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1. Journal of Materials Science: Materials in Medicine (2022) 33:3 https://doi.org/10.1007/s10856-021-06626-3 BIOMATERIALS SYNTHESIS AND CHARACTERIZATION Review Article Bioactive glasses incorporating less-common ions to improve biological and physical properties Usanee Pantulap 1 ● Marcela Arango-Ospina 1 ● Aldo R. Boccaccini 1 Received: 19 September 2021 / Accepted: 7 November 2021 / Published online: 23 December 2021 © The Author(s) 2021 Abstract Bioactive glasses (BGs) have been a focus of research for over fi ve decades for several biomedical applications. Although their use in bone substitution and bone tissue regeneration has gained important attention, recent developments have also seen the expansion of BG applications to the fi eld of soft tissue engineering. Hard and soft tissue repair therapies can bene fi t from the biological activity of metallic ions released from BGs. These metallic ions are incorporated in the BG network not only for their biological therapeutic effects but also in many cases for in fl uencing the structure and processability of the glass and to impart extra functional properties. The “ classical ” elements in silicate BG compositions are silicon (Si), phosphorous (P), calcium (Ca), sodium (Na), and potassium (K). In addition, other well-recognized biologically active ions have been incorporated in BGs to provide osteogenic, angiogenic, anti-in fl ammatory, and antibacterial effects such as zinc (Zn), magnesium (Mg), silver (Ag), strontium (Sr), gallium (Ga), fl uorine (F), iron (Fe), cobalt (Co), boron (B), lithium (Li), titanium (Ti), and copper (Cu). More recently, rare earth and other elements considered less common or, some of them, even “ exotic ” for biomedical applications, have found room as doping elements in BGs to enhance their biological and physical properties. For example, barium (Ba), bismuth (Bi), chlorine (Cl), chromium (Cr), dysprosium (Dy), europium (Eu), gadolinium (Gd), ytterbium (Yb), thulium (Tm), germanium (Ge), gold (Au), holmium (Ho), iodine (I), lanthanum (La), manganese (Mn), molybdenum (Mo), nickel (Ni), niobium (Nb), nitrogen (N), palladium (Pd), rubidium (Rb), samarium (Sm), selenium (Se), tantalum (Ta), tellurium (Te), terbium (Tb), erbium (Er), tin (Sn), tungsten (W), vanadium (V), yttrium (Y) as well as zirconium (Zr) have been included in BGs. These ions have been found to be particularly interesting for enhancing the biological performance of doped BGs in novel compositions for tissue repair (both hard and soft tissue) and for providing, in some cases, extra functionalities to the BG, for example fl uorescence, luminescence, radiation shielding, anti-in fl ammatory, and antibacterial properties. This review summarizes the in fl uence of incorporating such less-common elements in BGs with focus on tissue engineering applications, usually exploiting the bioactivity of the BG in combination with other functional properties imparted by the presence of the added elements. These authors contributed equally: Usanee Pantulap, Marcela Arango- Ospina * Aldo R. Boccaccini aldo.boccaccini@ww.uni-erlangen.de 1 Department of Materials Science and Engineering, Institute of Biomaterials, University of Erlangen-Nuremberg, 91058 Erlangen, Germany 1234567890();,: 1234567890();,: Graphical Abstract 1 Introduction Bioactive glasses (BGs) are being increasingly investigated for both bone and soft tissue engineering applications [ 1 , 2 ]. BGs exhibit a unique bone-bonding ability by forming a hydroxyapatite surface layer after incubation in physiolo- gical fl uids and simultaneously support biological regen- erative processes such as angiogenesis and osteogenesis during their dissolution [ 3 , 4 ]. Furthermore, speci fi c com- positions of BGs can provide antibacterial activity [ 5 – 8 ] and/or induce an anti-in fl ammatory response [ 9 , 10 ]. BGs have thus great potential in bone regeneration, drug delivery systems, as well as in soft tissue repair and wound healing [ 11 , 12 ]. In 1969, Hench et al. used the Na 2 O – CaO – SiO 2 phase diagram to develop the fi rst BG, named “ 45S5 BG, ” with composition: 45 SiO 2 – 24.5 CaO – 6P 2 O 5 – 24.5 Na 2 O (in wt.%). 45S5 BG has been considered in medical appli- cations since 1985. The fi rst 45S5 BG surgical implants were solid parts used to replace the small bones in the middle ear to treat conductive hearing loss [ 13 ]. Over the last 50 years, numerous BG compositions in the silicate, borosilicate, borate, and phosphate systems have been developed and characterized [ 14 – 16 ]. In general, the addi- tion of glass modi fi ers has signi fi cant effects on glass properties, including bioactivity. BG compositions similar to 45S5 BG have been investigated. For example, ICIE16- BG [ 17 ], with a higher amount of CaO and lower amount of Na 2 O compared to 45S5 BG, along with K 2 O, has been shown to exhibit a larger sintering window that allows the shaping of 3D structures without crystallization [ 18 , 19 ]. Another silicate BG that has received much attention is the 13 – 93 composition, which has shown less tendency to crystallize when sintered and is known to generate 3D scaffolds with superior mechanical properties [ 20 , 21 ]. Moreover, boron-containing BGs have demonstrated that boron addition into silicate BGs enhances the degradation rate [ 16 ], the process of apatite formation [ 22 , 23 ], antibacterial properties [ 23 ], osteogenesis [ 24 – 26 ], angio- genesis [ 26 – 28 ], and has also an effect on the BG mechanical strength [ 22 , 29 ]. Boron-doped BGs have been shown to be attractive materials for applications in soft and hard tissue engineering [ 15 , 30 ]. The chemical composition of phosphate-based BGs has also been studied to tailor the glass structure and to improve dissolution behavior and bioactive characteristics for biomedical applications [ 31 , 32 ]. The modi fi cation of chemical compositions of BGs has been investigated as an approach to improve mechanical properties and glass durability. For example, aluminum ions have been incorporated in BGs to reinforce mechanical performance. Various studies have investigated Al 2 O 3 - doped 45S5 BGs (sol – gel and melt-derived) in terms of bioactivity and physical properties, demonstrating improved mechanical properties but reduced bioactivity for compo- sitions with more than 1 mol% Al 2 O 3 compared to bare 45S5 BGs. Moreover, sol – gel glasses with low amounts of Al 2 O 3 (0.5 – 1 mol%) showed enhanced mechanical proper- ties without signi fi cant reduction of bioactivity [ 33 – 36 ]. Biologically active ions have become widely used for enhancing the biological and physical effectiveness of BGs, aiming at developing multifunctional biomaterials for a wide range of biomedical applications. Metallic ions are not only essential for the human health but also could be an alternative to highly-priced pharmaceuticals [ 37 , 38 ]. Sig- ni fi cant research has been published on incorporating metallic ions (or bioinorganics) in BGs [ 39 – 43 ] as well as in the fi eld of calcium phosphates [ 44 – 46 ]. The use of several biologically active ions has been prevalent in recent years, namely, Ag + ,Li + ,Co 2 + ,Ca 2 + ,Cu 2 + ,Zn 2 + ,Sr 2 + ,Fe 2 + , Mg 2 + ,Ga 3 + , and B 3 + have been added to silicate, phos- phate, and borate BG systems to promote functional prop- erties such as osteogenesis, angiogenesis, bioactivity, antibacterial effects, and immunomodulation for tissue regeneration, as well as for infection and cancer treatment [ 40 , 47 , 48 ]. Several comprehensive reviews on such BGs 3 Page 2 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 incorporating “ common ” biologically active ions are available [ 8 , 15 , 31 , 39 – 42 , 49 – 54 ]. Recently, a signi fi cant number of BGs doped with what can be called less-common (or even exotic) ions, including rare earth elements, have started to be reported. Such BGs are attractive for tissue regeneration applications because of the functional properties, biological activity, and therapeutic effects provided by such ions. There has been no previous review article focusing on the development and applications of such BGs containing less-common ions. Therefore, this review article covers comprehensively literature reports on less-common ion-doped BGs, which include rare earth, metal, and non-metal elements: Ba 2 + ,Bi 3 + ,Cl – ,Cr 6 + , Dy 3 + ,Eu 3 + ,Gd 3 + ,Yb 3 + ,Th 3 + ,Ge 2 + ,Au 3 + ,Ho 3 + ,I – ,La 3 + , Mn 2 + ,Mo 6 + ,Ni 2 + ,Nb 5 + ,N 3 – ,Pd 2 + ,Rb + ,Sm 3 + ,Se 4 + , Ta 5 + ,Te 4 + ,Tb 3 + ,Er 3 + ,Sn 2 + ,W 6 + ,V 5 + ,Y 3 + , and Zr 4 + . Figure 1 shows the periodic table of the elements high- lighting the different ions that are considered basic con- stituents for the production of BGs or those mainly used to impart biological and therapeutic functionalities to BGs. An overview of BG formulations incorporating less-common ions, their applications and properties, including the synthesis method, is presented in Table 1 for rare earth elements and Table 2 for other less-common (biologically active) ions. Considering the increasing number of pub- lications in the fi eld of ion-doped BGs, the authors proposed a basic classi fi cation of the ions based on their primary function in the BG and, for the purpose of this review, the number of studies that have considered the respective ions for their biological effects. Based on the information shown in Fig. 2 , the selection of ions for such classi fi cation, and thus the decision on which publications should be included in this review, was done considering the number of publications reporting the application of a given ion in BGs in the last 20 years. Ions used in less than 30 publications (up to August 31, 2021) were considered “ less-common ions ” and were thus included in this review (clearly this is an arbitrarily chosen number, but necessary to establish a criterion to identify such less-common ions). 