Optimization of the process of obtaining bioactive glass 58s

Description

1 / 9 “OPTIMIZATION OF THE PROCESS FOR OBTAINING 58S BIOACTIVE GLASS” Field of invention

[001] The present invention is situated in the field of biomaterials, with application directed towards the development of bioactive materials for bone and tissue regeneration. This technology describes an innovative and rapid methodology for the synthesis and obtaining of 58S bioactive glass through sol-gel rotation, standing out for the significant reduction in processing time. The objective is to obtain bioactive glass with the composition of 58S through an optimized synthesis while maintaining the vitreous structure and bioactive properties of the material. This approach aims to meet the needs of applications in the field of tissue regeneration. Background of the Invention

[002] The skin is considered the largest organ in the human body, composed of three layers called the epidermis, dermis, and hypodermis or subcutaneous tissue (Losquadro, 2017). The epidermal and dermal regions comprise the immune mechanism and provide a favorable environment for tissue maintenance and regeneration. (VIG et al., 2017).

[003] Skin lesions result from the disruption of the skin or mucous membrane lining caused by external damage. These lesions are classified as acute or chronic. Acute lesions are sudden wounds that typically heal within 8 to 12 weeks, depending on size, extent, and depth. On the other hand, chronic wounds result from abnormal and disordered healing processes, such as burns and pressure ulcers (Dhivya et al., 2015). Petition 870250016961, dated 28 / 02 / 2025, page 11 / 24 2 / 9

[004] In the United States, it is estimated that between 2 and 4.5 million people suffer from chronic wounds, resulting in an annual economic cost of approximately US$25 billion. These high numbers are related to the aging of the global population and the increased incidence of diseases such as diabetes, highlighting the need for investments in the area of ​​wound healing (Derakhshandeh et al., 2018).

[005] Biomaterials are substances designed for use in living tissues, for therapeutic or diagnostic purposes, totally or partially replacing organs whose functions have been compromised (Ali and Bhuiyan, 2021). Especially in recent decades, the increase in the prevalence of chronic diseases, the high occurrence of accidents, and the aging population have led to a greater demand for these materials (Baino et al., 2016; Kammerling et al., 2021).

[006] Bioactive glasses are defined as “a non-crystalline, out-of-equilibrium material that has been engineered to induce specific biological activity” (Shearer, Montazerian, and Mauro, 2023). They are silicate-based inorganic materials, typically composed of Na2O, SiO2, CaO, and P2O5, which bring unique characteristics to many biomedical applications (Negut and Ristoscu, 2023).

[007] Bioactive glasses (BGs) can bind to living tissues, stimulate bone regeneration, dissolve in body fluids, induce osteoblast proliferation, and exhibit antimicrobial properties (Spirandeli et al., 2020). They also promote fibroblast migration, growth factor release, extracellular matrix synthesis, and modulate inflammatory responses in wound healing (Yu et al., 2016; Xie et al., 2019).

[008] Bioactive glasses, for the most part, have an amorphous nature, with a structure composed of network formers and modifiers, in addition to Petition 870250016961, dated 28 / 02 / 2025, page 12 / 24 3 / 9 Intermediate oxides. Network formers are capable of constituting the structure of glasses independently of the addition of other components. Among the most investigated network formers for bioactive glasses are silica (SiO2), followed by phosphorus pentoxide (P2O5) and boron trioxide (B2O3). Network modifiers, on the other hand, alter the structure of the glass by coupling with oxygen atoms. Intermediate oxides, in general, can play the role of modifiers or be incorporated as network formers in the glass structure (Zheng and Boccaccini, 2017).

[009] Bioactive glass 58S, with a composition of 58% SiO2, 33% CaO, 9% P2O5 by weight or 60% SiO2, 36% CaO, 4% P2O5 by mole (Chen et al., 2018, Moghanian et al., 2018). This bioactive glass demonstrates good mechanical strength, excellent apatite-forming activity, and high biocompatibility.

