WO2024134524A1 - Matériau composite à base de verre bioactif et de phosphate de calcium amorphe et procédé pour sa production - Google Patents

Matériau composite à base de verre bioactif et de phosphate de calcium amorphe et procédé pour sa production Download PDF

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WO2024134524A1
WO2024134524A1 PCT/IB2023/062999 IB2023062999W WO2024134524A1 WO 2024134524 A1 WO2024134524 A1 WO 2024134524A1 IB 2023062999 W IB2023062999 W IB 2023062999W WO 2024134524 A1 WO2024134524 A1 WO 2024134524A1
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acp
particles
composite material
mbgn
composite
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PCT/IB2023/062999
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English (en)
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Lorenzo DEGLI ESPOSTI
Michele Iafisco
Aldo R. BOCCACCINI
Kai ZHENG
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Consiglio Nazionale Delle Ricerche
Friedrich-Alexander-Universität Erlangen-Nürnberg
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Publication of WO2024134524A1 publication Critical patent/WO2024134524A1/fr

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  • the present invention refers to a composite material comprising or consisting of amorphous calcium phosphate and bioactive glass and its use as remineralizing agent in dentistry and for bone regeneration.
  • dental caries is the most widespread non-communicable disease which affects both industrialized and developing countries.
  • the disease results from a prevalence of acidogenic bacteria in the biofilm that permanently colonizes any oral surface.
  • These cariogenic bacteria produce organic acids, and the consequence is a lowering of the pH in the microenvironment of teeth surfaces (enamel and dentine), which triggers the dissolution of their mineral component, hydroxyapatite (HA, Caio(P04)e(OH)2).
  • HA dissolution is referred to as the “demineralization process” and leads to the formation of dental cavities.
  • Demineralization is a reversible process if the damaged tissues are exposed to an oral environment that favors the opposite process, “remineralization”.
  • Demineralized enamel is naturally remineralized by the epitaxial growth of residual HA crystals that act as nucleation sites, as saliva provides a supersaturated environment rich of Ca 2+ and PO4 3 " ions.
  • remineralization of enamel by saliva alone is seldom achieved. Therefore, it is required the use of an external source of Ca 2+ and PO4 3 " ions to increase ion supersaturation to efficiently prevent demineralization and boost remineralization.
  • This is the aim of remineralizing agents, which restore the structure and preserve the mechanical properties of dental hard tissues by releasing Ca 2+ and PO4 3 " ions, [1J mimicking the spontaneous remineralization process induced by saliva.
  • ACP is particularly appealing in dentistry due to its ability to release a higher amount of ions in comparison to crystalline calcium phosphates phases.
  • Several ACP products are actually marketed for dental remineralization in formulations that are directly applied on tooth surface (i.e. tooth mousses) having a good level of literature evidence for this use (systematic reviews).
  • ACP is an unstable material that rapidly transforms into more thermodynamically stable crystalline phases (e.g., HA) in solution or in dry state by reacting with atmospheric water. Due to this instability, use and handling of ACP is difficult, and several additives were studied to stabilize ACP.
  • W02020/002517 and WO2016/012452 describe a fluoride-doped amorphous calcium phosphate (F-ACP) stabilized by citrate ions that in aqueous solution gives burst release of Ca 2+ , PO4 3 ; and F’ ions, is able to crystallize into HA when in contact with enamel and dentine, inhibits cariogenic biofilm formation, and shows a strong remineralizing activity.
  • F-ACP has been proved, therefore, to be an excellent material for dental remineralization.
  • the main limit of all ACP materials is that their burst release lasts for a short timeframe, and thus several applications of the product are needed for a complete remineralization.
  • BGs bioactive glasses
  • HA-forming ability bioactive (HA-forming ability)
  • osteoconductive osteoconductive
  • osteoinductive gives a controlled release of bioactive ions in the surrounding environment.
  • bioactive glass nanoparticles BGN
  • BGN bioactive glass nanoparticles
  • BG have found a successful application as remineralizing agents.