2 Rare earth elements-containing bioactive glasses The incorporation of biologically active ions, including less-common ions, provides BG matrices with additional biological functionalities, therapeutic effects, and physical properties, for example, induction of hydroxyapatite for- mation, enhanced differentiation and proliferation of bone- forming cells, stimulating effects on angiogenic growth factors and improvement in mechanical properties [ 41 ]. Several studies have reported the use of rare earth elements in BGs to achieve different biological and functional properties. In this section, the effects of the incorporation of rare earth elements in different types of BGs are discussed. 2.1 Europium (Eu) Eu is a rare earth element that is not naturally present in the human body; however, as other elements, it can be incorporated into the bod y via ingestion of food and inhalation of dust particles. Normally these elements are naturally eliminated, but small amounts may deposit in organs. Traces of Eu have been found in brain tissue and kidney stones [ 55 ]. Due to the luminescent properties of Eu 3 + ions, silicate and phosphate bioactive glasses doped Fig. 1 Periodic table of the elements highlighting the classical ions used to produce BGs, ions highly investigated to provide biological and therapeutic properties to BGs, and less-common ions in BGs, which are the ones covered in this review Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 3 of 41 3 Table 1 Compositions of rare earth elements-containing bioactive glasses for medical applications Ion Glass composition Applications Synthesis technique Additional formation Ref. Dysprosium (Dy) 61.2 B 2 O 3 – 8.8 Li 2 O – 61.2 Dy 2 O 3 (wt.%) Drug delivery and radiation therapy Melt-quenching Microspheres with a particles size range from 45 to 150 μm [ 133 ] 50 SiO 2 – 30 CaO – 10 Fe 2 O 3 – 10 Dy 2 O 3 (mol%) Radiotherapy and hyperthermia Sol – gel Porous glass powder after thermal treatment at 500 and 800 °C [ 135 ] Europium (Eu) 70 SiO 2 – 20 CaO – 5P 2 O 5 with 5 Eu 2 O 3 (or Tb 2 O 3 ) (mol%) Bone regeneration and drug delivery Sol – gel Mesoporous nano fi bers with an average diameter of 100 – 120 nm [ 59 ] 100 SiO 2 with 1, 2, and 3 Eu 2 O 3 (mol%) Skin and bone regeneration Sol – gel Mesoporous nanospheres with a particle size range of 280-300 nm [ 69 ] SiO 2 – CaO – P 2 O 5 with 5 Eu 2 O 3 (mol%) Drug delivery Sol – gel Mesoporous powder [ 58 ] 60 SiO 2 – 36 CaO – 4P 2 O 5 with 0, 0.5, 1, and 2 Eu 2 O 3 (mol%) Bone regeneration Sol – gel Mesoporous nanospheres with a particle size around 500 nm [ 57 ] 80 SiO 2 – 16 CaO – 4P 2 O 5 with 1, 2, and 3 Eu 2 O 3 (mol%) Cell imaging and bone regeneration Sol – gel Nanoparticles with a particle size range of 200 – 400 nm [ 60 ] 80 SiO 2 – 15 CaO – 5P 2 O 5 with 0, 1, 2, and 5Eu 2 O 3 (mol%) Cell imaging and bone regeneration Sol – gel Mesoporous bioactive glass scaffolds with a pore size range of 300 – 500 μm [ 70 ] Gadolinium (Gd), Ytterbium (Yb) and Thulium (Tm) 47.28 SiO 2 – 31.39 Na 2 O – 15.33 CaO – 6 P 2 O 5 with 2.5 Gd 2 O 3 or Yb 2 O (wt.%) Tissue engineering Melt-quenching Glass powder with a particle size of less than 125 μm [ 85 ] SiO 2 – CaO – Gd 2 O 3 with the Ca:Gd molar ratios 3:1 and 5:1 Bone regeneration Sol – gel Combination of mesoporous calcium silicate scaffold with chitosan using lyophilization technique [ 90 ] 84 SiO 2 – 12 CaO – 4P 2 O 5 with the Ca:Gd molar ration 3:1, 5:1, and 7:1 Bone regeneration Sol – gel Microsphere powder with a particle size around 300 nm + BG scaffold using lyophilization technique [ 89 ] 47.28 SiO 2 – 31.39 NaO 2 – 15.33 CaO – 6 P 2 O 5 with 2.5 Gd 2 O 3 or 2.5 Yb 2 O 3 or 0.5 Fe 2 O 3 (wt.%) Biomedical applications Melt-quenching Glass powder with a particle size of less than 75 μm [ 84 ] 63 SiO 2 – 37 CaO with 0.15, 0.3 and 0.5 Tm 2 O 3 and 0, 1, 2, 3 and 4 Yb 2 O 3 (mol.%) Regenerative medicine or drug delivery Sol – gel Glass powder with a particle size range of 80 – 120 nm [ 91 ] Holmium (Ho) 58 SiO 2 – 33 CaO – 9P 2 O 5 with 1.25, 2.5 and 5 Ho 2 O 3 (wt.%) Brachytherapy Sol – gel Glass powder [ 78 ] 58 SiO 2 – 33 CaO – 9P 2 O 5 with 1.25, 2.5, 3.75, and 5 Ho 2 O 3 (wt.%) Brachytherapy Sol – gel Glass powder incorporated into the Poloxamer 407 hydrogel (20 wt.%) [ 79 ] Lanthanum (La) 67 SiO 2 – 5Na 2 O – 24 CaO – 4P 2 O 5 with 5 La 2 O 3 (or CuO) (mol%) Tissue engineering Sol – gel Glass powder with a particle size of less than 63 μm and BG scaffolds with macropores in the range of 300 – 500 μm using the robocasting technique [ 124 ] 64.4 SiO 2 – 2.48 Na 2 O – 21.53 CaO – 4.55 P 2 O 5 with 0, 1, 3 and 5 wt.% La 2 O 3 (or/and CuO) Tissue engineering Sol – gel Glass powder with a particle size range of 3.5 – 4.6 μm [ 123 ] 3 Page 4 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 Table 1 (continued) Ion Glass composition Applications Synthesis technique Additional formation Ref. 25 Na 2 O – 25 CaO – 50 P 2 O 5 with 5 and 10 La 2 O 3 (mol%) Drug delivery Sol – gel Mesoporous nanoparticles with a particle size range of 25 – 100 nm [ 118 ] 58 SiO 2 – 38 CaO – 4P 2 O 5 – 1La 2 O 3 (wt.%) Bone regeneration Sol – gel Glass powder [ 125 ] 20 Na 2 O – 14 CaO – 66 P 2 O 5 with 0, 0.1, 0.3, 0.7 and 1 La 2 O 3 (mol%) Tissue engineering Melt-quenching Glass powder with a particle size range of 106 – 180 μm [ 116 ] Samarium (Sm) 45 SiO 2 – 24.5 Na 2 O – 24.5 CaO – 6P 2 O 5 with 0, 1, 2, 3, and 4 Sm 2 O 3 (wt.%) Bone regeneration Melt-quenching Glass powder [ 97 ] 46.1 SiO 2 – 24.4 Na 2 O – 26.9 CaO – 6P 2 O 5 with 0, 0.2, and 2 Sm 2 O 3 (wt.%) Tissue engineering Melt-quenching Glass powder with a particle size of around 100 μm [ 93 ] SiO 2 – CaO – P 2 O 5 with 0, 0.5, and 1 Sm 2 O 3 (mol%) Bone cancer Sol – gel Combination of mesoporous bioactive glass with alginate powder with a particle size of around 1200 μm [ 98 ] 45.6 SiO 2 – 24.4 Na 2 O – 26.9 CaO – 2.6 P 2 O 5 with 0.5 Sm 2 O 3 (mol%) Biomedical applications Melt-quenching Glass fi ber with a diameter of 100 μm from the glass melt [ 96 ] 10 Na 2 O – 15 CaO – 65 P 2 O 5 – 15 CaF 2 with 0, 0.5, 1, and 2 Sm 2 O 3 (mol%) Bone regeneration Melt-quenching Mixing of 2.5% glass powder with 97.5% of hydroxyapatite powder (wt.%) [ 99 ] Terbium (Tb) and Erbium (Er) 79.5 SiO 2 – 15 CaO – 5P 2 O 5 with 0.5 and 1 Tb 2 O 3 (mol%) Bone regeneration Sol – gel Mesoporous nanospheres with a particle size range of 100 – 200 nm [ 130 ] 53 SiO 2 – 6Na 2 O – 20 CaO – 4P 2 O 5 – 12 K 2 O – 5 MgO with 1, 3, 5 Tb 2 O 3 or 1, 3, 5 Er 2 O 3 or 0.5, 1.5, and 2.5 with co-dopingTb 2 O 3 and Er 2 O 3 (wt.%) Bioimaging Sol – gel Glass powder with a particle size range of 1.45 – 3.57 μm [ 132 ] 30 Na 2 O – 25 CaO – 45P 2 O 5 with 0, 1, 3, and 5 Y 2 O 3 (mol%) Radiotherapy Melt-quenching Glass powder [ 113 ] 62.35 SiO 2 – 15.85 Na 2 O – (20.80 – x ) CaO – 1.0 P 2 O 5 with x = 0 and 4.68 Y 2 O 3 (mol%) Radiotherapy Melt-quenching Glass powder [ 112 ] 58 SiO 2 – 33 CaO – 9P 2 O 5 with 10 Y 2 O 3 (wt.%) Radiotherapy Sol – gel Glass powder with an average particle size of 1μm [ 105 ] Yttrium (Y) 6 Na 2 O – 20 CaO – 4P 2 O 5 – 12 K 2 O – 5 MgO – 52 B 2 O 3 – 1Y 2 O 3 (wt.%) Tissue engineering Melt-quenching Glass powder with a particle size range of 100 – 300 μm [ 114 ] Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 5 of 41 3 Table 2 Formulations of bioactive glasses incorporating less-common elements according to the envisaged medical applications Ion Glass composition Applications Synthesis technique Additional formation Ref. Barium (Ba) 44.85 SiO 2 – 24.3 Na 2 O – 26.9 CaO – 2.6 P 2 O 5 – 1.35 BaO (mol%) Tissue engineering Sol – gel Glass powder with a particle size range of 508 ± 39 and 403 ± 42 nm [ 9 ] 60 SiO 2 – 36 CaO – 4P 2 O 5 with 0, 5, and 10 BaO and 0, 10, and 15 Fe 2 O (mol%) Cancer hyperthermia Sol – gel Glass powder with a particle size range of 100 – 200 nm [ 154 ] 15 SiO 2 – 20 Na 2 O – 10 CaO – 50 B 2 O 3 – 5Al 2 O 3 with 0, 5, 10, 20, and 30 BaO (wt.