calculation formula of NC is: wherein the calculation formula of NC is: formula: is the molar percentage of SiO in the medical bioactive glass; MMO is the molar percentage of alkaline earth metal oxide in the medical bioactive glass; is the molar percentage of alkali metal oxide in medical bioactive glass; It is the molar percentage of alkali metal oxide in medical bioactive glass.
  • the medical bioactive glass of the present application also includes a function-adjusting metal oxide, and the function-adjusting metal oxide is one of CuO, ZnO, Fe 2 O 3 , SnO, CeO 2 , CoO and MnO 2 or Multiples, when mixed, in any proportion.
  • the medical bioactive glass of the present application also includes fluoride, and the fluoride is one or more of CaF 2 , SrF 2 , MgF 2 and LaF 3 , in any proportion when mixed.
  • the aforementioned chlorides are one or more of CaCl 2 , SrCl 2 , BaCl 2 , ZnCl 2 , LaCl 3 and KCl, in any proportion when mixed;
  • the alkali metal oxide is K 2 O ;
  • the alkaline earth metal oxide is one or more of MgO, CaO, BaO and SrO, when mixed, in any proportion.
  • the medical bioactive glass of the present application also includes fluoride, and the fluoride is one or more of CaF 2 , SrF 2 , MgF 2 and LaF 3 , in any proportion when mixed.
  • each raw material component is as follows:
  • phase state of the medical bioactive glass of the present application is amorphous bioactive glass, or bioactive glass ceramics containing a crystalline phase in a bioactive glass matrix.
  • the preparation method of the above-mentioned medical bioactive glass is prepared by high-temperature melting and quenching (melt-quench), and the specific steps are as follows:
  • the cold water in the step 1) refers to water with a temperature of 0-30°C; the drying temperature in the step 2) is 60-80°C, and the drying time is 5-24 hours.
  • This application also relates to the application of the medical bioactive glass in medicine, as the raw material components of the following medical products: tooth protection varnish, mouthwash, bone graft material, functional tooth paste, dental desensitization agent, root canal Filling materials, composite resin filling materials, adhesives, wound dressings; the functional dental strips include whitening tooth strips and remineralization tooth strips.
  • tooth protection varnish used in bone graft materials, it has a good bone formation effect, and also has other auxiliary therapeutic effects such as antibacterial, anti-inflammatory and anti-tumor.
  • SiO 2 is used as a network former of the glass structure, forming a glass network structure through bridging oxygen;
  • P 2 O 5 exists in the form of orthophosphate to modify the glass structure;
  • metal chloride or its crystallization Hydrates do not affect the network connectivity of the glass, but can expand the structure of the glass and regulate the biological activity of the glass;
  • the network modifier changes the network connectivity of the glass by destroying the bridging oxygen bond between Si and bridging oxygen and forming a non-bridging oxygen bond ;
  • Fluoride does not affect the network connectivity of the glass, but can modify the glass structure in the form of CaF + or SrF +, etc., and adjust the physical, chemical and biological functions of the bioactive glass.
  • chloride ions can expand the glass structure, improve the degradability of the glass and the ability to generate apatite, so the NC of the bioactive glass of the application
  • the value is greater than 2.4, or even equal to 3.18
  • the bioactive glass still has high biological activity, and at the same time, as the NC value increases, the degradation rate of the glass slows down; when 1.5 ⁇ NC ⁇ 2.0 of the bioactive glass, the bioactive glass has Excellent biological activity, and with the increase of chlorine content in bioactive glass, the degradation rate of bioactive glass is accelerated.
  • the medical bioactive glass of the present application by adjusting the contents of alkaline earth metal oxides, alkali metal oxides, silicon dioxide and phosphorus pentoxide within a limited range, the medical bioactive glass can be
  • the NC value adjustment value is within the expected range, so that its physical and chemical properties and biological properties can be adjusted, and it has a wide range of application prospects, such as fluorine protective paint, mouthwash, bone graft materials, functional dental strips (whitening tooth strips and rejuvenation strips) Mineralized dental strips), desensitizers, root canal filling materials, composite resin filling materials, adhesives, wound dressing additives, etc.
  • the degradation rate of the glass can be regulated by adjusting the NC value of the chlorine-containing bioactive glass, so as to solve the problem that the degradation rate of the current bone graft material is different from its osteogenesis rate. matching problem.
  • the preparation method of the present application adopts a high-temperature melting and quenching preparation process, which can be used for large-scale and batch production of bioactive glass.
  • Figure 1 is an X-ray diffraction pattern of bioactive glasses with different network connectivity
  • Figure 2 is a diagram of the concentration of calcium ions released by bioactive glasses with different network connectivity soaked in Tris solution for different times;
  • Fig. 3 is the X-ray diffraction pattern of the solid powder collected after the bioactive glass whose network connectivity is 3.35 soaks in Tris solution for different time;
  • Fig. 4 is the 31 P solid-state nuclear magnetic resonance wave diagram of the solid powder collected after the bioactive glass with a network connectivity of 3.27 was soaked in Tris solution for different times;
  • Figure 5 is the 31 P solid-state NMR wave diagram of the solid powder collected after the bioactive glass with a network connectivity of 1.5 was soaked in Tris solution for different times;
  • Fig. 6 is that the bioactive glass in embodiment 1 is used as bone graft material, implants the calvarial defect of rat after 4 weeks, the Micro-CT picture of bone tissue (BG is the defect of implanting bioactive glass, C is blank control group );
  • Fig. 7 is the bioactive glass that can be used as mouthwash additive in embodiment 2, and the scanning electron micrograph of Streptococcus co-cultivation after 24 hours, wherein figure (a) is the culture medium group that does not contain bioactive glass, figure ( b) is the culture medium group containing bioactive glass;
  • Fig. 8 is in embodiment 3, can be used as the bioactive glass of tooth protection varnish, after soaking in artificial saliva 24 hours scanning electron micrograph;
  • Figure 9 is a transmission electron micrograph of the bioactive glass that can be used as a wound dressing additive in Example 6, co-cultured with Streptococcus sanguinis for 4 hours;
  • Figure 10 is a diagram of the formation of the blood vessel lumen after the bioactive glass provided in Example 6 and human umbilical vein endothelial cells were cultured in the bioactive glass extract for 6 hours;
  • Figure 11 is a picture of the wound on the back of the mouse before being treated with the bioactive glass provided in Example 6 and after 6 days of treatment.