  • a serious drawback that hinders this application is that BG cannot release a large amount of Ca 2+ and PO4 3 " ions and is not able to perform completely its remineralization function to form HA because it is diluted away by salivary action in a short time before it attaches to dental surfaces.
  • the present invention relates to an amorphous calcium phosphate/bioactive glass composite material (ACP/BG).
  • ACP/BG amorphous calcium phosphate/bioactive glass composite material
  • This composite material possesses both the short-time ion release capability of ACP as well as the long-time ion release of BG and thus (i) efficiently remineralizes damaged enamel, and (ii) induces the formation of a new HA layer onto enamel and dentin surface.
  • ACP component has a twofold action: (i) gives a burst ion release for initial HA formation (Ca 2+ , PO4 3 F- as well as Sr 2+ , Mg 2+ , Zn 2+ ) and (ii) acts as nucleation site for HA growth by attaching onto enamel and dentine surface, while the ion-doped BG component provides for a sustained ion release of remineralizing and biologically active ions (e.g., Ca 2+ , PO4 3 ", F; Si 4+ , Sr 2+ , Zn 2+ Mg 2+ ), thereby generating a continuous remineralization.
  • remineralizing and biologically active ions e.g., Ca 2+ , PO4 3 ", F; Si 4+ , Sr 2+ , Zn 2+ Mg 2+
  • the ACP/BG composite material is obtained by embedding BG particles in a matrix of ACP nanoparticles in order to maximize homogenization between the two components and to produce a composite with high uniformity from the macro- to the nano-scale. This has been achieved with a process that includes a step of precipitating ACP onto BG particles.
  • the BG particles can be nano-, micro-, or macro-particles.
  • the particles can also be porous or mesoporous
  • the invention relates also to the use of the composite material of the invention for use in the prevention of dental demineralization and to boost remineralization.
  • the composite material here disclosed is used as remineralizing agent thanks to its ability to restore the structure and preserve the mechanical properties of dental hard tissues by releasing Ca 2+ and PO4 3 " ions, thereby mimicking the spontaneous remineralization process induced by saliva.
  • the composite material can also be used for bone regeneration.
  • FIG. 1 SEM micrographs of (A) ACP/BG 80/20 composite, (B) 60/40 composite, (C) 40/60 composite, and (D) ACP+BG physical mixture, (E) ACP/MBGN 80/20 composite, (F) 60/40 composite, (G) 40/60 composite, and (H) ACP+MBGN physical mixture. Light grey arrows point at BG or MBGN particles, black arrows at ACP particles.
  • FIG. 1 SEM micrograph of (A) ACP/MBGN 80/20, (B) ACP/MBGN 60/20, (C) ACP/MBGN 40/60, (D) pure MBGN, and (E) pure ACP after incubation in SBF for 7 days.
  • the composite material of the invention comprises or consists of bioactive glass particles and amorphous calcium phosphate particles as an intimate and homogenous mixture obtained by precipitating ACP onto BG particles.
  • BG particles are chosen among macroscopic particles, micrometric particles or nanoparticles. Each of them can be microporous or mesoporous. BG nanoparticles are defined as BGN and mesoporous BG nanoparticles are defined as MBGN.
  • Compositions of macro and micrometric BG particles typically contain SiC>2, CaO, Na2 ⁇ D and P2O5 in different ratios.
  • Other components e.g., ZnO, CuO, SrO, can also be incorporated in BG compositions.
  • Compositions of BGN and MBGN typically contain SiO2 and CaO in different ratios.
  • BGN are made of 90% SiO2 and 10% CaO
  • MBGN are made of 10% CaO and 90% SiO2.
  • Other components e.g., ZnO, CuO, SrO, can also be incorporated into BG nanoparticles and MBGN
  • ACP is in the form of nanoparticles.
  • ACP is doped with one or more of the following ions: F, Zn, Mg, Sr, Na, K, Fe, Cu, Cl, Ag.
  • the composite material comprises ACP in an amount ranging between 1 % wt and 99% wt and BG in an amount ranging from 99% wt and 1 % wt.
