Soft mechanochemical synthesis and thermal stability of hydroxyapatites with different types of substitution published by Ural Federal University eISSN 2411-1414; chimicatechnoacta.ru ARTICLE 2022, vol. 9(3), No. 20229305 DOI: 10.15826/chimtech.2022.9.3.05 1 of 7 Soft mechanochemical synthesis and thermal stability of hydroxyapatites with different types of substitution Natalya V. Eremina a* , Svetlana V. Makarova a , Denis D. Isaev ab , Natalia V. Bulina a a: Institute of Solid State Chemistry and Mechanochemistry, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia b: Novosibirsk State University, Novosibirsk 630128, Russia * Corresponding author: eremina@solid.nsc.ru This paper belongs to the CTFM'22 Special Issue: https://www.kaznu.kz/en/25415/page. Guest Editors: Prof. N. Uvarov and Prof. E. Aubakirov. © 2022, the Authors. This article is published in open access under the terms and conditions of the Creative Com- mons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Abstract The feasibility of soft mechanochemical synthesis was studied here for hydroxyapatite with various types of substitution. It was shown that this method allows obtaining hydroxyapatites substituted with copper or iron cations and hydroxyapatites cosubstituted with zinc cations and silicate groups. Thermal stability of the synthesized sam- ples was evaluated. It was found that to preserve phase homogeneity of the material, the temperature during the preparation of ceramic products and coatings should not exceed 600–800 °C. An exception is the hydroxyapatite where a hydroxyl group is expected to be replaced by a copper cation during the synthesis at a degree of substitution x = 0.5. For this sample, the temperature of the the heat treatment can be increased to 1100–1200 °C because copper cations return to the hydroxyapatite crystal lattice at these temperatures, and the material becomes single-phase. Keywords mechanochemical synthesis hydroxyapatite substitution iron cupper zinc silicate thermal stability Received: 23.06.22 Revised: 18.07.22 Accepted: 18.07.22 Available online: 26.07.22 1. Introduction Hydroxyapatite (HA) is an inorganic material of chemical composition Ca10(PO4)6(OH)2 which crystalizes in hexago- nal syngony with a P63/m space group [1]. The HA unit cell contains 10 calcium cations located at two nonequivalent positions: four cations at the Ca1 site and six cations at the Ca2 site, which are surrounded by nine and seven oxygen ions, respectively. In addition to calcium ions, the HA unit cell contains six phosphate and two hydroxyl groups. The latter are located on the c axis in a hexagonal channel formed by calcium ions and by oxygen ions from phosphate tetrahedrons. HA is widely used in various fields of medicine and is a suitable material for the construction of biocompatible ce- ramic products, composites, bone defect fillers, medical ce- ments, and implant coatings [2–4]. Methods are being de- veloped for 3D printing of custom implants, where HA serves as either an additive or a base material from which a product is created [5, 6]. Prospective applications include drug delivery and tissue engineering because HAs appear to be promising carriers of growth factors, bioactive peptides, and various types of cells [7]. In the crystal lattice of HA, all ions can be substituted with isovalent or heterovalent ions of other chemical ele- ments or their chemical groups [8]. Stoichiometric HA has a low resorption rate, which is a disadvantage of bioresorb- able materials based on this substance [9]. In addition, stoi- chiometric HA does not have antibacterial properties. Nonetheless, the introduction of substituent ions into this material can substantially improve required characteris- tics. For example, doping of HA with copper, iron, zinc, or silver ions can give antibacterial properties to HA-based materials and thereby can prevent inflammation and stim- ulate new bone growth, which is important for surgical ap- plications [10]. Silicon ions decrease the