%) Radiation shielding Melt-quenching Glass powder [ 160 ] Bismuth (Bi) 53 SiO 2 – 23 Na 2 O – 20 CaO – 4P 2 O 5 with 1, 2, 4, and 8 Bi 2 O 3 (wt.%) Bone regeneration Melt-quenching Glass powder with a particle size less than 45 μm [ 346 ] Chlorine (Cl) 50 SiO 2 – 50 CaO with 0 – 43.1 CaCl 2 (mol%) Toothpaste additives Melt-quenching Glass [ 325 ] 38.1 SiO 2 – 55.5 CaO – 6.3 P 2 O 5 with 0 – 16.6 CaCl 2 (mol%) Bone regeneration Melt-quenching Glass powder with a particle size less 38 μ m [ 327 ] 38.1 SiO 2 – 55.5 CaO – 6.3 P 2 O 5 with 0 – 21.5 CaCl 2 and 0 – 13.4 CaF 2 (mol%) Dental toothpastes or resorbable bone substitutes Melt-quenching Glass powder with a particle size less 45 μ m [ 329 ] Chromium (Cr) 5 SiO 2 – 20 Na 2 O – 20 CaO – 2P 2 O 5 – 43 B 2 O 3 with 0 – 1Cr 2 O 3 (mol%) Bone regeneration Melt-quenching Glass powder [ 241 ] Germanium (Ge) 48 SiO 2 – 12 CaO – 36 ZnO with 0, 6.5, 7, and 8 GeO 2 (mol%) Bone fi lling materials Melt-quenching Glass powder with a particle size around 6 μm [ 335 ] 48 SiO 2 – 6 CaO – 2P 2 O 5 – 36 ZnO – 8 SrO with 6 and 12 GeO 2 (mol%) Spinal orthopedic procedures Melt-quenching Glass powder with a maximum particle size of 45 μ m [ 336 ] 9.9 Na 2 O – 51. P 2 O 5 – 20.8 K 2 O – 8 BaO – 7.2 Al 2 O 3 – 0.2 Sb 2 O 3 – 0.2188 La 2 O 3 – 0.5 Nb 2 O 5 – 0.5 Y 2 O 3 – 0.9 Yb 2 O 3 with 0.7 – 84.4 GeO 2 (mol%) Nuclear radiation shielding applications Melt-quenching Glass [ 337 ] Gold (Au) 60 SiO 2 – 32 CaO – 8P 2 O 5 with 0, 0.05, 0.075, 0.1, 0.15, and 0.2 Au 2 O (mol%) Biomaterial Sol – gel Glass powder with a particle size about 100 μm [ 305 ] 60 SiO 2 – 36 CaO – 4P 2 O 5 (mol%) with 0.1 and 1 (wt%) gold nanoparticles Biomaterial Sol – gel Glass powder [ 306 ] Iodine (I) 6 Na 2 O – 20 CaO – 4P 2 O 5 – 12 K 2 O – 5 MgO – 52.9 B 2 O 3 – 0.1 I (wt.%) Tissue engineering Melt-quenching Glass powder with a particle size range of 100 – 300 μm [ 114 ] 6Na 2 O – 20 CaO – 4P 2 O 5 – 10 K 2 O – 5 MgO – 53 B 2 O 3 – 2 I (wt.%) Bone regeneration Melt-quenching Glass powder with a particle size less than 45 μm [ 331 ] 6Na 2 O – 20 CaO – 4P 2 O 5 – 12 K 2 O – 5 MgO – 52 B 2 O 3 (wt.%) with 0.2 wt.% NaI Nerve regeneration Melt-quenching Glass powder (50 wt.%) incorporated into the PCL polymer (50 wt.%) [ 332 ] Manganese (Mn) 5 SiO 2 – 20 Na 2 O – 15 CaO – 55 P 2 O 5 – 5B 2 O 3 with 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.8, and 1 MnO (wt.%) Bone regeneration Melt-quenching Glass powder [ 288 ] 60 SiO 2 – 36 CaO – 4P 2 O 5 with 0, 2.5, and 5 MnO 2 (mol%) Bone regeneration Sol – gel Glass powder with a particle size of less than 150 μm [ 278 ] 60 SiO 2 – 36 CaO – 4P 2 O 5 with 0, 1, 2.5, and 5 MnO (mol%) Bone regeneration Sol – gel Glass powder with a particle size range of 38 – 150 μm [ 284 ] 43.29 SiO 2 – 4.49 Na 2 O – 31.02 CaO – 11 P 2 O 5 – 0.19 K 2 O – 2.76 MgO – 0.50 La 2 O 3 – 0.99 Ta 2 O 5 – 0.89 MnO (wt.%) Coatings Sol – gel Glass powder [ 388 ] 50 SiO 2 – 40 CaO – 10 P 2 O 5 with 0 and 5 MnO (mol%) Bone regeneration Sol – gel Mesoporous powder with a particle size range of 100 – 120 nm [ 287 ] 45 Si 2 O – 15 Na 2 O – 26 CaO – 3P 2 O 5 – 4K 2 O – 7 MgO with 0, 0.25, and 0.5 MnO (mol %) Bone regeneration Melt-quenching Glass powder with a particle size of less than 32 μm [ 282 ] 50 SiO 2 – 40 CaO – 10 P 2 O 5 with 0, 3, 5, and 7 MnO (mol%) Bone regeneration Sol – gel Mesoporous powder with a particle size range of 110 ± 10 nm [ 285 ] 3 Page 6 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 Table 2 (continued) Ion Glass composition Applications Synthesis technique Additional formation Ref. 60 SiO 2 – 36 CaO – 4P 2 O 5 with 0, 3, and 5 MnO (mol%) Bone regeneration Sol – gel Glass powder [ 283 ] 92 SiO 2 – 8 CaO with 0, 3.3, and 4.2 MnO (mol%) Tissue regeneration Sol – gel Glass powder with a particle size range of 112.2 ± 13.5 and 139.6 ± 8.9 nm [ 389 ] Molybdemiun (Mo) 70 SiO 2 – 25 CaO – 5P 2 O 5 with 0, 2, 5, and 7.5 MoO 3 (mol%) Cartilage/bone Sol – gel Scaffolds with cylindrical pores with an approximate diameter of 8 mm and height of 2 mm using 3D printing [ 256 ] 60 SiO 2 – 30 CaO – 10 P 2 O 5 with 0, 3, 5, and 10 MoO 3 (mol%) Interface regeneration Sol – gel Glass powder [ 255 ] 45 CaO – 48 P 2 O 5 – 5K 2 O – 2B 2 O 3 with 0, 1, 3, 5, and 7 MoO 3 (mol%) Bone regeneration Melt-quenching Glass powder [ 257 ] Nickel (Ni) 46.1 SiO 2 – 24.5 Na 2 O – 26.9 CaO – 2.6 P 2 O 5 with 0, 0.41, 0.82, 1.23, and 1.65 Nb 2 O 5 (mol%) Bone regeneration Melt-quenching Glass [ 313 ] 46.14 SiO 2 – 24.40 Na 2 O – 26.91 CaO – 2.55 P 2 O 5 with 0, 0.41, 0.82, 1.23, and 1.65 Nb 2 O 5 (mol%) Bone regeneration Melt-quenching Glass [ 314 ] 46.14 SiO 2 – 24.40 Na 2 O – 26.91 CaO – 2.55 P 2 O 5 with 0, 0.41, 0.82, 1.23, and 1.65 Nb 2 O 5 (mol%) Bone regeneration Melt-quenching Glass [ 315 ] Niobium (Nb) 46.1 SiO 2 – 24.5 Na 2 O – 26.9 CaO – 2.6 P 2 O 5 with 0,1.0, 2.5, and 5.0 Nb 2 O 5 (mol%) Tissue engineering Melt-quenching Glass powder [ 230 ] 20 SiO 2 – 24.5 Na 2 O – 24.5 CaO – 31B 2 O 3 with 0, 2.5, 5, and 10 Nb 2 O 5 (mol%) Bone regeneration Melt-quenching Glass powder [ 229 ] 46.1 SiO 2 – 24.5 Na 2 O – 26.9 CaO – 2.6 Nb 2 O 5 (mol%) Bone regeneration Melt-quenching Glass powder with a particle size range of 40 – 63 μm [ 233 ] Nitrogen (N) 55 SiO 2 – 31.5 Na 2 O – 13.5 CaO with 0, 1, 2, 3, and 4 Si 3 N 4 (mol%) Bone regeneration Melt-quenching Glass [ 355 ] 55 SiO 2 – 31.5 Na 2 O – 8.5 CaO – 5 CaF 2 with 0, 1, 2, 3, and 4 Si 3 N 4 (mol%) Bone regeneration Melt-quenching Glass [ 356 ] 55 SiO 2 – 29 Na 2 O – 13.5 CaO – 2.5 P 2 O 5 with 1, 2, 3, and 4 Si 3 N 4 (mol%) Bone regeneration Melt-quenching Glass [ 357 ] 45 SiO 2 – 24.5 Na 2 O – 24.5 CaO – 6P 2 O 5 with 0, 5.51, and 10.69 Si 3 N 4 (wt.%) Bone regeneration Melt-quenching Glass [ 358 ] Palladium (Pd) 80 SiO 2 – 15 CaO – 5P 2 O 5 (mol%) with addition of 0.46, 0.96, 1.20, and 2.30 % PdCl 2 Catalytic oxidation of benzyl alcohol Sol – gel Mesoporous powder [ 319 ] Rubidium (Rb) 80 SiO 2 – 15 CaO – 5P 2 O 5 with x = 0, 1, 2, and 5 Rb 2 O (mol%) Bone regeneration Sol – gel Mesoporous bioactive glass scaffolds with macropores in the size range 350 – 550 μm using the foam replica method [ 142 ] 90 SiO 2 – 10 CaO with 0, 0.5, 1.5, and 2.5 Rb 2 O (mol%) Bone regeneration Sol – gel Nanoparticles with a particle size range of 100 – 114 nm [ 140 ] 80 SiO 2 – 15 CaO – 5P 2 O 5 with 0, 0.5, 1, 3, 5 and 10 Rb 2 O (mol%) Wound healing Sol – gel Nanoparticles with a particle size range of 350 – 430 nm [ 141 ] Selenium (Se) 60 SiO 2 – 36 CaO – 4P 2 O 5 with 0, 1, 3, and 5 SeO 3 (mol%) Bone regeneration Sol – gel Mesoporous powder with a particle size around 400 nm [ 376 ] 80 SiO 2 – 15 CaO – 5P 2 O 5 with 0 and 5 SeO 3 (mol%) Bone tumor therapy Sol – gel Mesoporous powder with a surface area range of 200 – 350 m 2 /g and a mesopore size range of 3 – 5nm [ 374 ] 40 SiO 2 – 43 CaO – 12 P 2 O 5 – 5 MgO with 0, 2, 4, 6, and 8 SrO, and 0, 2, 3, and 4 SeO 3 (mol%) Bone regeneration Sol – gel Mesoporous powder with a particle size range of 265 – 318 nm [ 390 ] 45 SiO 2 – 24.5 Na 2 O – 24.5 CaO – 6P 2 O 5 with 0.75, 1.5, 3, and 6 SeO 2 (wt.%) Bone cancer therapy Melt-quenching Glass powder [ 375 ] Tantalum (Ta) 80 SiO 2 – 15 CaO – 5P 2 O 5 with 0, 0.5, 5, and 10 Ta 2 O 5 (mol%) Tissue engineering Sol – gel Mesoporous powder with a particle size less than 45 μm [ 162 ] 58 SiO 2 – 37 CaO – 5P 2 O 5 with 0, 0.2, 0.4, 0.6, 0.8, and 1 Ta 2 O 5 (mol%) Bone regeneration Sol – gel Glass powder [ 173 ] 20 SiO 2 – 24.5 Na 2 O – 24.5 CaO – 31 B 2 O 3 with 0.5, 1, 2, and 3 Ta 2 O 5 (mol%) Bone regeneration Melt-quenching Glass powder [ 174 ] Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 7 of 41 3 Table 2 (continued) Ion Glass composition Applications Synthesis technique Additional formation Ref. Tellurium (Te) 26 Na 2 O – 21 CaO – 3P 2 O 5 – 50 TeO 2 (mol%) Bioactive implants Melt-quenching Glass powder with a particle size range of 75 – 150 μm [ 361 ] 48.6 SiO 2 – 16.7 Na 2 O – 34.2 CaO – 0.5 P 2 O 5 with 0, 1, and 5 TeO 2 (mol%) Bone regeneration Melt-quenching Glass powder with a particle size of less than 25 μm [ 366 ] Tin (Sn) (35 – 40) P 2 O 5 – (40 – 60) SnCl 2 with 5, 10, 15, and 20 SnCl 2 (mol%) Nuclear medicine Melt-quenching Glass [ 350 ] Tungsten (W) 44.7 SiO 2 – 24.9 Na 2 O – 24.9 CaO – 5.5 P 2 O 5 with 0, 1, 2, 3, and 4 WO 3 (wt.%) Radiation shielding materials Melt-quenching Glass [ 320 ] 5.50 Na 2 O – 18.50 CaO – 11.10 K 2 O – 4.60 MgO – 3.70 P 2 O 5 – 56.60 B 2 O 3 with 0, 0.5, 1, 2, and 4 WS 2 (wt.%) Radiation shielding materials Melt-quenching WS 2 nanoparticle-containing bioactive glass composites [ 321 ] 75 B 2 O 3 – 25 Li 2 O with 0, 1, 3, 5, and 7.5 WO 3 (mol%) Radiation shielding materials Melt-quenching Glass [ 322 ] Vanadium (V) 5.50 Na 2 O – 18.50 CaO – 11.10 K 2 O – 4.60 MgO – 3.70 P 2 O 5 – 56.60 B 2 O 3 with 0.5, 1, and 3 V 2 O 5 (wt.