  • the composite material comprises ACP in amount ranging between 20% and 80%, or 20% and 60%, or 20% and 40% and BG in an amount ranging from 80% and 20%, or 60% and 20%, or 40% and 20%.
  • the two components are intimately and homogenously intertwined together to yield the superior properties demonstrated by the composite material with respect to a simple mixture of the two components ACP and BG.
  • the composite material bypasses the intrinsic disadvantages that its constituting components have, such as poor ion release on the short timeframe, limited apatite formation, and no fluoride release for BG, and no sustained release and low stability for ACP.
  • the composite material is obtained with a process that comprises the following steps: a) Mixing an aqueous solution comprising a calcium salt and/or calcium hydroxide, BG particles and a sodium or potassium citrate salt and/or citric acid (solution A) with a solution comprising a phosphate salt and/or phosphoric acid and a carbonate salt and/or carbonic acid (solution B); b) Stirring the mixture for at least 3 seconds to allow the formation of a precipitate; c) Collecting and drying the precipitate.
  • the calcium salt is chosen among calcium chloride, calcium nitrate, calcium acetate, calcium lactate, calcium oxalate, calcium citrate, and calcium sulfate,
  • the sodium or potassium citrate salt is chosen among sodium citrate tribasic, sodium citrate dibasic, sodium citrate monobasic, potassium citrate tribasic, potassium citrate dibasic, and potassium citrate monobasic.
  • the phosphate salt is chosen among sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, or potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, or ammonium phosphate, ammonium hydrogen phosphate, ammonium dihydrogen phosphate.
  • the carbonate salt is chosen among sodium carbonate, sodium hydrogen carbonate, sodium dihydrogen carbonate, or potassium carbonate, potassium hydrogen carbonate, potassium dihydrogen carbonate, or ammonium carbonate, ammonium hydrogen carbonate, ammonium dihydrogen carbonate.
  • step b) The mixture is stirred in step b) for a time of 3 sec-1 h, preferably 10 sec-60 sec.
  • BG particles which can be BG macro or microparticles, BGN or MBGN are prepared with methods known in the art or are commercially available.
  • solution A can be optionally sonicated to disperse the BG particles and the pH of solution B can be optionally brought to a basic pH of above 9.
  • the amount of BG particles used can be varied to yield a final ACP:BG weight ratio of between 80:20, 60:40, or 40:60 for example.
  • Solution B can optionally include fluorine, and/or chlorine ions that are doping agents for ACP.
  • the mixing step a) is preferably performed at a temperature between 1-30°C, or 4-25°C, or 20-25°C.
  • the composite material obtained by the process of the invention has a structure in which the BG particles are surrounded and immersed in a matrix of ACP nanoparticles. There is no segregation between ACP and BG and the mixture is homogenous and intimately mixed, forming a deeply-intertwined composite.
  • a comparison between the composite of the invention and a physical mixture of ACP and BG show that the physical mixture is not homogenous, presenting micrometric granules of pure BGN/MBGN or pure ACP.
  • the composite of the invention has shown a good release of Ca, P, Si and optionally F, Zn and/or Mg, if doped with one or more of those ions.
  • the release is more intense for a first period of at least 2 h and remains sustained for a second period of up to 5 h. Afterwards the release gradually slows down continuing as a slow release up to 24 hours.
  • the release curves have been compared to pure ACP, which shows only a burst release of Ca, P, and F in less than 2 h, and to pure BG, whose release of Ca, P, and Si is less intense and is spread across the 24 h timeframe.
  • ACP/BG composites their release is intermediate between the ones of pure ACP and pure BG and depends on ACP:BG ratio, i.e. ACP-rich composites have a more intense Ca, P, and F release and less intense Si release, while in BG-rich composites the behavior is the opposite.
  • ACP:BG ratio i.e. ACP-rich composites have a more intense Ca, P, and F release and less intense Si release, while in BG-rich composites the behavior is the opposite.
  • ACP:BG ratio The most important finding is that ACP/BG composite has a stronger Ca, P, and F release and a weaker Si release than the ACP+BG physical mixture with identical weight ratio. This is the definitive proof that the composite preparation gives better ion-releasing properties which cannot be achieved by only mixing the two base ingredients.