crystallinity of the material and increase osseointegration and biocompatibil- ity [11, 12]. HA doped with iron ions has magnetic proper- ties used in biomedicine for heating mediators in cancer hy- perthermia therapy and in contrast agents for magnetic res- onance imaging [13]. Thermal stability of synthetic HA is crucial for the man- ufacture of ceramics and HA coatings. It is necessary to cor- rectly select the conditions of thermal treatment when a technological process is designed because when substituted HAs are heated, structural transformations can take place, http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2022.9.3.05 mailto:eremina@solid.nsc.ru http://creativecommons.org/licenses/by/4.0/ https://orcid.org/0000-0002-2692-9745 https://orcid.org/0000-0002-0770-5914 https://orcid.org/0000-0003-2346-9584 https://orcid.org/0000-0003-4751-0705 https://crossmark.crossref.org/dialog/?doi=https://doi.org/10.15826/chimtech.2022.9.3.05&domain=pdf&date_stamp=2022-7-26 Chimica Techno Acta 2022, vol. 9(3), No. 20229305 ARTICLE 2 of 7 accompanied by the formation of impurity phases [14, 15], which affect not only physical but also biological properties of the resultant product. The purpose of this work was to investigate the feasibil- ity of soft mechanochemical synthesis of HA containing dif- ferent substituents (Fe, Cu, or Zn simultaneously with Si) and to assess thermal stability of the obtained materials. 2. Experimental Samples of HA with various substituents were prepared via soft mechanochemical synthesis in an AGO-2 planetary ball mill (Russia). A detailed description of the synthesis condi- tions is provided in ref. [16]. Previously, it was reported that dopants complicate mechanochemical synthesis [17]; as a consequence, the duration of synthesis of substituted HAs was 40 min, whereas that of unsubstituted HA was 30 min. Expected reactions of mechanochemical synthesis are presented in Table 1. Reagents had purity grade not lower than “chemically pure.” Reaction 1 was expected to generate unsubstituted HA. In reactions 2, 3, 5 and 6, some calcium cations are substituted with either copper or iron cations, whereas in reactions 4 and 7, hydroxyl groups are replaced. To obtain Cu-substituted HA and Fe-substituted HA, the synthesis was carried out using either an oxide form (reac- tions 3–5) or a phosphate form of the substituent ion (reac- tions 2, 6, and 7). Reactions 8 and 9 imply the cosubstitu- tion of calcium cations by zinc cations and of the phosphate group by the silicate group. Sintering of the powders was conducted in a high-tem- perature electrical furnace PVK-1.4 at different tempera- tures for 2 h at heating and cooling rates of 5 °C/min in am- bient air. Powder X-ray diffraction (PXRD) patterns of the sam- ples were recorded on a D8 Advance powder diffractometer (Bruker, Germany) in Bragg–Brentano geometry with Cu Kα radiation. For the in situ PXRD analysis, a high-temperature chamber HTK 1200N (Anton Paar, Austria) was employed. A sample was heated stepwise in a corundum carrier in am- bient air at a heating rate of 12 °C/min. When a required temperature was reached, the heating was stopped, and the PXRD pattern was registered. X-ray phase analysis of the compounds was performed using a database of PXRD pat- terns, ICDD PDF-2. Unit cell parameters, crystallite size, and concentrations of crystal phases were determined by the Rietveld method implemented in the Topas 4.2 software (Bruker, Germany). The instrumental contribution was taken into account by the fundamental parameter method. Fourier transform infrared (FTIR) spectra were ac- quired with the help of an Infralum-801 spectrometer (Simex, Russia). The samples were prepared by the KBr pel- let method. 