%) Bioimaging Melt-quenching Glass powder with a particle size of around 3.66 μm for 3 wt.% V 2 O 5 [ 269 ] 5.50 Na 2 O – 18.50 CaO – 11.10 K 2 O – 4.60 MgO – 3.70 P 2 O 5 – 56.60 B 2 O 3 with 0.5, 1, and 3 V 2 O 5 (wt.%) Medical radiation Melt-quenching Glass powder [ 270 ] 5.50 Na 2 O – 18.50 CaO – 11.10 K 2 O – 4.60 MgO – 3.70 P 2 O 5 – 56.60 B 2 O 3 with 0.5, 1, and 3 V 2 O 5 (wt.%) Soft tissue repair and in wound healing Melt-quenching Glass powder with a particle size of around 14 μm and scaffolds with an average pore size of 500 μm using foam replication method [ 268 ] 5.50 Na 2 O – 18.50 CaO – 11.10 K 2 O – 4.60 MgO – 3.70 P 2 O 5 – 56.60 B 2 O 3 with 0.5, 1, and 3 V 2 O 5 (wt.%) Bone regeneration Melt-quenching Glass powder with a particle size of around 2 μm and scaffolds with an average pore size of 100 – 500 μm using foam replication method [ 266 ] 57.2 Si – 35.3 Ca – 7.5 P with 0, 0.71, 2.78, and 6.67 V (mol%) Bone regeneration Sol – gel Mesoporous powder with a speci fi c surface area range of 647 – 349 m 2 /g [ 271 ] Zirconium (Zr) 53 SiO 2 – 6Na 2 O – 20 CaO – 4P 2 O 5 – 12 K 2 O – 5 MgO with 0, 0.5, 1.0, 1.5, and 2.0 ZrO 2 (wt.%) Bone regeneration Melt-quenching Glass powder [ 197 ] 22 Na 2 O – 24 CaO – 46 P 2 O 5 – 8 ZnO with 0, 0.1, 0.3, 0.5, and 0.7 ZrO 2 (mol%) Bone regeneration Melt-quenching Glass parts with dimensions 1.5 cm × 1.5 cm × 0.2 cm [ 175 ] 60 SiO 2 – 36 CaO – 4P 2 O 5 with 0, 5 and 10 ZrO 2 (mol%) Bone regeneration Sol – gel Glass powder [ 198 ] 60 SiO 2 – 31 CaO – 4P 2 O 5 – 5 ZrO 2 with 0, 2, 4, and 6 ZnO (mol%) Bone regeneration Sol – gel Glass powder [ 391 ] 3 Page 8 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 with europium (Eu-BGs) have been designed for appli- cations in drug delivery systems [ 56 – 59 ], cell imaging [ 60 – 67 ], optical devices [ 68 ], and bone and skin regen- eration [ 69 – 74 ]. Eu-BGs were shown to emit strong red luminescence features at 590 nm and 612 – 616 nm when exposed to UV radiation [ 56 , 69 , 70 ]. In other studies, the intensity of emission was found to increase as the fraction of europium ions increased [ 69 , 70 ]. The change in luminescence intensity of Eu 3 + has been monitored to track the release of ibuprofen (IBU) [ 56 , 58 ]. Fan et al. [ 58 ] observed the IBU release p rocess using luminescence functionalized Eu-doped mes oporous bioactive glasses (Eu-MBGs) in the system SiO 2 – CaO – P 2 O 5. The release of IBU from Eu-MBG in SBF increased the photo- luminescence intensity of Eu 3 + at 590 and 621 nm, reaching the highest value when IBU was completely removed. The quenching effect was weakened by the release of IBU, resulting in the increase of emission intensity [ 56 , 58 ]. Moreover, Huang et al. [ 59 ]showed that the IBU release rate of Eu-doped mesoporous bioactive glass nano fi bers (MBGNFs) with 5 mol% Eu 3 + (or Tb 3 + ) in the system 70 SiO 2 – 25 CaO – 5P 2 O 5 (mol%) was more rapid than for IBU-loaded MBG due to the disordered nanoporous channels present in the nano fi bers. Zhang et al. [ 57 ] observed that increasing concentration of Eu in MBG nanospheres with composition 60 SiO 2 – (36 – x )CaO – x Eu 2 O 3 – 4P 2 O 5 , x = 0.5, 1, and 2 mol%, changed the size, morphology, and pore structure of mesoporous silica supporting a controll ed release of doxorubicin (DOX), a drug used for cancer treatment [ 57 ]. Xue et al. [ 60 ]demonstratedthat fl uorescent Eu ions in BG nano- particles (80 SiO 2 – 16 CaO – 4P 2 O 5 mol%) were used to mark living murine calvaria-derived pre-osteoblastic (MC3T3-E1) cells for in vitro cytotoxicity studies with high red fl uorescence and low background noise. Besides, Wu et al. [ 70 ] investigated the degradation of Eu-MBGs scaffolds (80 SiO 2 – 15 CaO – 5P 2 O 5 , mol%) using a spectro fl uorimeter to measure luminescence intensity at 615 nm. Also, they detected in vivo new bone formation in a bone defect promoted by Eu ions release (wavelength of 610 nm), indicating tha t Eu addition can have also a biological effect, as discussed next. Eu-BGs have shown bioactive behavior in SBF [ 57 , 60 ]. Eu incorporation in B G nanoparticles had no signi fi cant effect on apatite mineralization [ 60 ], although the morphology of the formed apatite layer changed as the doping Eu content raised [ 57 ]. Moreover, Wu et al. observed that ionic dissolution products of Eu- containing MBGs (5 mol%) at varying concentrations (from 6.25 to 100 mg/ml) fac ilitated proliferation and osteogenic differentiation o f bone marrow stromal cells (BMSCs) by upregulating the expression of osteogenic genes(Runx2,COL1,OPN,OSX,andBSP)andby inducing ALP activity (6.25 and 25 mg/ml). However, the ALP activity decreased when the glass concentration was increased to 100 mg/ml. These results were com- pared to a control group that did not have conditioned medium. Similarly, europium-doped mesoporous silica nanospheres (Eu-MSNs) have been shown to sub- stantially upregulate osteogenic markers (ALP, OPN, OCN, COL1, and Runx2) of BMSCs and to enhance the expression levels of CD31, PDGFR α / β ,VEGFR1/2,and MMP9 angiogenic makers of human umbilical vein endothelial cells (HUVECs) i ndicating the promotion of both osteogenic and angio genic differentiation [ 69 ]. The addition of europium also h ad positive therapeutic effects on pro-in fl ammatory macrophage cells (RAW 264.7) treated with Eu-MSN (0.2 mg/ml), resulting in reduced pro-in fl ammatory genes IL-18, IL-6, IL-1 β , OSM MyD88, Ticam1, and Ticom2 [ 69 ]. In addition, 2 mol% Eu-doped MSN and Eu-free MSN suspensions at a concentration of 0.2 mg/ml showed no cytotoxic effect on RAW 264.7 cells, while Eu-doped MSN induced macrophage proliferation. In contrast, non-doped MSN had no effect on macrophage proliferation [ 69 ]. Simi- larly, other studies have shown that Eu-BG had no cytotoxic effect on MC3T3-E1 cells at concentrations rangingfrom40to250μg/ml[ 60 ] and osteosarcoma MG 63 cells at different concentrations (between 50 and 200 μg/ml) compared to undoped BG [ 57 ]. Other studies have reported the possible in vitro cytotoxicity of Eu- containing BGs [ 57 , 60 , 69 ]. Moreover, in vivo studies of Eu-doped MSN have demonstrated that Eu accelerated the formation of new bone in a rat defect site after between 4 and 12 weeks of implantation [ 69 , 70 ]andit Fig. 2 Number of publications in the last 20 years containing the keywords “ bioactive glasses ” or “ bioglass ” and the corresponding ions. The criteria used for the search considered that the keywords should appear on the title of the publication and//or the abstract. Data obtained from the database Scopus ( www.scopus.com ) and Web of Science ( www.webofscience.com ) Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 9 of 41 3 promoted new blood vessels growth, collagen deposi- tion, and re-epithelializ ation at the wound site [ 69 ]. 2.2 Holmium (Ho) It has been reported that holmium may have an in fl uence on accelerating metabolism in humans [ 75 ]. In addition, Poniedzialek et al. [ 76 ] investigated the possible presence of Ho in human colostrum milk, developed at the fi rst stage of breast milk. In the fi eld of BGs, Ho has been used mainly in silicate-based systems [ 77 – 79 ]. For example, sol – gel- derived holmium-doped 58S bioactive glasses (Ho-BGs) with compositions 58 SiO 2 – 33 CaO – 9P 2 O 5 – x Ho 2 O 3 ( x = 1.25, 2.5, and 5 wt.%) have been shown to promote the proliferation of MC3T3-E1 cells in relation to the con- centrations of Ho 2 O 3 [ 78 ]. Moreover, the addition of Ho was shown to signi fi cantly affect the dissolution behavior due to the presence of Si-O-Ho covalent bonds in the glass network, which reduced the dissolution rate of the glass without slowing down the bioactive behavior. Ho-BG powders exhibited apatite-like structures on the surface for all Ho 2 O 3 concentrations [ 78 ]. These results showed that Ho-containing BGs could be an interesting alternative for bone tissue regeneration. Zambanini et al. [ 79 ] investigated 58S BGs (58 SiO 2 – 33 CaO – 9P 2 O 5 ) containing various amounts of Ho 2 O 3 (1.25, 2.5, 3.75, and 5 wt.%) incorpo- rated into a Poloxamer 407 hydrogel (20 wt.%) for bra- chytherapy applications [ 80 ]. The hydrogel was integrated with Ho 2 O 3 containing BG, and it was found that the glass particles greatly in fl uenced the hydrogel self-assembly potential. In contrast, the hydrogel viscosity was sig- ni fi cantly reduced at 37 °C. Furthermore, the hydrogel containing 5 wt.% Ho-BG particles enhanced the pro- liferation of MC3T3-E1 cells [ 79 ]. Clearly, given the scar- city of investigations, the potential of Ho-BGs in tissue engineering applications remains unexplored. 