[010] The 58S composition exhibits low crystallinity, a higher apatite formation rate than other compositions, and significant degradation, with consequent release of soluble silica and high resorption rates. The release of calcium, silicon, and phosphorus ions promotes gene expression and osteoblast proliferation, facilitating rapid bone formation (Oliveira et al., 2022).

[011] 58S glass has been applied together with hydrogels and ointments for wound regeneration. The literature shows that bioactive 58S glass can improve angiogenesis by stimulating the proliferation and migration of endothelial cells (Mao et al., 2015). In addition, bioactive 58S glass can stimulate the production of VEGF and FGF2, which are growth factors necessary for effective wound healing (Lin et al., 2012). Petition 870250016961, dated 28 / 02 / 2025, page 13 / 24 4 / 9

[012] Several processing methods are employed in the manufacture of BGs, among them are the traditional melt quenching technique and the sol-gel method. The sol-gel process offers more refined control, both physical and chemical, of the final product, enabling significant customization. The sol-gel synthesis route stands out for its better control of microstructure, homogeneity and particle size (Fiume et al., 2018).

[013] Furthermore, the microporosity and high specific surface area of ​​glasses obtained from the sol-gel method promote rapid dissolution and accelerated formation of hydroxyapatite on the glass surface. This occurs due to its high surface area and the presence of micro / nano porosity (Baino et al., 2018).

[014] The sol-gel method is a process that can be summarized in distinct steps, which include the hydrolysis and condensation of the precursors, followed by the drying and stabilization of the final material. The sol-gel methodology can be conducted under acidic or basic conditions (Zheng and Boccaccini, 2017).

[015] The production of bioactive glasses (BGs) via the sol-gel route involves three main steps: the preparation of the precursor solution (sol), the gelation of the sol, and the subsequent removal of solvents and salts. This last step is carried out through a heat treatment that, in addition to eliminating residues, promotes the structural stabilization of the material. This process results in gel-derived glasses, also known as gel glasses, characterized by their unique structure and properties (Shearer, Montazerian and Mauro 2023).

[016] Among the advantages of the sol-gel process are simplicity, greater purity and efficiency in the incorporation of dopants, in addition to the fact that it can provide faster formation of hydroxyapatite (Hap) due to greater Petition 870250016961, dated 28 / 02 / 2025, page 14 / 24 5 / 9 surface area of ​​the particles, which are generally nanoscale (Zohourfazeli et al., 2021).

[017] Among the disadvantages of the sol gel process, the high energy consumption and prolonged processing time raise concerns regarding productivity, efficiency, and increased costs. This can impact overall production competitiveness in terms of time and energy efficiency for commercial applications. (Canas et al., 2024).

[018] US patent 20170266231 A1 and US 10646514 B2, entitled “METHODS OF PROCESSING COMPOSITIONS "BIOACTIVE VITROCERAMICS DERIVED FROM SOL GEL AND METHODS OF USING THEM" refers to the invention of a process method for removing organic residues and impurities from bioactive compounds derived from sol-gel, as well as compositions that include these bioactive compounds after processing, improving their properties for biomedical applications. Our patent differs in the formulation, composition, time, and environment in which the sample was subjected to heat treatment for residue removal while preserving the good properties of the material.

[019] US Patent 6171986 B1, entitled “BIOACTIVE SOL-GEL COMPOSITIONS AND METHODS,” refers to the invention of a method for the production process of bioactive glasses, including the preparation of a reactive mixture for the formation of a sol-gel, its aging, drying near equilibrium, and heating of the dried gel. Bioactive glass compositions obtained by this method are also presented. Our patent differs in the preparation of the mixture for the formation of the solution, as well as in the time for removing residues to obtain the bioactive glass while preserving its properties. Petition 870250016961, dated 28 / 02 / 2025, page 15 / 24 6 / 9