  • Medical bioactive glass is a bioactive glass - ceramic containing a small amount of crystalline phase in the bioactive glass matrix .
  • method (melt-quench) wherein the content of P2O5 is 5.0mol%; the content of CaF2 is 3.0mol%, the content of CaCl2 is 14.0mol%; the content of MnO2 is 5.0mol%; in addition, The content of the components of the bioactive glass satisfies: NC is 2.5;
  • the above-mentioned medical bioactive glass is prepared by high-temperature melting and quenching (melt-quench), and the specific steps are as follows:
  • the medical bioactive glass prepared above is used as the bioactive glass of the bone graft material.
  • Medical bioactive glass is an amorphous amorphous phase bioactive glass, which is made of SiO 2 , P 2 O 5 , CaO, CaCl 2 , and CuO by high-temperature melting and quenching (melt-quench), of which P 2 O 5
  • the content of CaCl 2 is 3.0mol%
  • the content of CaCl 2 is 56.0mol%
  • the content of CuO is 1mol%.
  • NC is 1.6;
  • the above-mentioned medical bioactive glass is prepared by high-temperature melting and quenching (melt-quench), and the specific steps are as follows:
  • the medical bioactive glass prepared above can be used as the bioactive glass with antibacterial mouthwash additive.
  • Medical bioactive glass is a bioactive glass ceramic containing a small amount of crystalline phase in the bioactive glass matrix. It is made of SiO 2 , P 2 O 5 , SrO, ZnO, CaO, SrCl 2 , SrF 2 (melt-quench), wherein the content of P 2 O 5 is 4.0mol%, the content of SrF 2 is 1.0mol%, the content of SrCl 2 is 0.5mol%, and the content of ZnO is 0.1mol%.
  • the biological activity The content of the composition of the glass satisfies: NC is 1.8;
  • the above-mentioned medical bioactive glass is prepared by high-temperature melting and quenching (melt-quench), and the specific steps are as follows:
  • Medical bioactive glass is a bioactive glass ceramic containing a small amount of crystalline phase in the bioactive glass matrix. It is made of SiO 2 , P 2 O 5 , SnO, MgO, CaO, LaF 2 , CaCl 2 , LaCl 3 It is made by melt-quench method, wherein the content of P 2 O 5 is 1.0 mol%, the content of LaF 3 is 1.0 mol%, and the total content of CaCl 2 and LaCl 3 is 3.0 mol%. In addition, the content of bioactive glass The content of the components meets: NC is 2.7;
  • the above-mentioned medical bioactive glass is prepared by high-temperature melting and quenching (melt-quench), and the specific steps are as follows:
  • the medical bioactive glass prepared above as a composite resin filling material as a composite resin filling material.
  • Medical bioactive glass is a bioactive glass ceramic containing a small amount of crystalline phase in the bioactive glass matrix. It is composed of SiO 2 , P 2 O 5 , K 2 O, Fe 2 O 3 , MgO, CaO, KCl, ZnCl 2 2 is made by high temperature melting and quenching method (melt- quench ), wherein the content of P2O5 is 8.0mol%, the content of Fe2O3 is 3.0mol%; the total content of KCl, ZnCl2 and BaCl2 is 12.0 mol%, and the ratio between them is 1:1:1.
  • the content of the components of the bioactive glass satisfies: NC is 3.35;
  • the above-mentioned medical bioactive glass is prepared by high-temperature melting and quenching (melt-quench), and the specific steps are as follows:
  • the medical bioactive glass prepared above can be used as a bone graft material with anti-tumor potential.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Medical bioactive glass is an amorphous amorphous phase bioactive glass, which is made of SiO 2 , P 2 O 5 , CaO, SrCl 2 , CeO 2 , CuO, and CoO through high-temperature melting and quenching (melt-quench),
  • the content of P 2 O 5 is 5.0mol%
  • the content of SrCl 2 is 25.0mol%
  • the total content of CeO 2 , CuO, CoO is 20mo%
  • the ratio between them is 1:1:2.
  • biological The content of the components of the active glass satisfies: NC is 2.1;
  • the above-mentioned medical bioactive glass is prepared by high-temperature melting and quenching (melt-quench), and the specific steps are as follows:
  • bioactive glass of the medical wound auxiliary material additive prepared above.
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Medical bioactive glass is an amorphous amorphous phase bioactive glass, which is made of SiO 2 , P 2 O 5 , CaO, MgF 2 , CaCl 2 , and SrO through high-temperature melting and quenching (melt-quench), where P The content of 2 O 5 is 4.5 mol%, the content of MgF 2 is 0.5 mol%, and the content of CaCl 2 is 30.0 mol%. In addition, the content of the components of the bioactive glass satisfies: NC is 1.5;
  • the above-mentioned medical bioactive glass is prepared by high-temperature melting and quenching (melt-quench), and the specific steps are as follows:
  • bioactive glass prepared above as a desensitizer additive.
  • Figure 1 is the X-ray diffraction pattern of bioactive glasses with different network connectivity. As shown in Figure 1, all glass glasses contain an amorphous glass phase, and the glass with NC less than 2.57 contains hydroxyapatite; NC Bioactive glasses with values greater than 3.18 contain a small amount of SiO 2 crystalline phase in addition to the glass phase.
  • Figure 2 is a schematic diagram of the concentration of calcium ions released by bioactive glasses with different network connectivity soaked in Tris solution at different times. It can be degraded even when it is young, indicating that even if the NC value of chlorine-containing bioactive glass is greater than 2.4, the glass has high biological activity; at the same time, the release of calcium ions in glass with NC value greater than 2.57 is lower than that of glass with NC value less than or equal to 2.57.