3. Results and Discussion 3.1. Mechanochemical synthesis 3.1.1. Cu-substituted HA Figure 1a shows that PXRD patterns of HA samples contain- ing copper are identical and match the pattern of unsubsti- tuted HA. The observed reflections belong to the HA phase (card PDF 40-11-9308), indicating that the obtained sam- ples are single-phase. The absence of any reflections of im- purity phases suggests that the synthesis procedures pro- duced expected substances in accordance with the expected reactions (Table 1). It is obvious that when either the oxide form or the phosphate form of a substituent ion is used, in- itial reagents are not detectable among the products; there- fore, any of the reagents tested here can be utilized for the synthesis of Cu-substituted HA. Infrared spectra of all synthesized samples (Figure 1b) show absorption bands corresponding to the HA structure. There are bands of the phosphate ion (572, 602, 960, 1048, and 1089 cm–1), OH group (630 and 3573 cm–1), and of carbonate group (CO3)2– (1420 and 1470 cm–1); the latter came from ambient air during the mechanochemical synthesis. It should be noted that the intensity of the absorption bands of the hydroxyl group is identical between the samples obtained via reactions 3 and 4, although judging by the reactions given in Table 1, the concentrations of the hydroxyl group should differ by a factor of 2. Therefore, in the sample 0.5Cu(О)–OH, copper ions do not replace hydroxyl groups. Table 1 Expected reactions of mechanochemical synthesis (MCS). Number Equations for the expected chemical reaction Sample name 1 6CaHPO4 +4CaO MCS → Ca10(PO4)6(OH)2 +2H2O 0.0HA 2 5.5CaHPO4 + 4CaO + 0.5Сu(HPO4)H2O MCS → Ca9.5Cu0.5(PO4)6(OH)2 +nH2O 0.5Cu(P)–Ca 3 6CaHPO4 +3.5CaO+0.5CuO MCS → Ca9.5Cu0.5(PO4)6(OH)2 +nH2O 0.5Cu(O)–Ca 4 6CaHPO4 +4CaO+0.5CuO MCS → Ca10(PO4)6(OH)1Cu0.5O+nH2O 0.5Cu(O)–OH 5 6CaHPO4 +3.5CaO+0.25Fe2O3 MCS → Ca9.5Fe0.5(PO4)6(OH)1.5O0.5 +nH2O 0.5Fe(O)–Ca 6 5.334CaHPO4 + 3.666CaO + 0.333Fe3(PO4)2 ∙ 8H2O MCS → Ca9Fe1(PO4)6(OH)2 +nH2O 1.0Fe(P)–Ca 7 5.67CaHPO4 + 4.33CaO + 0.166Fe3(PO4)2 ∙ 8H2O MCS → Ca10(PO4)6(OH)1Fe0.5O+nH2O 0.5Fe(P)–OH 8 4.4CaO+5.4CaHPO4 +0.2SiO2 ∙ nH2O+0.2Zn(H2PO4)2 ∙ 2H2O MCS → Ca9.8Zn0.2(PO4)5.8(SiO4)0.2(OH)1.8 +nH2O 0.2Zn0.2Si 9 6CaO+3CaHPO4 +1SiO2 ∙ nH2O+1Zn(H2PO4)2 ∙ 2H2O MCS → Ca9Zn1(PO4)5(SiO4)1(OH)1 +nH2O 1.0Zn1.0Si Chimica Techno Acta 2022, vol. 9(3), No. 20229305 ARTICLE 3 of 7 Figure 1 PXRD patterns (a) and FTIR spectra (b) of as-synthesized samples 0.0НА (1), 0.5Cu(P)–Ca (2), 0.5Cu–Ca (3), and 0.5Cu– OH (4) according to the (1) – (4) reactions. Table 2 Structural characteristics of the HA phase in the synthe- sized samples. Sample name а (Å) с (Å) Crystallite size (nm) 0.0HA 9.437(1) 6.892(1) 24.9(2) 0.5Cu(P)–Ca 9.431(2) 6.879(1) 20.4(2) 0.5Cu(O)–Ca 9.435(1) 6.881(1) 20.2(2) 0.5Cu(O)–OH 9.432(2) 6.887(1) 20.2(2) 1.0Fe(P)–Ca 9.436(2) 6.877(1) 20.3(2) 0.5Fe(P)–OH 9.435(2) 6.886(1) 20.7(2) 0.2Zn0.2Si 9.435(1) 6.889(1) 20.9(2) 1.0Zn1.0Si 9.434(2) 6.891(1) 16.4(3) Note: The estimated standard deviations of the refined values are in parentheses. At the same time, the intensity of absorption bands is much higher in the 0.5Cu(О)–OH sample than in the other ones. It can be concluded that in the 0.5Cu(О)–OH sample, copper cations occupy positions of calcium cations, and the shortage of phosphate ions is compensated by the carbonate ion, which can occupy the phosphate group’s position. Con- sequently, in the samples 0.5Cu(О)–OH and 0.5Cu(O)–Ca, copper cations replace calcium cations. A possible stoichio- metric formula of the resultant Cu-substituted HA in the sample 0.5Cu(О)–OH can be written as Ca10−xСux(PO4)6−y(CO3)y(OH)2−yОy, where y = х/1.67. Crystal lattice parameters of the synthesized Cu-substi- tuted HAs are lower than those of unsubstituted HA (Ta- ble 2). The smaller ionic radius of copper as compared to calcium should diminish the lattice parameters, as observed in our case. The slight difference in the parameter c be- tween the samples 0.5Cu(О)–Ca and 0.5Cu(О)–OH can be explained by an influence of the carbonate ion. The size of the crystallites decreases with the introduction of the cop- per cation (Table 2), meaning that the substituent ion com- plicates the formation of the HA crystal lattice. Thus, after 30 min of mechanochemical processing of the mixtures in accordance with reactions 2–4, in all cases, the structure of Cu-substituted HA forms with localization of copper ions at the positions of calcium ions. Therefore, the expected substitution of the hydroxyl group with copper cations does not proceed under our conditions of mechano- chemical synthesis. For the synthesis of Cu-substituted HA, it is possible to use both copper oxide and copper (II) hy- drogen orthophosphate monohydrate. 