  • the composite of the invention can also be used to achieve dentin desensitization by occluding the dentinal tubules.
  • Another use of the composite of the invention is for bone regeneration.
  • the composite material can also be used for bone regeneration. Owing to its outstanding remineralization and ion release capacity, the composite material can be used as bone defect filler to accelerate formation of HA and stimulate osteogenesis and angiogenesis.
  • the composite material can also be used to fabricate orthopedic implant coating or bone tissue engineering scaffolds for bone repair and regeneration. The fast release of Ca 2+ and PO4 3 " ions from ACP facilitates bone bonding while sustained release of biologically active ions from BGs ensures favorable biological responses for bone regeneration.
  • the invention refers also to a method to prevent dental demineralization and/or to boost dental remineralization which includes a step of applying the composite material on dental hard tissues.
  • Calcium chloride dihydrate (CaCl2-2H2O, >99.0% pure), hydrochloric acid (HCI, >37.0% pure), sodium citrate tribasic dihydrate (Na3(C6H5O7) 2H2O, >99.0% pure, hereafter called sodium citrate), sodium phosphate dibasic dihydrate (Na2HPO4-2H2O, >99.0% pure), sodium carbonate monohydrate (Na2CO3-2H2O, >99.0% pure), sodium fluoride (NaF, >99.0% pure), MBGN, BGN, BG. MBGN were synthesized and characterized as reported by Zheng et al. [3] using a microemulsion-based sol-gel method.
  • TEOS tetraethyl orthosilicate
  • VWR calcium nitrate tetrahydrate
  • BGN nanoparticles were synthesized using a modified Stober method (Zheng K, et al. Timing of calcium nitrate addition affects morphology, dispersity and composition of bioactive glass nanoparticles[J], RSC advances, 2016, 6(97): 95101 -95111 ).
  • a solution (A) composed of 2.25 mL of tetraethyl orthosilicate (TEOS, 98%, Sigma-Aldrich) and in 25 mL of ethanol (96% VWR) was mixed with Solution B that was prepared by mixing 4.5 mL of ammonium hydroxide solution (28.0- 30.0%, Sigma-Aldrich), 8.12 mL of ethanol and 12.38 mL of deionized water. After leaving the reaction to proceed for 30 min, 1.45 g of calcium nitrate tetrahydrate was added. The mixtures were allowed to react for a further 90 min before collection by centrifugation at 7197 ref for 25 min.
  • TEOS tetraethyl orthosilicate
  • the obtained particles were dispersed and washed twice with deionized water and once with ethanol.
  • the collected particles were subsequently dried at 60 °C overnight before calcination at 700 °C for 2 h with a heating rate of 2 °C/min.
  • ACP/BG composites were prepared by mixing at room temperature equal volumes of two aqueous solutions, consisting of (A) 100 mM CaCl2 + 100 mM sodium citrate + X mg/mL BG (either BG, BGN, or MBGN) and (B) 120 mM Na 2 HPO 4 + 200 mM Na 2 CO 3 + 50 mM NaF.
  • solution (A) was sonicated at 20% amplitude for 3 min with a pulsation of 5 s under ice cooling employing a Vibracell VCX 500 tip sonicator (SONICS, Newtown, CT, USA) to disperse BG, while the pH of solution (B) was brought to 9.5 with HCI 37 wt.%.
  • the precipitate was left to stir for at least 30 s at room temperature and afterwards the particles were collected by centrifugation (7000 RPM, 5 min, 4 °C) and repeatedly washed with ultrapure water. Finally, the materials were freeze-dried for 24h.
  • the 60:40 wt.% ACP+BG physical mixture was prepared by hand mixing together 240 mg of ACP powder and 160 mg of BG powder (either BG, BGN, or MBGN) until complete homogeneity was achieved.