  • Figure 3 is the X-ray diffraction pattern of the solid powder collected after the bioactive glass with a network connectivity of 3.35 was soaked in Tris solution for different time, as shown in Figure 3, the bioactive glass with NC value of 1.5 was soaked in Tris solution After one hour, the intensity of the amorphous glass signal (25-32°(2 ⁇ )) in the XRD pattern decreases, and the signal of the silica gel layer (20-25°(2 ⁇ )) increases, suggesting that the glass undergoes rapid degradation and forms a silica gel layer; With the prolongation of immersion time, the signal intensity of amorphous glass gradually weakened, and the signal peak intensity matched with hydroxyapatite gradually increased, and there was no obvious change after 9 hours; these suggested that the glass-ceramic had high biological activity, and immersion for 1 hour That is, glass degradation can be seen, and obvious apatite formation can be seen in 6 hours. In addition, almost all the phosphate radicals released in the glass are consumed to form hydroxyapatite at 9 hours
  • Figure 4 is the 31 P solid-state NMR wave diagram of the solid powder collected after the bioactive glass with a network connectivity of 3.27 was soaked in Tris solution for different times. As shown in Figure 4, the bioactive glass with an NC value of 3.27 was in The 31 P solid-state NMR spectra showed a single peak before and after soaking in Tris solution. The chemical shift of 31 P in unsoaked bioactive glass (0h) is about 2.5ppm, suggesting that in pristine glass, P exists in the form of orthophosphate, and the valence electrons are balanced by CaCl + .
  • Figure 5 is the 31 P solid-state NMR wave diagram of the solid powder collected after the bioactive glass with network connectivity of 1.5 was soaked in Tris solution for different time, as shown in Figure 5, the bioactive glass with NC value of 1.5 was in The 31 P solid-state NMR spectra showed a single peak before and after soaking in Tris solution.
  • the chemical shift of 31 P in unsoaked bioactive glass (0h) is about 2.6ppm, suggesting that in pristine glass, P exists in the form of orthophosphate, and the valence electrons are balanced by CaCl + .
  • the bioactive glass with an NC value of 1.5 can quickly generate hydroxyapatite after soaking in Tris for 3 hours. From 3 hours to 9 hours, the amount of hydroxyapatite generated gradually increases. almost no change at all. It can be seen that the bioactive glass with NC value of 1.5 has good biological activity.
  • Fig. 6 is that the bioactive glass in embodiment 1 is used as bone graft material, implants the calvarial defect of rat after 4 weeks, the Micro-CT picture of bone tissue (BG is the defect of implanting bioactive glass, C is blank control group ), wherein, (a) is the bioactive glass BG of Example 1 as the bone graft material, after implanting the skull defect of rats for 4 weeks, the Micro-CT front view of the bone tissue, (b) is the section view; as shown As shown in Figure 6, there is a large amount of new bone formation in the bone defect area implanted with BG, and the newly generated bone tissue almost runs through the entire defect area, while only a small amount of new bone formation can be seen in the control group. It can be seen that the bioactive glass involved in the present application has good osteogenic effect and can be used as a bone graft material for clinical bone defect repair.
  • Fig. 7 is in embodiment 2, can be used as the bioactive glass of mouthwash additive, and the scanning electron micrograph of Streptococcus co-cultivation 24 hours, wherein (a) is the culture medium group not containing bioactive glass, (b) It is the medium group containing bioactive glass, as shown in Figure 7, compared with the medium group without bioactive glass, the medium containing bioactive glass can obviously destroy the structure and activity of streptococcus, and then inhibit or kill dead bacteria. It can be seen that the bioactive glass involved in this application has good antibacterial effect and can be used as an additive to mouthwash or root canal sealant.
  • Fig. 8 is in embodiment 3, can be used as the bioactive glass of tooth protection varnish, after immersing in the artificial saliva 24 hours scanning electron micrographs, as shown in Fig. 8, the bioactive glass designed by the present application can rapidly Degradation, release fluoride ions, and generate fluorapatite needle-like crystals, which have good acid resistance, and the released fluoride ions can also inhibit demineralization and promote remineralization.
  • Figure 9 is a transmission electron micrograph of the bioactive glass that can be used as a wound dressing additive in Example 6, co-cultured with Streptococcus sanguis for 4 hours, wherein (a) is a culture medium group that does not contain bioactive glass, ( b) is the group containing bioactive glass medium, as shown in Figure 9, Streptococcus sanguis has a good growth state in the medium group not containing bioactive glass, and Streptococcus sanguis has complete cell wall, cell membrane and cell wall simultaneously
  • the structure of the genetic material within, and the bacteria treated with the bioactive glass provided in Example 6 of the present application have significantly reduced volume, reduced electron density, incomplete cell structure, and rupture; in addition, it can also be seen that granular black glass degradation products enter Inside the cell, and the genetic material inside the cell is destroyed. It can be seen that the bioactive glass doped with CeO 2 and CoO involved in this application has good antibacterial and bactericidal effects.
  • FIG 10 is a diagram of the formation of the blood vessel lumen after the bioactive glass provided in Example 6 is cultured with human umbilical vein endothelial cells in the bioactive glass extract for 6 hours, wherein (a) does not contain CeO 2 , CoO
  • the situation figure of the bioactive glass (b) is the bioactive glass provided in Example 6, as shown in Figure 10, the human umbilical vein endothelial cells are co-cultured in the bioactive glass not containing CeO 2 , CoO, no A closed lumen can be seen, and after co-cultivation with the bioactive glass provided in Example 6, a large amount of closed lumen can be seen. Therefore, the bioactive glass provided in Example 6 of the present application has the ability to promote the formation of a closed vascular lumen .