3.1.2. Fe-substituted HA In the PXRD patterns of the samples synthesized with the introduction of iron (Figure 2a), one can see that the 0.5Fe(O)–Ca sample, which was obtained using iron (III) oxide, contains reflections of Fe2O3, which was employed as the initial reagent, i.e. the source of the iron cation (Fig- ure 2a). In the sample 1.0Fe(P)–Ca, where iron (II) ortho- phosphate hydrate was chosen as the initial reagent (the iron source), only reflections of HA were detectable, with- out additional reflections. Therefore, iron (III) oxide does enter into the mechanochemical reaction forming the Fe- substituted HA. The 1.0Fe(P)–Ca sample turned out to be single-phase even at a dopant concentration two times higher than that in the case of the sample 0.5Fe(O)–Ca. The sample 0.5Fe(P)–OH, where the hydroxyl group was ex- pected to be replaced by iron cations from iron (II) ortho- phosphate hydrate, also proved to be single-phase. Table 2 indicates that after the introduction of iron cat- ions in the phosphate form, in all cases, parameter a stay almost the same while parameter c declines relative to un- substituted HA. The FTIR spectra of the samples 1.0Fe(P)–Ca and 0.5Fe(P)–OH (Figure 2b) are similar to the spectra of un- substituted HA and of Cu-substituted HA. All absorption bands of the HA structure are present. During the mecha- nochemical synthesis, the substitution of the hydroxyl group during the attempted introduction of iron cations ob- viously does not proceed either because a more intense ab- sorption band of the carbonate group is visible in the 0.5Fe(P)–OH spectrum. According to the literature, high-temperature processing of a material at 1100 °C is performed to place copper and iron cations in the hydroxyl channel [18, 19]. In mechanochemical synthesis, such a temperature is unattainable, which is why it is evidently impossible to synthesize HA containing copper and iron cations in the hydroxyl channel. Chimica Techno Acta 2022, vol. 9(3), No. 20229305 ARTICLE 4 of 7 Figure 2 PXRD patterns (a) and FTIR spectra (b) of as-synthesized samples 0.0НА (1), 0.5Fe(O)–Ca (2), 1.0Fe(P)–Ca (3), and 0.5Fe(P)–OH (4) according to the (1), (4) – (6) reactions. 3.1.3. Zn-Si-substituted HA The analysis of the PXRD patterns revealed that after cosubsti- tution with zinc and silicate the synthesized samples are sin- gle-phase (Figure 3a). The lattice parameters of the obtained samples are virtually identical to those of the unsubstituted HA (Table 2). This is probably because the substitution of calcium cations by zinc cations should reduce the lattice parameters owing to a decrease in the ionic radius, while the substitution of the phosphate tetrahedron by the silicate tetrahedron should lead to an increase. After the cosubstitution, the contri- butions of the substituents cancel each other out. In the FTIR spectra of the samples 0.2Zn0.2Si and 1.0Zn1.0Si (Figure 3b), there are all absorption bands char- acteristic of HA. The intensity of hydroxyl bands in the spectra declines with the increasing concentration of the introduced ions, consistently with the equation of the ex- pected reaction (Table 1). In this context, the diminished number of hydroxyl groups is a consequence of compensa- tion of the silicate group’s excess negative charge as com- pared to the phosphate group, which is being replaced. Figure 3 PXRD patterns (a) and FTIR spectra (b) of as-synthesized samples 0.0НА (1), 0.2ZnSi (2), and 1.0Zn1.0Si (3) according to the (1), (7) – (8) reactions. 