[020] US Patent 20230192529 A1, entitled “CONTINUOUS SOLGEL PROCESS FOR THE PRODUCTION OF SILICATE-CONTAINING GLASSES AND VITROCERAMICS,” refers to the invention of a continuous Sol-gel process method for the production of silicate-containing glasses and vitroceramics, comprising the following steps: 1: Hydrolyze a silicon tetraalkoxide and a functional alkoxide in alcohol with mineral acid in reactor R1 to obtain product (A). 2: Prepare product (B) in reactor R2 with a metal alkoxide and alcohol. 3: Mix products (A) and (B) in reactor R3 to form a presol and obtain product (C). 4: Add water or diluted acid to product (C) to promote gelation. 5: Mold the sol into shapes to obtain aerogels. 6: Dry the aerogels to form xerogels. 7: To synthesize xerogels in order to obtain silicate glasses and glass-ceramics.Our patent differs in the method of mixing the precursors, the preparation time, and the removal of residues, while preserving the characteristics of the bioactive glass.

[021] French patent WO 2009013497 A1, entitled “SOL-GEL BIOACTIVE GLASS”, refers to the invention of a bioactive glass derived from the sol-gel method comprising less than about 30 ppm of nitrate species. Our patent differs in the proportion of precursors, temperatures and time used during the mixing, gelation and stabilization steps of the gel to obtain the bioactive glass.

[022] Japanese patent JP 5399246 B2, entitled “SOL-GEL METHOD”, refers to the invention of a sol-gel process for the production of glass monoliths using a dispersion step of pyrogenic silica in water with an acidic pH. Our patent differs in the types of precursors used, in the gel formation steps and in obtaining the bioactive glass, leading to better reproducibility.

[023] Thai patent TW I311549 B, entitled “PROCESS FOR PRODUCING MONOLITHS BY MEANS OF THE SOL-GEL PROCESS” Petition 870250016961, dated 28 / 02 / 2025, page 16 / 24 7 / 9 refers to the invention of a sol-gel process for the production of glass monoliths. Our patent differs in the types of precursors used, the time and temperatures used during the material stabilization stage, providing a faster process with a lower defect rate.

[024] Chinese patent CN 103958422 B, entitled “METHOD FOR OBTAINING MATERIAL BY SOL-GEL”, refers to a method for manufacturing objects from materials obtained by sol-gel, including the steps of molding, gelation, and drying using a mold. The mold used has a closed chamber with a material that allows the release of gases formed during the process. Our patent differs by not using a mold for this process, allowing greater freedom in shaping the material, enabling the creation of more complex and porous structures without the geometric limitations imposed by the mold. This can favor bioactivity in biomedical applications, for example, by increasing the surface area and interaction with biological fluids. Brief description of the figures

[025] Figure 1 shows the block diagram representing the steps of the methodology used for the preparation and characterization of 58S glass.

[026] Figure 2 shows the TGA and DTG thermogravimetric curves of the dry 58S gels obtained between 25° and 900°C, at a heating rate of 5°C / min, under an air flow of 100 mL / min.

[027] Figure 3 shows the X-ray diffraction spectrum of the 58S glass sample after stabilization, obtained in Θ-2Θ mode, with scanning in the range of 10° to 80°. Petition 870250016961, dated 28 / 02 / 2025, page 17 / 24 8 / 9

[028] Figure 4 shows the characteristic infrared spectrum of 58S glass after thermal stabilization, recorded in absorbance mode in the range of 4000 to 400 cm-1. Detailed description

[029] The step-by-step process for obtaining glass via the optimized route is shown in Figure 1. This new procedure allows obtaining the final product faster and with less energy expenditure.