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Abstract

本申请公开了一种医用生物活性玻璃及其制备方法和应用，包括以下原料成分和含量：SiO 220-60mol％；P 2O 53-8mol％；金属氯化物或其结晶水合物0.5-56mol％；网络修饰体20-60mol％；功能调节金属氧化物0.1-20mol％；氟化物0.1-9mol％，网络修饰体包括碱金属氧化物或/和碱土金属氧化物，具体为K 2O、MgO、CaO、BaO和SrO中的一种或多种；功能调节金属氧化物为CuO、ZnO、Fe 2O 3、SnO、CeO 2、CoO和MnO 2中的一种或多种，氟化物为CaF 2、SrF 2、MgF 2和LaF 3中的一种或多种，氯化物为CaCl 2、SrCl 2、BaCl 2、ZnCl 2、LaCl 3和KCl中的一种或多种。

Description

一种医用生物活性玻璃及其制备方法和应用
本申请要求于2021年09月28日提交中国专利局、申请号为202111144492.8、申请名称为“一种医用生物活性玻璃及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请属于生物医用材料技术领域，具体涉及医用生物活性玻璃及其制备方法和应用。
背景技术
生物活性玻璃(bioactive glass，BAG)是一类能对机体组织进行修复、替代与再生、具有能使组织和材料之间形成键合作用的无机非金属材料。首个生物活性玻璃45S5在1969年由Hench发现，是由SiO 2，Na 2O，CaO和P 2O 5等基本成分组成的硅酸盐玻璃。生物活性玻璃能在体液中降解，释放活性离子(Ca 2+、Si 4+、PO 4 3-等)，可生成与骨骼主要成分相同的羟基磷灰石(HAP，Ca 5(PO 4) 3OH)，能与宿主骨形成亲密的键合，诱导骨再生，促进成骨细胞基因表达、增加DNA的合成量，刺激血管生成，加速软硬组织的修复。在牙科和骨科具有广泛应用前景。生物活性玻璃的降解产物能够促进生长因子的生成、促进细胞的繁衍、增强成骨细胞的基因表达和骨组织的生长，是迄今为止唯一既能够与骨组织成键结合，同时又能与软组织相连接的人工生物材料。
生物活性玻璃的理化性质和生物学功能可通过其组成成分、结构和形态来调控，进而满足不同的临床需求。通过调整生物活性玻璃组分，引入不同的化学元素能够调控结构和功能或赋予玻璃特殊的性质，例如在生物活性玻璃中添加锶，氯能够加速生物活性玻璃降解，提高其生物活性；添加锌、镁、钴、氟等能让玻璃具有抗菌性；添加锶、氟能够增 强生物活性玻璃的成骨功效等。现已有相关的研究，例如中国专利申请CN200780029345.8生物活性玻璃，公开了一种生物活性玻璃，其包括Sr和Si0 2，SrO的摩尔百分数是0.2％至45％，还包括Na、K、Ca、P 20 5、Mg、Zn、B 2O 3、F或Ag中的一种或多种源，其中以CaF 2、SrF 2、MgF 2、NaF或KF中的一种或多种提供所述F，且CaF 2、SrF 2、MgF 2、NaF或KF的总摩尔百分数是0％至50％，包含0％至30％总摩尔百分数的Na离子源和/或K离子源，包含0％至50％摩尔百分数的CaO，包含0％至14％摩尔百分数的P 20 5，其包含0％至40％摩尔百分数的MgO，其包含0％至10％摩尔百分数的ZnO，包含0％至15％摩尔百分数的B 20 3。研究还发现，通过改变玻璃中网络形成体(如SiO 2，通过桥氧离子与其他网络形成体相连)和网络修饰体(如Na 2O、CaO等，通过打断桥氧与网络形成体元素之间的桥氧键而产生非桥氧离子的氧化物)的含量比例可以改变玻璃的网络联通性(即每个玻璃骨架单位中桥氧键的平均数目)，进而调控材料的降解速率，以满足不同的应用需求。例如降低玻璃中网络形成体和网络修饰体的比例，可以使得玻璃的结构从三维网络结构向链状结构改变，进而降低玻璃的稳定性，提高降解性，形成生物活性玻璃，反之。研究结果显示当生物活性玻璃的网络联通性为1.9-2时，具有良好的生物活性，即可降解性和生成类磷灰石的能力。当生物活性玻璃的网络联通性大于2.6时，几乎不具有生物活性。
在进一步的体外研究发现，由SiO 2-Na 2O-CaO-P 2O 5组成的一些生物活性玻璃在模拟体液内浸泡24小时后才能检测到少量的矿化羟基磷灰石形成，且降解后会引起溶液pH的快速升高。这意味着含有这类生物活性玻璃作为再矿化牙膏添加剂或脱敏剂时，无法快速、高效和可控的达到理想的矿化效果。此外，过高的pH会损害细胞、组织，且对于生物活性玻璃作为植骨材料应用时，会出现材料降解过快，降解速率与骨修复重建速率不协调。
因此，结合应用需求，开展新型生物活性玻璃的个性化开发及研究很有必要。
发明内容
本申请的目的在于提供一种医用生物活性玻璃及其制备方法和应用，所述医用生物活性玻璃可用于牙科和骨科中。
本申请的目的通过以下技术方案实现：
本申请首先提供了一种医用生物活性玻璃，包括以下原料成分：SiO 2、P 2O 5、金属氯化物或其结晶水合物、网络修饰体；所述网络修饰体包括碱金属氧化物或/和碱土金属氧化物；所述医用生物活性玻璃的网络连通性NC为1.5-3.35；其中NC的计算公式为：其中NC的计算公式为：
Figure PCTCN2022121906-appb-000001
公式中：
Figure PCTCN2022121906-appb-000002
为医用生物活性玻璃中SiO 2的摩尔百分含量；M MO为医用生物活性玻璃中碱土金属氧化物的摩尔百分含量；
Figure PCTCN2022121906-appb-000003
为医用生物活性玻璃中碱金属氧化物的摩尔百分含量；
Figure PCTCN2022121906-appb-000004
为医用生物活性玻璃中碱金属氧化物的摩尔百分含量。