3.2. Thermal stability 3.2.1. Cu-substituted HA Examination of the synthesized samples by high-tempera- ture in situ diffractometry (Figure 4) showed that these samples differ in thermal stability. As illustrated in Fig- ure 4a, the unsubstituted HA is stable up to 1200 °C. Rais- ing the temperature of the thermal treatment enhances the intensity of the reflections and decreases their half-width, thereby indicating the growth of crystallites during the sample heating. There are no reflections of impurity phases in the patterns. As for the 0.5Cu(O)–Ca sample, in which the dopant was expected to replace calcium ions, its thermal stability is much lower as compared to the unsubstituted HA. Already at 700 ºC, copper (II) oxide separates, which is present in the sample up to 1000 °C (Figure 4b, Table 3). A further increase in temperature causes the CuO reflec- tions to disappear from the diffraction pattern. Table 3 Concentrations of impurity phases in substituted-HA samples in the in situ experiment, as evidenced by diffraction patterns processed by the Rietveld method. Sample name Impurity phase (wt.%) Temperature (ºC) 500 600 700 800 900 1000 1100 1200 0.5Cu(O)–Ca β-Ca3(PO4)2 – – – 17 26 27 31 34 CuO – – 1 2 2 1 – – 0.5Cu(O)–OH CuO – 3 4 4 4 3 – – 1.0Fe(P)–Ca β-Ca3(PO4)2 – – – 36 57 71 72 74 Fe2O3 – – – 1 4 6 7 7 Fe3O4 – – – 2 3 2 2 2 0.5Fe(P)–OH Fe2O3 – – – – 1 2 2 – Fe3O4 – – – 2 2 2 2 1 Chimica Techno Acta 2022, vol. 9(3), No. 20229305 ARTICLE 5 of 7 Therefore, there is a reverse process at 1000 °C, namely, diffusion of copper ions into the hydroxyl channel of HA. Additionally, at 800 °C, a large amount of another impurity phase, -Ca3(PO4)2, emerges, whose concentration goes up with temperature. In the 0.5Cu(О)–OH sample, the release of copper oxide starts at a lower temperature – 600 °C. At 1100 and 1200 °C, CuO reflections are absent, and the sample be- comes single-phase. It is known that prolonged annealing at 1100 °C of a mixture of reagents containing CuO gives rise to HA containing linear oxocuprate groups in the hy- droxyl channel [18, 20]. Accordingly, it is likely that at 1100 °C, copper ions of the 0.5Сu(О)–Ca sample localize to the hydroxide channel, thus yielding the Ca10(PO4)6(OH)2–2xCuxO2x structure, and the sample goes back to being single-phase (Figure 4b, Table 3). Thus, the sample 0.5Cu(O)–Ca is thermally stable up to 700 °C. Stability of 0.5Cu(О)–OH is lower by 200 °C, but at 1100 °C, the newly formed copper (II) oxide phase disap- pears making the material single-phase again. Figure 4 In situ high-temperature PXRD patterns of samples 0.0HA (a), 0.5Cu(O)–Ca (b), and 0.5Cu(O)–OH (c). 3.2.2. Fe-substituted HA In the diffraction pattern of the 1.0Fe(P)–Ca sample, reflec- tions of Ca3(PO4)2 and Fe2O3 phases are clearly visible. Mod- eling of the diffraction patterns by the Rietveld method de- tected reflections of the Fe3O4 phase as well (Table 3). Judg- ing by these data, thermal stability of the materials contain- ing iron cations (samples 1.0Fe(P)–Ca (a) and 0.5Fe(P)–OH) is equally low. The introduced cation is re- leased in the oxide form starting at a temperature of 800 °C in both cases (Table 3). The sum of concentrations of the oxide phases is approximately twofold for the 1.0Fe(P)–Ca sample than for 0.5Fe(P)–OH because the concentration of introduced iron is 2 times higher in the former case than in the latter. The concentration of -Ca3(PO4)2 seen in the 1.0Fe(P)–Ca sample increases with temperature, reaching a maximum at 1200 °C (Figure 5a, Table 3). In contrast to the doping with copper cations, in the sam- ples with iron cations, there is no complete disappearance of the substituent ion during the high-temperature treatment. Perhaps the reason is lower solubility of iron in HA. Thus, we can assume that the samples 1.0Fe(P)–Ca and 0.5Fe(P)–OH are thermally stable up to 800 °C. 3.2.3. Zn-Si-substituted HA After the cosubstitution with zinc cations and silicate groups, the material also has lower thermal stability than the unsubstituted HA. In the PXRD patterns