  • Powder X-ray diffraction PXRD: PXRD patterns of the samples were recorded on a D8 Advance diffractometer (Broker, Düsseldorf, Germany) using Cu Ka radiation generated at 40 kV and 40 mA. PXRD patterns were collected in the 10 - 60° 29 range with a step size of 0.02 degree and a collection time of 0.5 s.
  • FT-IR Fourier transform infrared spectroscopy
  • SSABET Specific Surface Area analysis
  • Thermal characterization Thermogravimetry analysis (TGA) of the samples was performed with a STA 449F3 Jupiter instrument (Netzsch GmbH, Selb, Germany). 10 mg of the samples were placed in an alumina crucible and an empty crucible was used as a reference. The crucibles were heated from room temperature to 1100 °C with a heating rate of 10 °C/min under air flow.
  • SEM Scanning electron microscopy
  • sample powders were dispersed into 10mL of artificial saliva prepared as modified Tani-Zucchi solution containing KCI 20mM, KSCN 5.3mM, Na2HPO4 1.4mM, NaHCOs 15mM, and lactic acid 10mM.
  • the suspension was maintained at 37 °C under shaking.
  • 8m L of the supernatant that was separated from the solid phase by centrifugation at 7000 rpm for 5m in
  • ICP-OES and fluoride ion selective electrode was removed for ions quantification by ICP-OES and fluoride ion selective electrode. After that, samples were rinsed with 8m L of fresh artificial saliva, and the suspension was again shacked at 37 °C until the next time point.
  • ICP-OES inductively-coupled plasma optical emission spectrometry
  • ICP-OES ion-selective electrode for fluoride
  • ICP-OES was performed with an Agilent 5100 instrument (Agilent Technologies, Santa Clara, CA, USA), while ISEF was an Intellical ISEF121 electrode (Hach Lange, Loveland, CO, USA).
  • the supernatants were diluted 1 :3 with a 1 wt. % HNOs aqueous solution.
  • F analyses were performed as suggested by instrument manufacturer. Standard fluoride solutions were prepared from a certified standard (1 ,000 ppm F certified standard, Sigma Aldrich, St. Luis, MO, United States); the calibration curve was then obtained by analyzing the standard solutions on the same day they were prepared.
  • the pellet was washed with ultrapure water and freeze-dried. Afterward, the dried materials were analyzed by PXRD, SEM, and SEM-EDS as reported above.
  • ACP+BG physical mixtures are not homogeneous, presenting micrometric granules of pure BGN/MBGN or pure ACP ( Figure 1 H). In some granules it is possible to observe a mixture of MBGN and FACP particles, but it is likely that the mixing occurred only on the surface of granules.
  • compositions are similar to the nominal ones, although that with 20/80 sample for MBGN is rich in MBGN component (20/80) while with BG there is less excess of BG (40/60).
  • ACP/MBGN 60/40 55/45 ⁇ 5 ACP/BG 60/40 60/40 ⁇ 5
  • Ca/Si and P/Si ratios decrease when MBGN is increased, as expected.
  • Ca/P molar ratio of 20/80 composite (1.82) is close to ACP Ca/P value (ca. 1.80) as ACP is the dominant component in the composite, while in composites with higher MBGN content the Ca/P ratio increases to ca. 2-4 because also MBGN contains calcium.
  • the SEM-EDS spectra of ACP+MBGN physical mixtures varies greatly depending on the sampled region, passing from a Si-rich composition for BG granules to a CaP-rich composition for ACP ones.
  • the high SSABET values of pure MBGN and ACP are due to their extensive micro- and meso-porosities [3, 5].
  • the ACP+MBGN physical mixture has a higher SSABET than the corresponding composite (220 vs 163 m 2 g’ 1 , respectively), which is another proof that the same particle homogenization cannot be achieved through simple mixing.
  • ACP/MBGN 20/80 sample its SSABET (284 ⁇ 28 m 2 g -1 ) is similar to the SSABET of pure MBGN.
  • the FT-IR spectra of the composites gives a further confirmation about their nature (Figure 2C,D).