进一步的，本申请的医用生物活性玻璃，还包括功能调节金属氧化物，所述功能调节金属氧化物为CuO、ZnO、Fe 2O 3、SnO、CeO 2、CoO和MnO 2中的一种或多种，当混合时，为任何比例。
进一步的，本申请的医用生物活性玻璃，还包括氟化物，所述氟化物为CaF 2、SrF 2、MgF 2和LaF 3中的一种或多种，当混合时，为任何比例。
进一步的，上述述氯化物为CaCl 2、SrCl 2、BaCl 2、ZnCl 2、LaCl 3和KCl中的一种或多种，当混合时，为任何比例；所述碱金属氧化物为K 2O；所述碱土金属氧化物为MgO、CaO、BaO和SrO中的一种或多种，当混合时，为任何比例。
进一步的，本申请的医用生物活性玻璃，还包括氟化物，所述氟化物为CaF 2、SrF 2、MgF 2和LaF 3中的一种或多种，当混合时，为任何比例。
更进一步的，本申请的医用生物活性玻璃中，各原料成分的摩尔含量如下：
SiO 2 20-60mol％；
P 2O 5 3-8mol％；
金属氯化物或其结晶水合物0.5-56mol％；
网络修饰体20-60mol％；
功能调节金属氧化物0.1-20mol％；
氟化物0.1-9mol％。
更进一步的，本申请的医用生物活性玻璃，其相态为无定形的生物活性玻璃，或者为生物活性玻璃基质中含有结晶相的生物活性玻璃陶瓷。
上述医用生物活性玻璃的制备方法，是通过高温熔融冷淬(melt-quench)制备而成，具体步骤如下：
1)按照配方设计的重量比例称取各原料，混合均匀后置于铂金坩锅中，1250-1620℃下熔融处理1-2h，将得到的均一混合物置于冷水中或金属板上使其骤冷；
2)将上步骤得到的物料置于烘箱中干燥，然后通过研磨获得所述医用生物活性玻璃。
制备方法中，所述步骤1)中的冷水是指温度为0-30℃的水；所述步骤2)的干燥温度是60-80℃，时间是5-24小时。
本申请还涉及所述的医用生物活性玻璃在医学中应用，用作以下医学产品的原料组分：牙保护漆、漱口水、植骨材料、功能型牙贴、牙用脱敏剂、根管充填材料、复合树脂充填材料、粘接剂、伤口敷料；所述功能型牙贴包括美白牙贴和再矿化牙贴。用于植骨材料中，具有良好的成骨效果，同时还具有抗菌、抗炎和抗肿瘤等其他辅助治疗功效。
与现有技术相比，本申请具有以下优点：
1、本申请的生物活性玻璃中，SiO 2作为玻璃结构的网络形成体，通过桥氧形成玻璃网络结构；P 2O 5以正磷酸根的形式存在，修饰玻璃结构；金属氯化物或其结晶水合物不影响玻璃的网络联通性，但可扩张玻璃的结构，调节玻璃的生物活性；网络修饰体通过破坏Si与桥氧间的桥氧键，形成非桥氧键来改变玻璃的网络联通性；氟化物也不影响玻璃的网络联 通性，但可以以如CaF +或SrF +等形式修饰玻璃结构，调节生物活性玻璃的理化及生物学功能。
2、生物活性玻璃的NC值与其生物活性(降解性和生成磷灰石的能力)存在一定的相关性。当NC值大于2.4时，生物活性玻璃几乎无生物活性，体内研究显示其几乎无成骨能；接近2.0时，生物活性玻璃具有良好的生物活性；从2.0至2.4(2.0＜NC≤2.4)，生物活性玻璃的生物活性随NC值的增加而降低。当NC值小于1.8时，生物活性玻璃大量结晶，生物活性降低。而本申请中，因为加入氯化物，在不影响玻璃的网络联通性的同时，氯离子能够扩张玻璃结构，提高玻璃的降解性和生成磷灰石的能力，因此本申请的生物活性玻璃的NC值大于2.4，甚至等于3.18时，生物活性玻璃仍具有较高的生物活性，同时随着NC值增加，玻璃的降解速率减慢；当生物活性玻璃的1.5＜NC＜2.0时，生物活性玻璃具有优良的生物活性，且随着生物活性玻璃中氯含量的增加，生物活性玻璃的降解速率加快。
3、本申请的医用生物活性玻璃，根据NC计算公式，通过在限定的范围内调整其中碱土金属氧化物、碱金属氧化物、二氧化硅和五氧化二磷的含量，可以将医用生物活性玻璃的NC值调整值期望的范围内，从而其理化性质和生物学性能可调控，具有很广泛的应用前景，如氟保护漆、漱口水、植骨材料、功能型牙贴(美白牙贴和再矿化牙贴)、脱敏剂、根管充填材料、复合树脂充填材料、粘接剂、伤口敷料添加剂等。同样，将本申请所述的医用生物活性玻璃用作植骨材料，可以通过调节含氯生物活性玻璃的NC值来调控玻璃的降解速率，解决当前植骨材料的降解速率与其成骨生成速率不匹配的问题。
4、本申请组分中的功能调节金属氧化物，比如掺入金属元素，如铜、锌、铁、钴和锰等，其在生物活性玻璃体系中有足够SiO 2用于形成玻璃网络骨架结构时，具有NC调节功能，充当类似于碱金属和碱土金属氧化物的网络修饰体功能，用于调节体系的NC值，同时具有治疗功能，额外赋予生物活性玻璃抗菌，抗炎和抗肿瘤的作用。
5、本申请的制备方法采用高温熔融冷淬制备工艺，该方法可进行大规模、批量的生物活性玻璃生产。
附图说明
从下面结合附图对本申请实施例的详细描述中，本申请的这些和/或其它方面和优点将变得更加清楚并更容易理解，其中：
图1是含有不同网络连通性的生物活性玻璃的X射线衍射图；
图2是含有不同网络连通性的生物活性玻璃浸泡在Tris溶液中不同时间释放出钙离子的浓度的图；
图3是网络连通性为3.35的生物活性玻璃在Tris溶液中浸泡不同时间后收集到的固体粉末的X射线衍射图；
图4是网络连通性为3.27的生物活性玻璃在Tris溶液中浸泡不同时间后收集到的固体粉末的 31P固态核磁共振波普图；
图5是网络连通性为1.5的生物活性玻璃在Tris溶液中浸泡不同时间后收集到的固体粉末的 31P固态核磁共振波普图；
图6是实施例1中的生物活性玻璃作为植骨材料，植入大鼠的颅骨缺损4周后，骨组织的Micro-CT图(BG为植入生物活性玻璃的缺损，C为空白对照组)；
图7是实施例2中的可用作漱口水添加剂的生物活性玻璃，与链球菌共培养24小时后的扫描电镜图，其中图(a)为不含生物活性玻璃的培养基组，图(b)为含生物活性玻璃的培养基组；