of the sample 0.2Zn0.2Si at 1000 °C, reflections of additional phases come into being, such as ZnO and β-Ca3(PO4)2 (Figure 6a). In the 1.0Zn1.0Si sample, ZnO reflections appear already at 800 °C, but the β-Ca3(PO4)2 phase still forms at 1000 °C (Figure 6b). Figure 5 In situ high-temperature PXRD patterns of samples 1.0Fe(P)–Ca (a) and 0.5Fe(P)–OH (b). Chimica Techno Acta 2022, vol. 9(3), No. 20229305 ARTICLE 6 of 7 Figure 6 PXRD patterns of samples 0.2Zn0.2Si (a) and 1.0Zn1.0Si (b) after heating. Therefore, thermal stability of cosubstituted Zn-Si-HA depends on concentrations of the substituent ions. The higher their concentrations, the lower is the stability of the material. Obviously, during the thermal treatment, zinc cat- ions leaving their positions (previously belonging calcium ions) create vacancies at the former calcium positions. A large number of such vacancies promotes structural trans- formations, which generate the β-Ca3(PO4)2 and ZnO phases. 4. Conclusions It was demonstrated that Cu-substituted HA and Fe-substi- tuted HA can be synthesized mechanochemically via the in- troduction of the dopants at calcium positions. For the syn- thesis of such materials, 40 min is sufficient when an ap- propriate mixture of initial reagents is mechanochemically processed in a planetary ball mill. It was shown that for the synthesis of Cu-substituted HA, either copper (II) oxide or copper (II) hydrogen orthophosphate monohydrate can be utilized as a reagent providing the substituent ion. As for the synthesis of Fe-substituted HA, the stablest oxide of the substituent (Fe2O3) is not suitable, but iron (II) orthophos- phate hydrate is suitable. The mechanochemical method also allows to synthesize HA with cosubstitution of calcium cations by zinc and of phosphate tetrahedra by silicate ones. For this synthesis, silicic acid, and zinc (II) dihydrogen phosphate hydrate can be used. Thermal stability of the obtained substituted HAs is signif- icantly lower than that of the stoichiometric unsubstituted HA. At 600–800 °C, in the substituted-HA samples containing cop- per, iron, or zinc at the position of calcium ions with a degree of substitution (x) of ≥0.5, a release of the corresponding ox- ides is observed, pointing to the diffusion of the substituent ions onto the surface of substituted-HA particles. The created vacancies at calcium ions’ positions promote structural trans- formations, which give rise to the β-Ca3(PO4)2 phase. It was demonstrated here that in the HA sample where copper cations are expected to replace the hydroxyl group, a CuO phase emerges during the thermal treatment at 600 °C. On the other hand, a further increase in tempera- ture, to 1100 °C, results in a single-phase material in which copper cations redissolve in the crystal lattice of HA, thereby most likely localizing to the hydroxyl channel. The observed changes in phase composition of the syn- thesized samples can significantly affect the properties of the materials. Low thermal stability of the materials im- poses limitations on the manufacture of ceramic products or coatings from HA containing such substituents as copper, iron, or zinc ions. Supplementary materials No supplementary materials are available. Funding The synthesis and analysis of the iron compounds was car- ried out within a grant from the Russian Science Founda- tion (No. 21-12-00251). The research on the compounds containing copper, zinc, and silicon was conducted within the framework of a state assignment for the Institute of Solid State Chemistry and Mechanochemistry SB RAS (pro- ject No. 121032500064-8). Acknowledgments None. Author contributions Conceptualization: B.N.V., E.N.V. Data curation: M.S.V. Funding acquisition: B.N.V. Investigation: M.S.V., I.D.D. Methodology: B.N.V., E.N.V., M.S.V. Project administration: B.N.V. Resources: M.S.V., I.D.D. Visualization: E.N.V. Writing – original draft: E.N.V., M.S.V, I.D.D. Writing – review & editing: B.N.V. 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