  • the main IR bands correspond either to phosphate groups in an amorphous environment (vs, vi, and V4PO4 modes as broad bands at 1010, 960, and 555 cm -1 , respectively) or silicate groups (Si-O-Si stretching, bending, and rocking modes at 1075, 800, and 450 cm -1 , respectively) [8, 9],
  • the relative intensity of all these bands is correlated to the ACP:BG ratio and shift accordingly.
  • the key tests to evaluate remineralization capability of ACP/BG composites were (i) their ion release in an acidic artificial saliva that mimics a carious oral environment (modified Tani-Zucchi solution), and (ii) their capability to induce HA crystallization when are in contact with simulated body fluid.
  • ACP/BG composites their release is intermediate between the ones of pure ACP and BG and depends on ACP:BG ratio, i.e. ACP-rich composites have a more intense Ca, P, and F release and less intense Si release, while in BG-rich composites the behavior is the opposite ( Figure 3A-D).
  • ACP/BG 60:40 composite has a stronger Ca, P, and F release and a weaker Si release than the ACP+BG physical mixture with identical weight ratio. This is the definitive proof that the composite preparation gives better ion-releasing properties which cannot be achieved by only mixing the two base ingredients.
  • the other key test to evaluate remineralization capability of ACP/BG composites is the assessment of their capability to induce HA crystallization when are in contact with simulated body fluid (SBF) by the simultaneous (i) crystallization of ACP into HA as well as (ii) the precipitation of calcium and phosphate ions contained in SBF into new mineral by interaction with ACP/BG.
  • SBF simulated body fluid
  • the amount of precipitated ions is directly proportional to ACP:BG ratio, while Si release is inversely proportional to it. After three days of incubation all phosphate in solution has been consumed, while only a part of Ca and Mg have been removed.
  • ACP/MBGN composites in SBF is controlled by ACP:BG ratio.
  • Ca, Mg, and P data suggest that all composites induce the precipitation of a Mg-doped calcium phosphate phase until all P in solution has been consumed, and the precipitation is faster for ACP and ACP-rich composites.
  • BG immersed in SBF induce the formation of HA while ACP converts into HA, therefore the new crystals observed in the composites are HA nanocrystals formed ion release and reprecipitation given by both MBGN and ACP (thicker needle crystals), as well as by ACP direct conversion (thinner needle crystals).
  • ACP component controls HA formation kinetics, and induces the formation of new HA nanocrystals in proportion to ACP:MBGN weight ratio.

Abstract

L'invention concerne un matériau composite de phosphate de calcium amorphe/verre bioactif (ACP/BG). Ce matériau composite possède à la fois l'aptitude à la libération d'ions à court terme du ACP et à la libération d'ions à long terme du BG et ainsi (i) reminéralise efficacement l'émail endommagé et (ii) induit la formation d'une nouvelle couche d'HA sur l'émail et la surface de dentine. Le matériau composite d'ACP/BG est obtenu par incorporation de particules de BG dans une matrice de nanoparticules d'ACP afin de maximiser l'homogénéisation entre les deux constituants et de produire un composite présentant une uniformité élevée à partir de l'échelle macrométrique à l'échelle nanométrique. Ceci a été obtenu par un procédé qui comprend une étape de précipitation d'ACP sur des particules de BG. Les particules de BG peuvent être des nanoparticules, des microparticules ou des macroparticules. Les particules peuvent également être poreuses ou mésoporeuses. L'invention concerne également l'utilisation du matériau composite de l'invention pour une utilisation dans la prévention de la déminéralisation dentaire et pour stimuler la reminéralisation. En d'autres termes, le matériau composite divulgué ici est utilisé en tant qu'agent de reminéralisation grâce à son aptitude à restaurer la structure et à préserver les propriétés mécaniques de tissus dentaires durs par la libération d'ions Ca2+ et PO43−, imitant ainsi le processus de reminéralisation spontanée induit par la salive. Le matériau composite peut également être utilisé pour la régénération osseuse.
PCT/IB2023/062999 2022-12-22 2023-12-20 Matériau composite à base de verre bioactif et de phosphate de calcium amorphe et procédé pour sa production WO2024134524A1 (fr)

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