图8为实施例3中，可用作牙保护漆的生物活性玻璃，在人工唾液中浸泡24小时后的扫描苗电镜图；
图9是实施例6中，可用作伤口辅料添加剂的生物活性玻璃，与血链球菌共培养4小时后的透射电镜图；
图10是实施例6提供的生物活性玻璃，与人脐静脉内皮细胞在生物活性玻璃浸提液中培养6小时后血管管腔形成的情况图；
图11小鼠背部的伤口在经实施例6提供的生物活性玻璃处理前和处理6天后的情况图。
具体实施方式
以下通过实施例进一步详细描述本申请，但这些实施例不应认为是对本申请的限制。
实施例1：
医用生物活性玻璃，为生物活性玻璃基质中含有少量结晶相的生物活性玻璃陶瓷，是由SiO 2、P 2O 5、CaF 2、K 2O、CaO，MnO 2、CaCl 2通过高温熔融冷淬法(melt-quench)制成，其中P 2O 5的含量为5.0mol％；CaF 2的含量为3.0mol％，CaCl 2的含量为14.0mol％；MnO 2的含量为5.0mol％；此外，生物活性玻璃的组成成分的含量满足：NC为2.5；
上述医用生物活性玻璃，是通过高温熔融冷淬(melt-quench)制备而成，具体步骤如下：
1)按照配方设计的重量比例称取各原料，混合均匀后置于铂金坩锅中，1580℃下熔融处理1h，将得到的均一混合物置于冷水中使其骤冷；
2)将上步骤得到的物料置于烘箱中干燥，60℃，24小时，然后通过研磨获得粒径在100-1000μm大小的医用生物活性玻璃。
上述制备得到的医用生物活性玻璃作为植骨材料的生物活性玻璃。
实施例2：
医用生物活性玻璃，为无定形非晶相生物活性玻璃，是由SiO 2、P 2O 5、CaO、CaCl 2、CuO通过高温熔融冷淬法(melt-quench)制成，其中P 2O 5的含量为3.0mol％，CaCl 2的含量为56.0mol％，CuO的含量为1mol％，此外，生物活性玻璃的组成成分的含量满足：NC为1.6；
上述医用生物活性玻璃，是通过高温熔融冷淬(melt-quench)制备 而成，具体步骤如下：
1)按照配方设计的重量比例称取各原料，混合均匀后置于铂金坩锅中，1250℃下熔融处理1h，将得到的均一混合物置于冷水中使其骤冷；
2)将上步骤得到的物料置于烘箱中，80℃，5小时，然后通过研磨获得粒径为小于38μm的医用生物活性玻璃。
上述制备得到的医用生物活性玻璃可作为具有抗菌漱口水添加剂的生物活性玻璃。
实施例3：
医用生物活性玻璃，为生物活性玻璃基质中含有少量结晶相的生物活性玻璃陶瓷，是是由SiO 2、P 2O 5、SrO、ZnO、CaO、SrCl 2、SrF 2、通过高温熔融冷淬法(melt-quench)制成，其中P 2O 5的含量为4.0mol％，SrF 2的含量为1.0mol％，SrCl 2的含量为0.5mol％，ZnO的含量为0.1mol％，此外，生物活性玻璃的组成成分的含量满足：NC为1.8；
上述医用生物活性玻璃，是通过高温熔融冷淬(melt-quench)制备而成，具体步骤如下：
1)按照配方设计的重量比例称取各原料，混合均匀后置于铂金坩锅中，1450℃下熔融处理1h，将得到的均一混合物置于冷水中使其骤冷；
2)将上步骤得到的物料置于烘箱中干燥，70℃，10小时，然后通过研磨获得粒径为小于38μm的医用生物活性玻璃。上述制备得到的作为用作牙保护漆添加剂的医用生物活性玻璃。
实施例4：
医用生物活性玻璃，为生物活性玻璃基质中含有少量结晶相的生物活性玻璃陶瓷，是由SiO 2、P 2O 5、SnO、MgO、CaO、LaF 2、CaCl 2、LaCl 3、通过高温熔融冷淬法(melt-quench)制成，其中P 2O 5的含量为1.0mol％，LaF 3的含量为1.0mol％，CaCl 2、LaCl 3的总含量为3.0mol％，此外，生物活性玻璃的组成成分的含量满足：NC为2.7；
上述医用生物活性玻璃，是通过高温熔融冷淬(melt-quench)制备而成，具体步骤如下：
1)按照配方设计的重量比例称取各原料，混合均匀后置于铂金坩锅中，1580℃下熔融处理1h，将得到的均一混合物置于冷水中使其骤冷；
2)将上步骤得到的物料置于烘箱中干燥，65℃，20小时，然后通过研磨获得粒径为小于38μm的医用生物活性玻璃。
上述制备得到的作为复合树脂充填材料的医用生物活性玻璃。
实施例5：
医用生物活性玻璃，为生物活性玻璃基质中含有少量结晶相的生物活性玻璃陶瓷，是由SiO 2、P 2O 5、K 2O、Fe 2O 3、MgO、CaO、KCl、ZnCl 2、BaCl 2通过高温熔融冷淬法(melt-quench)制成，其中P 2O 5的含量为8.0mol％，Fe 2O 3的含量为3.0mol％；KCl、ZnCl 2和BaCl 2的总含量为12.0mol％，且它们之间的比例为1:1:1，此外，生物活性玻璃的组成成分的含量满足：NC为3.35；
上述医用生物活性玻璃，是通过高温熔融冷淬(melt-quench)制备而成，具体步骤如下：
1)按照配方设计的重量比例称取各原料，混合均匀后置于铂金坩锅中，1620℃下熔融处理1h，将得到的均一混合物置于冷水中使其骤冷；
2)将上步骤得到的物料置于烘箱中干燥，70℃，12小时，然后通过研磨获得粒径在100-1000μm大小的医用生物活性玻璃。
上述制备得到的可用作具有抗肿瘤潜能的植骨材料的医用生物活性玻璃。
实施例6：
医用生物活性玻璃，为无定形非晶相生物活性玻璃，是由SiO 2、P 2O 5、CaO，SrCl 2、CeO 2、CuO、CoO通过高温熔融冷淬法(melt-quench)制成，其中P 2O 5的含量为5.0mol％，SrCl 2的含量为25.0mol％， CeO 2、CuO、CoO的总含量为20mo％，且它们之间的比例为1:1:2，此外，生物活性玻璃的组成成分的含量满足：NC为2.1；