2.3 Gadolinium (Gd), ytterbium (Yb), and thulium (Tm) Gd has been widely used in contrast agents for magnetic resonance imaging aimed to be eliminated naturally from the body; however, it has been shown that Gd could deposit in the brain and bones [ 55 , 81 , 82 ]. Similarly, Yb belongs to the lanthanide series of elements that are not naturally present in the human body. This element is highly used in optics and as a doping agent to increase the mechanical properties of stainless steel. Furthermore, Yb has been reported to accumulate in soils and water mainly due to petrol producing industries or discarded household equip- ment [ 83 ]. Silicate-based bioactive glasses doped with gadolinium (Gd-BG) and ytterbium (Yb-BG) have been investigated [ 84 – 88 ] due to the characteristic features that these elements offer for biomedical applications in the fi elds of brachytherapy, luminescence-based imaging, and mag- netic resonance imaging [ 84 ]. In vitro bioactivity and bio- logical studies have been performed on Gd and Yb containing BGs (of composition 47.28 SiO 2 – 31.39 Na 2 O – 15.33 CaO – 6P 2 O 5 with 2.5 Gd 2 O 3 or Yb 2 O 3 wt.%), resulting in calcium phosphate deposition after 1 day of immersion in SBF and a lower dissolution behavior com- pared to the reference glass owing to the covalent character of the Si-O-Gd and Si-O-Yb bonds. In terms of cyto- compatibility, the authors reported viability higher than 80% of mesenchymal stem cells derived from deciduous teeth (SHEDs) [ 85 ]. Moreover, gadolinium has been shown to have favorable therapeutic effect on osteoinductivity. For example, Zhu et al. [ 89 ] demonstrated that Gd-BG meso- porous microspheres in chitosan scaffolds facilitated the proliferation, differentiation, and expression of ALP activ- ity, OCN, and BSP via Akt/GSK3 β activation of human bone marrow-derived mesenchymal stem cells (hBMSCs). The AKT/GSK3 signaling pathway is crucial for the sur- vival of human pluripotent stem cells (Fig. 3 ). Similarly, by triggering the Wnt/-catenin signaling pathway, Gd-doped mesoporous calcium silicate containing scaffolds facilitated the osteogenic potential of rBMSCs [ 90 ]. With Gd incor- poration in BG, the expression of osteogenic markers such as ALP activity, Runx2, and COL-1 increased [ 89 , 90 ]. Furthermore, in vivo studies in a mouse model demon- strated that Gd-BG incorporation in chitosan scaffolds promoted rapid and signi fi cant newly formed bone and collagen deposition in a calvarial defect after 8 – 12 weeks implantation [ 89 , 90 ]. Thulium has also been used with ytterbium to produce co-doped sol – gel-derived silica glass nanoparticles with different ratios of Tm 2 O 3 and Yb 2 O 3 for biological testing, bioimaging, and drug delivery systems [ 91 ]. Nanoparticles with basic SiO 2 -CaO, containing Tm 2 O 3 (0.15, 0.3, or 0.5 mol%) and Yb 2 O 3 (0, 1, 2, 3, or 4 mol%), showed amor- phous structure for lower dopant concentrations, while crystallization of calcium silicate was detected for the higher amounts of Tm 2 O 3 and Yb 2 O 3 . The authors con- cluded that samples with 0.3% Tm 2 O 3 and 4% Yb 2 O 3 are promising due to their higher emission intensity and single exponential decay time compared to the other tested concentrations. 2.4 Samarium (Sm) Sm, an element that has in principle no natural biological role, has been widely used as a radiopharmaceutical to treat cancer in bones [ 92 ]. Sm-doped bioactive glasses (Sm-BG) have shown photoluminescence properties characteristic of Sm 3 + ions and have been described as potential material for cancer treatment [ 93 – 95 ]. Baranowska et al. [ 96 ] used the luminescent 3 Page 10 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 properties (at 601 and 648 nm) of bioactive 45S5 BG fi bers doped with Sm 3 + to investigate the degradation behavior of the fi bers. Furthermore, in vitro formation of apatite-like structures on Sm-BG substrates was observed after incubation in SBF by Ershad et al. [ 97 ]. The authors found that adding Sm 2 O 3 to BGs up to a concentration of 3 wt.% increased the formation of hydroxycarbonate-apatite (HCA ) layer on the surface after 21 days. Furthermore, Sm-BGs exhibited enhanced mechan- ical properties. Young ’ s modulus (76.36 – 78.89 GPa), shear modulus (30.25 – 31.95 GPa), and bulk modulus of Sm- containing 45S5 BGs increased with increasing concentration of Sm 2 O 3 [ 97 ]. Poisson ’ s ratio, on the other hand, decreased as the concentration of Sm 2 O 3 increased. [ 97 ]. In addition, Zhang et al. [ 98 ] investigated the potential use of samarium (0.5 – 1 mol%) doped mesoporous BG and alginate-containing microspheres for drug delivery applications. The drug (DOX) was loaded in the microspheres with varying amounts of Sm. The release of DOX was proportional to the Sm doping con- centration due to the higher dissolution rates proportional to the Sm concentration [ 98 ]. Morais et al. [ 99 ] investigated melt-derived samarium- doped phosphate glasses (15 CaO – 10 Na 2 O – 15 CaF 2 – 65 P 2 O 5 , with Sm 2 O 3 ranging from 0.5 to 2 mol%) and hydroxyapatite to produce composites (BG-HA). A pro- portion of 2.5 wt.% Sm-doped BG to 97.5 wt.% hydro- xyapatite was used to make the composites. XRD analysis showed crystalline phases characteristic of hydroxyapatite and samarium oxide. Moreover, the addition of Sm 3 + ions in the composite increased surface hydrophilicity and fl ex- ural strength compared to Sm-free BG-HA. The highest concentration of Sm in the BG-HA composites affected in vitro the antibacterial activity and cytocompatibility behavior. Consequently, BG-HA doped with 2 mol% Sm 2 O 3 showed the best antibacterial performance against Staphylococcus aureus and S. epidermidis besides higher proliferation of MG 63 cells and upregulation of relevant osteogenic markers (Runx2, ALP, BMP-2, and OC) [ 99 ]. 2.5 Yttrium (Y) Yttrium has been used in the clinic in cancer treatment [ 92 ]. Various studies have investigated the incorporation of yttrium in BGs for applications in different fi elds including radiotherapy, dentistry, and bone tissue engineering [ 100 – 109 ]. Yttrium-doped glasses (Y-BGs) have reported good chemical durability and stability in in vivo radiotherapy settings [ 110 ]. Erbe and Day [ 111 ] investigated the effect of the processability of Y-containing glasses (17 Y 2 O 3 – 19 Al 2 O 3 – 64 SiO 2 mol%) on their chemical durability. Sol – gel-derived and melt-derived Y-doped glass micro- spheres have shown higher chemical durability than bulk particles due to their large surface area. A SiO 2 -rich surface on the microspheres triggered surface corrosion after 4 weeks in DI water or 12 M HCl. Moreover, the glass durability after the addition of 4.68 mol% of Y 2 O 3 in the BG composition (62.35 SiO 2 – 1.0 P 2 O 5 – 15.85 Na 2 O – 20.8 CaO mol%) was investigated by Christie et al. [ 112 ]. Molecular dynamics simulations revealed that the sub- stitution of 4.68 mol% Y 2 O 3 for CaO in the BG composition led to an increased dissolution rate compared to Y-free BG due to the generation of a fragmented silicate network, causing a lower network connectivity and glass durability. The yttrium release rate was computed using site-selectivity and clustering of yttrium cations [ 112 ]. Arafat et al. [ 113 ] investigated the degradation rate after the incorporation of Y 2 O 3 (3 and 5 mol%) in phosphate-based glasses (sub- stitution for Y 2 O 3 /Na 2 O) in phosphate buffer saline and ultra-pure water (Milli-Q water) at 37 °C over 28 days. The results showed a reduced degradation rate with increasing Y 2 O 3 content in the glass system 45 P 2 O 5 – 25 CaO – 30 Na 2 O (mol%). In addition, Y-doped BGs have also exhib- ited bioactive behavior. Tesfay et al. [ 105 ], for example, observed that Y-containing 58S BG led to rapid apatite-like formation after 6 h in SBF. Recent work has also shown that replacing B 2 O 3 with 1 wt.% Y 2 O 3 in the glass composition 53 B 2 O 3 – 20 CaO – 12 K 2 O – 6Na 2 O – 5 MgO – 4P 2 O 5 (wt.%) had a greater effect on the proliferation and migration of adipose stem cells (ASCs) in an α -minimal essential med- ium in vitro [ 114 ]. 