[030] For the preparation of the solution, TEOS was injected into a beaker containing a solution of absolute ethyl alcohol and nitric acid (1M) using a pump, at an infusion rate of 10 mL / h. The precursors TEP and calcium nitrate tetrahydrate were added alternately, with 1-hour stirring intervals. After the complete addition of the precursors, the solution was heated to 60°C on a stirring plate to accelerate gelation; this step lasted approximately 12 hours for gel formation. The gel was then dried for 24 hours at 150°C and thermally stabilized at 600°C for 3 hours, using a heating rate of 10°C / min. At the end of the process, a mortar was used to reduce the granules and a 75 µm sieve was used to obtain the powders. Tests performed

[031] Figure 2 presents the thermogravimetric analysis (TGA) and its derivative (DTG) curves of the dry gel, highlighting three distinct mass loss events. The first event corresponds to a loss of 17.02%, occurring between room temperature and approximately 160°C, attributed to the removal of water and alkoxide groups, with an endothermic peak around 150°C, as described by Moghanian et al. (2020). The second event, related to the decomposition of organic compounds, occurs between 160°C and Petition 870250016961, dated 28 / 02 / 2025, page 18 / 24 9 / 9 400°C, resulting in a mass loss of 23.10%. The third event, observed between 400°C and approximately 580°C, is attributed to the removal of residual nitrates, such as calcium nitrate, from the solution preparation stage, with a loss of 13.33%. In total, there was an accumulated mass loss of 46.55% (El-Kady et al., 2012). Thus, it is observed that the complete decomposition of organic compounds occurs from 600°C onwards, ensuring the thermal stabilization of the sample.

[032] X-ray diffraction was used to analyze the structure of the powders obtained after heat treatment of the samples synthesized by the sol-gel route. Figure 3 shows the characteristic X-ray diffractometry pattern of the bioactive glass produced. In this pattern, no evident crystalline peaks were detected, confirming the disordered and amorphous nature of the glassy structure (Lopes et al., 2019).

[033] In Figure 4, it is possible to identify the main typical bands corresponding to bioactive glasses. The absorbance between 440 and 470 cm-1 corresponds to the bending of Si-O bonds, and the presence of a double band between 500 and 600 cm-1, related to the PO angular deformation in PO43- groups, can be identified in all samples and is characteristic of phosphates. Values ​​close to 1030 and 1210 cm-1 correspond to the absorbance bands referring to the symmetric and asymmetric stretching, respectively, of Si-O-Si bonds. The existence of some other bands at approximately 3400 and 1600 cm-1 was identified, which are attributed to HOH and HO bonds, respectively (Vulpoi et al., 2012; Montazerian et al., 2015; Marsh et al., 2019). Discrete peaks in the region between 1400 cm-1 and 1500 cm-1 may be associated with CO vibrations of carbonate groups, originating from chemical reactions between the glass surface and the furnace atmosphere (Cerruti and Morterra, 2004; Perardi et al., 2005). Petition 870250016961, dated 28 / 02 / 2025, p. 19 / 24

Claims

1 / 1 CLAIMS 1. “OPTIMIZATION OF THE PROCESS FOR OBTAINING 58S BIOACTIVE GLASS” characterized by an innovation that corresponds to a methodology for adapting a sol-gel synthesis route with the main objective of reducing the time to obtain a material (bioactive glass) while preserving its structural characteristics.

2. “OPTIMIZATION OF THE PROCESS FOR OBTAINING BIOACTIVE GLASS 58S”, according to claim 1, characterized by a methodology for obtaining bioactive glass via the sol-gel route with process optimization, is constructed by the following steps: in a beaker, a solution of absolute ethyl alcohol and nitric acid (1M) (100) was prepared; then the precursors were added using an infusion rate of 10 mL / h; the precursors TEOS (200), TEP (300) and calcium nitrate tetrahydrate (400) were added alternately every 1 h of stirring after the addition of each reagent to the solution, remaining under vigorous magnetic stirring at room temperature throughout the synthesis, totaling approximately 4 hours; at the end of the addition of all the precursors, the solution was subjected to a temperature of 60°C on the stirring plate in order to accelerate the gelation process (500), totaling approximately 12 hours to obtain the gel and subsequently,The gels obtained were placed in an oven for 24 hours at 150°C (600) and after this step they were subjected to stabilization / heat treatment for a period of 3 hours and then, to obtain the powders, a mortar was used to reduce the size of the granules and a 75 µm sieve (700) was used. Petition 870250016961, dated 28 / 02 / 2025, page 20 / 24,

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