上述医用生物活性玻璃，是通过高温熔融冷淬(melt-quench)制备而成，具体步骤如下：
1)按照配方设计的重量比例称取各原料，混合均匀后置于铂金坩锅中，1380℃下熔融处理1h，将得到的均一混合物置于冷水中使其骤冷；
2)将上步骤得到的物料置于烘箱中干燥，75℃，12小时，然后通过研磨获得粒径为小于38μm的医用生物活性玻璃。
上述制备得到的医用伤口辅料添加剂的生物活性玻璃。
实施例7：
医用生物活性玻璃，为无定形非晶相生物活性玻璃，是由SiO 2、P 2O 5、CaO，MgF 2、CaCl 2、SrO通过高温熔融冷淬法(melt-quench)制成，其中P 2O 5的含量为4.5mol％，MgF 2的含量为0.5mol％，CaCl 2的含量为30.0mol％，此外，生物活性玻璃的组成成分的含量满足：NC为1.5；
上述医用生物活性玻璃，是通过高温熔融冷淬(melt-quench)制备而成，具体步骤如下：
1)按照配方设计的重量比例称取各原料，混合均匀后置于铂金坩锅中，1410℃下熔融处理1h，将得到的均一混合物置于冷水中使其骤冷；
2)将上步骤得到的物料置于烘箱中干燥，80℃，10小时，然后通过研磨获得粒径为小于38μm的医用生物活性玻璃。
上述制备得到的作为脱敏剂添加剂的生物活性玻璃。
实验例：
图1是含有不同网络连通性的生物活性玻璃的X射线衍射图，如图1所示，所有的玻璃玻璃都含有无定形的玻璃相，其中NC小于2.57的玻璃中含有羟基磷灰石；NC值大于3.18的生物活性玻璃中除了有玻璃相外含有少量SiO 2结晶相。
图2是含有不同网络连通性的生物活性玻璃浸泡在Tris溶液中不同时间释放出的钙离子浓度示意图，如图2所示，1.5≤NC≤3.35的含氯生物活性玻璃在Tris溶液中浸泡1小时候均可降解，提示含氯生物活性玻璃即使NC值大于2.4，玻璃一样具有很高的生物活性；同时NC值大于2.57的玻璃其钙离子的释放量低于NC值小于等于2.57的玻璃，提示我们在保证玻璃具有生物活性的前提下，可以通过调控含氯生物活性玻璃的NC值调节玻璃的降解速率。
图3是网络连通性为3.35的生物活性玻璃在Tris溶液中浸泡不同时间后收集到的固体粉末的X射线衍射图，如图3所示，NC值为1.5的生物活性玻璃在Tris溶液中浸泡一小时后，XRD图谱中的无定形玻璃信号(25-32°(2θ))强度降低，硅胶层的信号(20-25°(2θ))增强，提示在玻璃发生快速降解，生成硅胶层；随着浸泡时间的延长，无定形玻璃信号强度逐渐减弱，与羟基磷灰石匹配的信号峰强度逐渐增强，9小时后无明显变化；这些提示该玻璃陶瓷具有很高的生物活性，浸泡1小时即可见玻璃降解，6小时可见明显的磷灰石生成，此外在9小时时玻璃中释放的磷酸根几乎全部被消耗用于生成羟基磷灰石。
图4是网络连通性为3.27的生物活性玻璃在Tris溶液中浸泡不同时间后收集到的固体粉末的 31P固态核磁共振波普图，如图4所示，NC值为3.27的生物活性玻璃在Tris溶液中浸泡前后其 31P固态核磁共振波普图均为单一的峰。未浸泡的生物活性玻璃(0h) 31P的化学位移为2.5ppm左右，提示在原始玻璃中，P是以正磷酸根的形式存在，且由CaCl +平衡价电子。浸泡于Tris溶液后，生物活性玻璃的 31P的化学位移移至3.0ppm，且从3h至24h， 31P信号峰的半峰宽逐渐减小，这些提示浸泡后，P是以正磷酸根的形式存在，且主要由Ca 2+平衡价电子即快速生成羟基磷灰石，且从3h至24h，生成羟基磷灰石的量逐渐增加。由此可见含氯生物活性玻璃的生物活性可以突破当NC值大于2.4时，生物活性玻璃几乎无生物活性的限制，当其NC值为3.27时，仍具有良好的生物活性。
图5是网络连通性为1.5的生物活性玻璃在Tris溶液中浸泡不同时间后收集到的固体粉末的 31P固态核磁共振波普图，如图5所示，NC值为1.5的生物活性玻璃在Tris溶液中浸泡前后其 31P固态核磁共振波普图均为单一的峰。未浸泡的生物活性玻璃(0h) 31P的化学位移为2.6ppm左右，提示在原始玻璃中，P是以正磷酸根的形式存在，且由CaCl +平衡价电子。浸泡于Tris溶液后，生物活性玻璃的 31P的化学位移移至3.0ppm，且从3h至9h， 31P信号峰的半峰宽逐渐减小，从9h至24h， 31P信号峰的半峰宽几乎不变。这些提示NC值为1.5的生物活性玻璃在Tris中浸泡3h后，能快速生成羟基磷灰石，从3h至9h，生成羟基磷灰石的量逐渐增加，9h后生成的羟基磷灰石的量几乎没有变化。由此可见NC值为1.5的生物活性玻璃具有良好的生物活性。
图6是实施例1中的生物活性玻璃作为植骨材料，植入大鼠的颅骨缺损4周后，骨组织的Micro-CT图(BG为植入生物活性玻璃的缺损，C为空白对照组)，其中，(a)为实施例1的生物活性玻璃BG作为植骨材料，植入大鼠的颅骨缺损4周后，骨组织的Micro-CT正面图，(b)为切面图；如图6所示，植入BG的骨缺损区域有大量的新骨生成，且新生成的骨组织几乎贯穿整整个缺损区域，而对照组仅可见很少量的新骨形成。由此可见，本申请涉及的生物活性玻璃具有良好的成骨功效，可作为植骨材料，用于临床骨缺损修复。
图7是实施例2中，可用作漱口水添加剂的生物活性玻璃，与链球菌共培养24小时后的扫描电镜图，其中(a)为不含生物活性玻璃的培养基组，(b)为含生物活性玻璃培养基组，如图7所示，与不含生物活性玻璃的培养基组相比，含生物活性玻璃的培养基可以明显的破坏链球菌的结构和活性，进而抑制或杀死细菌。由此可见本申请中涉及的生物活性玻璃具有良好的抗菌功效，可作为漱口水或根管封闭剂的添加剂。
图8为实施例3中，可用作牙保护漆的生物活性玻璃，在人工唾液中浸泡24小时后的扫描电镜图，如图8所示，本申请设计的生物活性玻璃可以在唾液中快速降解，释放出氟离子，并生成氟磷灰石针状晶体， 该晶体在具有良好的耐酸性，所释放的氟离子还具有抑制脱矿和促进再矿化的作用。