2.6 Lanthanum (La) La is a rare earth element that is present at low levels in drinking water and food. It has been reported to have che- mical similarities to Ba, Sr, and Ca and has been recently investigated to replace calcium-based phosphate binders Fig. 3 Schematic diagram showing Gd dopant activation of the Akt/ GSK3 β signaling pathway [ 89 ]. Reproduced according to Creative Commons license (CC BY-NC 3.0) Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 11 of 41 3 needed in patients with kidney failure to reduce cardiovas- cular calci fi cation [ 115 ]. Therefore, tracing the accumulation of La in the body has become an important aspect for such applications, being bone the main accumulation site reported so far [ 81 ], next to breast milk [ 76 ] and brain tissue [ 55 ]. Lanthanum has been used to modify the properties of silicate and phosphate BGs [ 74 , 116 – 122 ]. Lanthanum-doped bioactive glasses (La-BGs) containing chitosan composite scaffolds signi fi cantly improved osteoblast performance in terms of promoting the proliferation and osteogenic differ- entiation of BMSCs by upregulating expression levels of osteogenic markers (ALP, OCN, BMP-2, and Runx2) and raising the protein expression of RK in comparison to the scaffold without La doping [ 117 ]. In contact with HUVECs, La-BG-based scaffolds signi fi cantly induced the expression levels of b-FGF, vascular endothelial growth factor (VEGF), PDGF, and qRT-PCR compared to La-free BG scaffolds [ 117 ]. In vivo, the implantation of La-BG containing chitosan scaffolds in rat calvarial defects induced bone regeneration and new blood vessel formation after 8 weeks of implantation [ 117 ]. The addition of La 2 O 3 (5 and 10mol%) to phosphate glass nanoparticles provided a sustained delivery of the anti- biotic cipro fl oxacin for up to 28 days; on the other side, pure glass nanoparticles showed sustained drug release for 20 days [ 118 ]. The viability of fi broblast baby hamster kidney cells (BHK) after exposure to La containing nanoparticles exhib- ited a lanthanum oxide concentration dependency. The cell viability increased from 80 to 93% with increasing La con- centration (from 0 to 10 mol%) [ 118 ]. Incorporation of lan- thanum ions in combination with copper ions in BG facilitated the formation of a hydroxyapatite layer on the BG surface after soaking in SBF [ 123 ], suppressed C13895 lymphoblast cytotoxicity [ 123 ], and improved mechanical properties [ 124 ]. In addition, Jodati et al. [ 125 ] found multiple advantages of magnesium-lanthanum dual doped BGs (1 wt.% La) in bone regeneration applications, with the glasses exhibiting increased bioactivity in terms of apatite formation ability and biocompatibility with SAOS-2 cells (human osteosarcoma). 2.7 Terbium (Tb) and erbium (Er) Tb and Er have been used in medical imaging applications [ 75 ]. Bioactive glasses doped with terbium (Tb-BG) have been recently studied for biomedical applications because of their attractive properties, such as bioactivity, biocompat- ibility, biodegradation, and non-toxicity [ 126 – 129 ]. Wang et al. [ 130 ] investigated the in fl uence of Tb on the apatite formation ability of mesoporous BG nanospheres (base composition: 79.5 SiO 2 – 15 CaO – 5P 2 O 5 mol%). It was reported that the incorporation of Tb 2 O 3 (0.5 and 1 mol%) led to enhanced hydroxyapatite formation after immersion in SBF for 3 days. The hydroxyapatite nucleation on the surface of Tb-MBG nanospheres was seen to increase by the release of Ca 2 + and Tb 3 + ions. Furthermore, by varying Tb concentrations, it was possible to tailor DOX release [ 130 ]. Moreover, Tb-MBG nanospheres showed a nontoxic effect on MC3T3-E1 cells in indirect cell culture experi- ments at concentrations of 50 and 100 μg/ml [ 130 ]. Huang et al. [ 59 ] also evaluated the biocompatibility of Tb 3 + (and Eu 3 + ) containing MBGNFs using the MTT assay at dif- ferent MBGNF concentrations (3.125, 6.25, 12.5, 25, 50, 100, and 200 μm/ml). In all conditions, the viability of L929 fi broblast cells was higher than 90%, suggesting no cyto- toxic effect of Tb 3 + (or Eu 3 + ) doped MBGNF. Under ultraviolet irradiation, Tb-MBGNF and Eu-MBGNF showed luminescence properties at 544 and 614 nm, respectively [ 59 ]. Furthermore, Li et al. [ 128 , 131 ] investigated co-doped BGs with Er and Yb to provide conventional BGs with luminescence properties for biological labeling and drug delivery applications. Er 2 O 3 (0.79 – 3.52 wt.%) and Yb 2 O 3 (6.36 – 28.12 wt.%) were incorporated in Ca-Mg-Si BGs [ 131 ], as well as Er 2 O 3 (1 – 2 wt.%) and Yb 2 O 3 (9 – 18 wt.%) in CaSiO 3 [ 128 ]. In both investigations, bioactivity studies showed that co-doped BGs exhibited apatite precipitation in interaction with SBF after 14 days [ 128 , 131 ]. Furthermore, these materials did not show cytotoxic behavior to MC3T3- E1 cells, human dermal fi broblasts cells (HDFs), and HUVECs [ 128 , 131 ]. In addition, culture of HDFs and HUVECs with the ionic extracts of the Er 3 + and Yb 3 + co- doped Ca-Mg-Si BGs showed enhanced cell proliferation, expression of angiogenic genes and cell migration in com- parison to non-doped glasses [ 131 ]. In a recent study, Deliormanli et al. [ 132 ] synthesized sol – gel-derived 13 – 93 BG doped with Er 2 O 3 (1 – 5 wt.%) and Tb 2 O 3 (1 – 5 wt.%) as well as co-doped BGs (Er 2 O 3 and Tb 2 O 3 from 0.5 to 2.5 wt.%). These BGs were successfully shaped into fi bers via electrospinning. The addition of Er 3 + and/or Tb 3 + to the BG structure has been shown to affect the photoluminescence and decay times of the BG particles and nano fi bers signi fi cantly. Consequently, the authors reported an effect of the BG morphology on the lumines- cence emission intensity and decay kinetics. The BG par- ticles exhibited stronger emission intensity while the electrospun nano fi bers longer decay times. Furthermore, the incorporation of Er 3 + and/or Tb 3 + into 13 – 93 BGs did not have an effect on hydroxyapatite formation after incubation in SBF for 30 days. The results were comparable to non- doped 13 – 93 BG particles and nano fi bers, even at the highest doping concentration. 2.8 Dysprosium (Dy) Dysprosium-containing glasses have been investigated as biodegradable radiation delivery vehicles for the treatment 3 Page 12 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 of rheumatoid arthritis [ 133 ]. Microspheres made of lithium borate glasses-containing dysprosium oxide have been reported in studies of Day et al. [ 133 , 134 ]. Melt-derived microspheres of composition 30 Dy 2 O 3 , 8.8 Li 2 O, and 61.2 B 2 O 3 (in wt.%) have been further processed by a nonuni- form reaction process with phosphate solutions to obtain highly porous dysprosium phosphate microspheres suitable for controlled delivery of drugs and radiation therapy. Moreover, P ă tca ş et al. [ 135 ] investigated the structural changes of sol – gel silicate glasses containing dysprosium and iron after different thermal treatments (composition: 50 SiO 2 , 30 CaO, 10 Fe 2 O 3 ,10 Dy 2 O 3 in mol%). Glasses treated at 500, 800, and 1200 °C exhibited decreasing sur- face area values at increasing temperature. Furthermore, nanocrystalline magnetite, hematite, and wollastonite pha- ses were detected in the samples treated at 800 and 1200 °C, which could lead to bioactive materials for applications on radiotherapy and hyperthermia. 3 Bioactive glasses doped with other elements Elements belonging to different classi fi cations in the peri- odic table such as alkali metals, transition metals and non- metals have also been incorporated in BGs. Table 2 sum- marizes the glass compositions and applications of the described systems and speci fi c examples are described in the following sections. 3.1 Alkali and alkaline-earth metals 3.1.1 Rubidium (Rb) Rubidium (Rb) is an important element present in human and animal tissues [ 136 ]. It is found in human organs such as the liver, kidneys, cerebrum, cerebellum, heart, pancreas, and spleen [ 137 , 138 ]. The application of Rb-containing BGs has been focused on bone regeneration and wound healing [ 139 – 141 ]. For example, incorporation of 0.5, 1.5, and 2.5 mol% Rb 2 O in bioactive glass nanoparticles (Rb- BGNs) of composition 90 SiO 2 – 10 CaO (mol%) with varying CaO:Rb 2 O ratio was shown to increase the apatite- forming ability in SBF compared to Rb-free BGNs [ 140 ]. The greater ionic radius of Rb (1.48) relative to Ca (0.99) and Si (0.42) contributed to an open silica network structure and accelerated the release of Rb + and Ca 2 + in SBF, leading to a higher apatite deposition rate [ 140 ]. The authors have discovered that varying Rb 2 O content had no signi fi cant effect on morphology, scale, shape, chemical composition, and structure of the sol – gel-derived BG [ 142 ]. Similarly, Rubidium-containing mesoporous bioactive glasses (Rb- MBGs) shaped into scaffolds (80 SiO 2 – (15- x ) CaO – 5 P 2 O 5 – x Rb 2 Owith x = 0, 1, 2, and 5 in mol%) were shown to exhibit enhanced bioactivity and promoted osteogenesis and angiogenesis [ 142 ]. Biomimetic surface mineralization of Rb-MBG scaffolds was assessed in SBF immersion resulting in the formation of a nanostructured apatite phase on the surface upon contact with SBF for 3 days. In terms of proliferation and osteogenic differentiation of human mesenchymal stem cells, the ALP activity and expression of COL-1, VEGF HIF-1 α , and Wnt/ß-catenin signaling, sig- ni fi cantly increased with Rb addition compared to Rb-free MBG scaffolds [ 142 ]. Similarly, the antibiotic enoxacin (ENX) was loaded into Rb-MBG scaffolds to explore the ability of the constructs to act as drug delivery carriers and speci fi cally to provide antibacterial effect [ 142 ]. It was found that 5 mol% Rb-doped MBG (5Rb-MBG) scaffolds and ENX-loaded 5Rb-MBG scaffolds reduced the viability of Escherichia coli and S. aureus compared to bare MBG scaffolds [ 142 ]. Rb-doped bioactive glass nanospheres (Rb- BGNs) for skin regeneration and wound healing applica- tions have been examined as alternative biomaterials for soft tissue regeneration [ 58 ]. He et al. [ 141 ] reported that BGNs with Rb content greater than 3 mol% were toxic to HUVECs, fi broblasts, and HaCaTs cells, while BGNs with Rb contents less than or equal to 3 mol% were nontoxic to the same cells. Interestingly, the ionic dissolution products of Rb-BGNs stimulated vascular tubule formation in contact with HUVECs through angiogenesis-related gene expres- sions such as HIF-1 α and VEGF, aided by growth- promoting molecules, for instance TGF- β 1, FGF2, PDGF, and EGF, as well as by triggering the ERK and P38 signaling pathways [ 141 ]. In vivo studies revealed that Rb-BGNs loaded with EGF accelerated wound healing of rats and have potential as endothelial growth factor trans- port vehicles with high bioactivity [ 141 ]. 3.1.2 Barium (Ba) Barium is a trace element found in the human body (22 mg in a 70 kg adult) [ 143 ]. Most Ba is found in bones and smaller amounts are present in muscle, skin, connective tissue, and lungs. Similar to other elements, barium can enter the body through the air, food, and drinking water containing this element; however, the quantity of Ba in food and water is generally insuf fi cient to cause health problems [ 143 ]. Dietary barium intake for adults has been reported in the range of 0.4 – 1.8 mg/day and exposure to 3 – 4 g of Ba has been found toxic [ 144 ]. Clinically, barium sulfate is used in screening treatments and x-ray images [ 144 ] and in the last years, it has been considered as a therapeutic ion since it has shown stimulative effects on bioactivity, anti- bacterial, and anti-in fl ammatory properties in BGs [ 9 , 63 , 87 , 145 – 158 ]. Majumdar et al. [ 9 ] synthesized nanoparticles of Ba-doped bioactive glass with composition Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 13 of 41 3 44.85 SiO 2 – 2.6 P 2 O 5 – 24.3 Na 2 O – 26.9 CaO – 1.35 BaO (mol %) by sol – gel process. XRD analysis con fi rmed the amor- phous nature of the bioactive glass containing BaO. Ba 2 + doping showed a positive effect on the bioactive behavior exhibiting the formation of HCA after immersion in SBF for 1 day. It was reported that Ba 2 + (radius = 135 pm) replaced Ca 2 + (radius = 100 pm) in the glass network, causing the glass network to become less rigid, resulting in a higher dissolution rate and faster ion release, enhancing bioactivity through the formation of hydroxyapatite. The cytocompatibility of Ba-containing BG and 45S5 BG as control was assessed using glioblastoma (C6 cells) and granulocytic 466 origin (K562) cells. Both Ba-containing BG and 45S5 BG enhanced proliferation in both cell lines without causing cytotoxicity. Moreover, in the same study, the ability of Ba 2 + to prevent the lipopolysaccharide- induced ampli fi cation of interleukin-6 (IL-6), tumor necro- sis factor- α (TNF- α ), and interleukin-10 (IL-10) was eval- uated indicating the anti-in fl ammatory effect of this ion [ 9 ]. In another approach, Paliwal et al. [ 159 ] synthesized melt- derived Ba-doped 45S5 BGs (1.3 BaO mol%) and evaluated their effect on gastro-duodenal ulcers. After soaking in SBF on days 6 and 7, Ba-doped BGs exhibited higher pH values than 45S5 BG, indicating that Ba-containing BGs may have an enhanced antacid-like effect over 45S5 BG. In an in vivo study using a rat model, gastric ulcers were induced by various ulcerogens such as ethanol, aspirin, pyloric ligation, and acetic acid, besides duodenal ulcers were induced by cysteamine. BGs were suspended and administered at dose levels of 0.3, 1.0, and 3 mg/kg. The results of the study revealed that Ba-BGs enhanced cell proliferation in the pyloric-induced gastric model and produced a protective layer on gastric and duodenum epithelium in the ethanol- induced gastric ulcer model. Furthermore, it was concluded that Ba-45S5 BGs in the dose of 3 mg/kg prevented and healed gastric-duodenal ulcers induced by different ulcero- gens [ 159 ]. For cancer hyperthermia applications, the combination of magnetic properties and bioactive behavior of Ba-containing BGs is gaining attention. Yazdanpanah et al. [ 154 ] investigated a CaO – P 2 O 5 – SiO 2 – BaO – Fe 2 O magnetic sol – gel-derived BG system. Apatite layer deposition on the glass surface was in fl uenced by the addition of Ba and Fe to the glass composition (0 – 10 mol% of BaO and 0 – 15 mol% of Fe 2 O 3 ). Bioactivity improved when BaO content increased; however, it declined as Fe concentrations increased. In addition, the Ba-containing BG was nontoxic to L929 mouse fi broblast cells. In another application, Zakaly et al. [ 160 ] investigated the nuclear radiation attenuation features of borosilicate glasses doped with barium as radiation shielding material. The melt- quenching technique was used to produce BGs with base composition: 50 B 2 O 3 – 20 NaO – 15 SiO 2 – 10 CaO – 5Al 2 O 3 (in wt.%) and increasing BaO content; from 0 to 30 wt.%. The density and hardness improved with increasing BaO content. XRD analysis con fi rmed that the incorporation of BaO did not affect the amorphous structure of the glasses. Furthermore, speci fi c material features such as mass attenuation coef fi cient (MAC), linear attenuation coef fi cient (LAC), mean free path ( λ ), and half-value layer (X1/2) can be used to study the effective radiation shielding of mate- rials. When 30 wt.% BaO was incorporated in the glass, the glass density increased (from 2.673 to 3.652 g/cm 3 ) result- ing in lower λ and X1/2 values, as well as higher MAC and LAC, indicating that there was a superior gamma shielding and enhanced transmission and optical bandgap. High- density glasses resulted in higher effective shielding than low-density glasses [ 160 ]. 3.2 Transition metals 3.2.1 Tantalum (Ta) Ta has been known as a biocompatible metal with superior properties in terms of corrosion resistance and bioactivity, consequently it has been considered for surgical implants [ 161 ]. The addition of tantalum to bioactive glasses has been reported in different investigations [ 151 , 162 – 172 ]. Silicate bioactive glasses produced by sol – gel in the system 58 SiO 2 – 37 CaO – 5P 2 O 5 (mol%) doped with 0.2 – 1mol% tantalum pentoxide (Ta 2 O 5 ) revealed a rapid in vitro acel- lular HCA deposition (6 h) after soaking in SBF. Doping with tantalum improved the ability of glasses to develop apatite-like structures at concentrations 0.2 – 0.6 mol%, but a retarding effect at higher Ta concentrations (0.8, and 1 Ta mol%.) was found. These glasses also showed an anti- bacterial effect against S. aureus and E. coli ;theseprop- erties make Ta a promising therapeutic dopant in bioactive glasses for bone tissue engineering [ 173 ]. Nagrath et al. [ 162 ] reported the hemostatic properties of Ta-doped MBGs of composition 80 SiO 2 – 15 CaO – 5P 2 O 5 (mol%), in which various Ta 2 O 5 concentrations were analyzed from 0 to 10 mol%. Ta supplementation showed hemostatic potential due to its negative zeta potential ( – 23 to – 31 mv), which enhanced the intrinsic mechanism of blood plasma coagulation and promoted hemostasis by decreasing the active partial thromboplastin and prothrombin times. According to cytotoxicity evaluation, Ta-MBGs (Ta con- centration of 0, 0.5, 1, and 5 mol%) did not have a negative effect on the viability of bovine fi broblast cells [ 162 ]. Moreover, the in vitro bioactivity and cytocompatibility of Ta-doped borosilicate BGs have also been reported [ 174 ], concluding that the addition of Ta from 0.5 to 3 mol% in borosilicate BGs had an in fl uence on the bioactive beha- vior, resulting in lower bioactivity for higher concentra- tions of Ta (3 mol%), without affecting cell viability (MG 63 cells). 3 Page 14 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 3.2.2 Zirconium (Zr) Zirconium as zirconium oxide has been used in the bio- medical fi eld for dental [ 175 ] and bone implants due to its superior mechanical properties and cytocompatibility [ 176 – 195 ]. Enhancement in mechanical stability and hydroxyapatite formation in silicate, borate, and phos- phate bioactive glasses has been observed by incorpor- ating zirconium [ 183 , 196 – 198 ]. Yadav et al. [ 197 ] reported that the addition of zirconium (up to 2.0 wt.%) in 13 – 93 bioactive glass resulted in a signi fi cantly faster dissolution rate and a higher pH of SBF solution depen- dent on the zirconium concentration. In order to facilitate bone tissue engineering, suitable mechanical properties of the scaffold materials are important. As reported by Kumar et al. [ 183 ], compressive strength values increased from 10 ± 2 to 19 + 2MPawhenZrO 2 nanoparticle con- tent was increased from 0 to 0.2 g in 56 SiO 2 – 34 CaO – 10 P 2 O 5 (mol%) bioactive glass scaffolds, leading to the formation of ZrSiO, ZrSiO 4 ,Zr 2 O(PO 4 ), and Ca(ZrO 3 ) crystalline phases. These values are comparable to the compressive strength of human cancellous bone, which ranges from 1.5 to 45 MPa [ 199 ]. By raising ZrO 2 con- centration to 5 wt.