图9是实施例6中，可用作伤口辅料添加剂的生物活性玻璃，与血链球菌共培养4小时后的透射电镜图，其中，(a)为不含生物活性玻璃的培养基组，(b)为含生物活性玻璃培养基组，如图9所示，血链球菌在不含生物活性玻璃的培养基组中具有很好的生长状态，同时血链球菌具有完整的细胞壁、细胞膜和胞内遗传物质的结构，而经过本申请实施例6提供的生物活性玻璃处理的细菌其体积明显缩小、电子致密度降低、细胞结构不完整、破裂；此外，还可见颗粒状的黑色玻璃降解产物进入细胞内部，且胞内遗传物质被破坏。由此可见，本申请中涉及的掺CeO 2、CoO的生物活性玻璃具有良好的抗菌和杀菌功效。
图10是实施例6提供的生物活性玻璃，与人脐静脉内皮细胞在生物活性玻璃浸提液中培养6小时后血管管腔形成的情况图，其中，(a)为不含CeO 2、CoO的生物活性玻璃的情况图，(b)为实施例6提供的生物活性玻璃，如图10所示，人脐静脉内皮细胞在不含CeO 2、CoO的生物活性玻璃共培养的情况下，未可见封闭的管腔，而与实施例6提供的生物活性玻璃共培养后，可见大量的封闭管腔形成，因此，本申请实施例6提供的生物活性玻璃具备促进封闭的血管管腔形成的能力。
图11小鼠背部的伤口在经实施例6提供的生物活性玻璃处理前和处理6天后的情况图，其中，(a)为第一只小鼠处理前的情况，(c)为第一只小鼠使用不含CeO 2、CoO的生物活性玻璃处理6天后的情况，(b)为第二只小鼠处理前的情况，(d)为第二只小鼠使用实施例6提供的生物活性玻璃处理后的情况，如图11所示，与不含功能调节金属氧化物的含氯生物活性玻璃相比，实施例6提供的生物活性玻璃可以明显缩小伤口的大小，促进软组织伤口愈合。
以上所述仅为本申请的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本申请创造构思的前提下，做出若干改进和 变化，这些都属于本申请的保护范围。

Claims (10)

  1. 一种医用生物活性玻璃，其中，包括以下原料成分：
    SiO 2、P 2O 5、金属氯化物或其结晶水合物、网络修饰体；
    所述网络修饰体包括碱金属氧化物或/和碱土金属氧化物；
    所述医用生物活性玻璃的网络连通性NC为1.5-3.35；
    其中NC的计算公式为：
    Figure PCTCN2022121906-appb-100001
    公式中：
    Figure PCTCN2022121906-appb-100002
    为医用生物活性玻璃中SiO 2的摩尔百分含量；M MO为医用生物活性玻璃中碱土金属氧化物的摩尔百分含量；
    Figure PCTCN2022121906-appb-100003
    为医用生物活性玻璃中碱金属氧化物的摩尔百分含量；
    Figure PCTCN2022121906-appb-100004
    为医用生物活性玻璃中碱金属氧化物的摩尔百分含量。
  2. 根据权利要求1所述的医用生物活性玻璃，其中，
    还包括功能调节金属氧化物，所述功能调节金属氧化物为CuO、ZnO、Fe 2O 3、SnO、CeO 2、CoO和MnO 2中的一种或多种，当混合时，为任何比例。
  3. 根据权利要求1所述的医用生物活性玻璃，其中，
    还包括氟化物，所述氟化物为CaF 2、SrF 2、MgF 2和LaF 3中的一种或多种，当混合时，为任何比例。
  4. 根据权利要求1所述的医用生物活性玻璃，其中，
    所述氯化物为CaCl 2、SrCl 2、BaCl 2、ZnCl 2、LaCl 3和KCl中的一种或多种，当混合时，为任何比例；
    所述碱金属氧化物为K 2O；所述碱土金属氧化物为MgO、CaO、BaO和SrO中的一种或多种，当混合时，为任何比例。
  5. 根据权利要求2所述的医用生物活性玻璃，其中，
    还包括氟化物，所述氟化物为CaF 2、SrF 2、MgF 2和LaF 3中的一种或多种，当混合时，为任何比例。
  6. 根据权利要求5所述的医用生物活性玻璃，其中，所述各原料成分的摩尔含量如下：
    SiO 2 20-60mol％；
    P 2O 5 3-8mol％；
    金属氯化物或其结晶水合物0.5-56mol％；
    网络修饰体20-60mol％；
    功能调节金属氧化物0.1-20mol％；
    氟化物0.1-9mol％。
  7. 根据权利要求6所述的医用生物活性玻璃，其中，所述医用生物活性玻璃的相态为无定形的生物活性玻璃，或者为生物活性玻璃基质中含有结晶相的生物活性玻璃陶瓷。
  8. 权利要求1-7中任一权利要求所述的医用生物活性玻璃的制备方法，其中，包括以下步骤：
    1)按照配方设计的重量比例称取各原料，混合均匀后置于铂金坩锅中，1250-1620℃下熔融处理1-2h，将得到的均一混合物置于冷水中或金属板上使其骤冷；
    2)将上步骤得到的物料置于烘箱中干燥，然后通过研磨获得所述医用生物活性玻璃。
  9. 根据权利要求6所述的医用生物活性玻璃的制备方法，其中，所述步骤1)中的冷水是指温度为0-30℃的水；
    所述步骤2)的干燥温度是60-80℃，时间是5-24小时。
  10. 权利要求1-7中任一权利要求所述的医用生物活性玻璃在医学中应用，其中，用作以下医学产品的原料组分：牙保护漆、漱口水、植骨材料、功能型牙贴、牙用脱敏剂、根管充填材料、复合树脂充填材料、粘接剂、伤口敷料；所述功能型牙贴包括美白牙贴和再矿化牙贴。
PCT/CN2022/121906 2021-08-31 2022-09-27 一种医用生物活性玻璃及其制备方法和应用 WO2023051559A1 (zh)

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