%, the microhardness of melt-derived borosilicate bioactive glass (31 B 2 O 3 – 20 SiO 2 – 24.5 Na 2 O – 24.5 CaO mol%) improved from 5.45 to 6.17 GPs, while the apatite-formation ability decreased [ 188 ]. ZrO 2 has been shown to display strong antibacterial properties. According to Kumar et al. [ 183 ], Zr-BG scaffolds showed antibacterial activity against S. aureus , E. coli ,and Pseudomonas aeruginosa , but only a weak effect on Bacillus subtilis . The biological behavior of Zr-containing 3D scaffolds with composition 60 SiO 2 – 36 CaO – 4P 2 O 5 mol% (58S BG) was investigated by Moghanian et al. [ 198 ]. After incubation for 7 and 14 days, 3D-porous 58S BG scaffolds containing 0 – 10 mol% ZrO 2 stimulated MC3T3-E1 cell adhesion on the scaffold and enhanced cell proliferation at more prolonged periods of incubation. The ALP activity of MC3T3-E1 cells increased with the presence of ZrO 2 in the 58BG scaffold at all time points. Interestingly, the glass containing 5 mol% Zr showed the highest ALP activity compared to the other BGs [ 198 ]. The non-cytotoxic effect of zirconium-doped bioactive glass (5 – 15 wt.% of nano ZrO 2 powder) as thin fi lm coatings on Cp-Ti substrates has also been investigated on MG 63 osteoblast cells [ 200 ]. Moreover, a recent study reported the advantages of 13 – 93 bioactive glass doped with zirconium (2 mol%) and silver oxide. Co-doping withZrandAgin13 – 93 BG improved cytocompatibility of U2OS cells, antibacterial effects against B. subtilis and E. coli , and led to mechanical properties enhancement in terms of compression strength, elastic modulus, and fl exural strength [ 201 ]. 3.2.3 Niobium (Nb) Therapeutic niobium ions have been shown to play an in fl uencing role in bioactivity, biocompatibility, and mechanical properties of bioactive glasses and bioceramics for regenerating bone tissue [ 202 – 228 ]. Bioactive bor- osilicate glass (31 B 2 O 3 – 20 SiO 2 – 24.5 Na 2 O – 24.5 CaO mol %) doped with niobium (Nb-borosilicate BG) has shown in vitro bioactivity in terms of hydroxyapatite forming ability when soaked in SBF solution after 7 days, exhibiting no cytotoxic effect on MG 63 cells. The ability to form an apatite layer and support cell viability was unaffected by different concentrations of Nb 2 O 5 (0 – 10 mol%) [ 229 ]. Nevertheless, the bioactivity of Nb-doped BG needs further investigation. Lopes et al. [ 230 ] investigated 45S5 BG with 2.5 and 5 mol% concentrations of Nb 2 O 5 , which showed a delayed formation of HCA on the BG surface compared to both 45S5 BG and 1 mol% Nb 2 O 5 -doped 45S5 BG. The presence of niobium in bioactive glasses could also promote osteogenic and angiogenic properties. In vitro cell studies have shown the cytocompatibility, osteostimulation, and osteoinduction of Nb-doped 45S5 BG [ 230 ]. In this study, Nb-substituted glasses had no negative effect on bone marrow-derived mesenchymal stem cells (BMSCs). Moreover, osteogenic differentiation of BMSCs was induced at concentrations of 1 and 2.5 mol% Nb 2 O 5 in 45S5 BG after 21 days using a glass concentration of 10 mg/ml [ 230 ]. In similar research, Miguez-Pacheco et al. [ 231 ] observed the in vitro behavior of ST-2 cells in RPMI medium exposed to extracts of 45S5 BG containing Nb 2 O 5 (0 – 1 mol%) powders. The results showed that the higher tested concentration of 10 mg/ml was toxic to cells, while 1 and 0.1 mg/ml concentrations did not show a negative effect on cells. When compared to undoped 45S5 BG, different Nb contents did not show signi fi cant effects on cell viability at low concentrations (0.1 and 1 mg/ml). On the other hand, at lower concentrations, there was a signi fi cant release of VEGF from ST-2 cells, indicating the potential angiogenic effect of Nb-BG. Furthermore, in vivo studies [ 232 – 234 ] showed the osteoestimulative potential of Nb-doped bioactive glass for bone replacement. Figure 4 illustrates the subperiosteal bone region growth promoted by Nb-45S5 BG (46.1 SiO 2 – 26.9 CaO – 24.4 Na 2 O – 1.3 P 2 O 5 – 1.3 Nb 2 O 5 mol.%) cylindrical rods after 28 days of implantation into a defect in rat calvaria with dimensions of 4 mm length and 2 mm diameter [ 232 ]. Similarly, Fig. 5 shows fully bone regeneration in a 5 mm rat calvarial defect after 8 weeks of implantation. In this study, a higher amount of Nb com- pared to the previous investigation was used (2.6 Nb 2 O 5 ) [ 233 ]. Phosphate-based glasses-containing Nb have also been reported by Obata et al. [ 235 , 236 ]. The biological properties of Nb-containing phosphate BGs (3 and 5 mol% Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 15 of 41 3 Nb 2 O 5 in the composition 60 CaO – 30 P 2 O 5 – 10 Na 2 Oin mol%) demonstrated higher ALP activity for Nb-BGs compared to Nb-free phosphate BG as well as an in fl uen- cing effect on differentiation and mineralization dependent on Nb concentration [ 236 ]. The incorporation of higher amounts of Nb 2 O 5 (0 – 60 mol%) in phosphate glasses has also been investigated [ 237 ]. Lima et al. [ 219 ] studied in vivo the effect of 30 mol% Nb 2 O 5 in the system P 2 O 5 – BaO – K 2 O after the implantation of granules in a rat model. After 3 and 9 weeks of implantation the authors reported blood vessel formation and no fi brous capsules around the granules. 3.2.4 Chromium (Cr) Chromium is one of the essential elements in the human body. It has a biological role that in fl uences the activity of insulin receptors [ 238 ]. Furthermore, chromium is one of the major trace elements regulating blood sugar and lipid levels in the body [ 239 ]. Recent reports indicate that an intake of 120 μ g of chromium per day is suf fi cient for adults to preserve their health [ 240 ]. Toxic daily doses exceed 200 μ g[ 240 ]. In bioactive glasses and bioceramics, chro- mium has shown promising effects by enhancing bioactiv- ity, antibacterial activity, and degradation properties [ 241 ]. Krishnamacharyulu et al. [ 241 ] investigated a chromium- doped calcium borosilicate glass produced via the conventional melt-quenching method with composition 43 B 2 O 3 – 5 SiO 2 – 2P 2 O 5 – 20 Na 2 O – 20 CaO (mol%). Varying concentrations of chromium oxide, ranging from 0 to 1 mol %, were incorporated in the BG. It was reported that the presence of Cr 2 O 3 as a network modi fi er changed the structure of the glass by breaking the network bonds and causing the formation of non-bridging oxygen. Further- more, the increment of Cr 2 O 3 concentrations enhanced chromium ions transfer from tetrahedral chromates (CrO 4 2 – ) to octahedral chromates (CrO 6 ), reducing the glass strength. The degradation rate of the glass in SBF increased for higher contents of Cr 2 O 3 due to octahedral chromates positions. The substitution of Cr 2 O 3 with CaO led to apatite formation in SBF solution after 28 days. Furthermore, the intensity of the XRD peak corresponding to HA increased as the Cr 2 O 3 concentration increased. Hence, with an increase in the Cr 2 O 3 content, the BG exhibited a superior bioactive behavior. The authors concluded that a high concentration of Cr 2 O 3 (1 mol%) promoted greater BG degradation and in vitro bioactivity. 3.2.5 Molybdenum (Mo) Molybdenum is a trace element required for several enzymes such as xanthine oxidoreductase, sul fi te oxidase, and mito- chondrial amidoxime reductase, being important for the meta- bolism of purines, sulfur-containing aminoacids, conversion of Fig. 4 In vivo implantation of Nb-containing 45S5 BG rods: a sub- periosteal new bone formation in rat tibia tissue defect after 28 days of implantation, hematoxylin & eosin staining, b growth area of subperiosteal bone in rats treated at different times [ 232 ]. Reproduced according to Creative Commons license (CC BY 4.0) 3 Page 16 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 aldehides to acids, protein synthesis stimulation, and body growth [ 242 – 245 ]. In the human body, molybdenum is found primarily in the adrenal glands, bones, liver, and kidneys [ 246 ]. For biomedical applications, Mo-containing biomaterials are attracting attention due to th eir antibacterial and antic- ancerogenic properties [ 245 , 247 – 254 ].AccordingtoPonta et al. [ 255 ], Mo-containing sol – gel derived SiO 2 – CaO – P 2 O 5 BGs have potential for applications in bone tissue engineering by stimulating in vitro apatite formation in SBF solution after 10 days. MoO 3 in the range of 3 – 10 mol% has been added and the in fl uence of Mo on bioactivity and biocompatibility of the BGs was investigated. XRD patterns of Mo-doped BG cal- cined at 600 °C con fi rmed the presence of hydroxyapatite and calcium molybdate (CaMoO 4 ) nanocrystals. Moreover, in vitro biological assays indicated that crystalline CaMoO 4 phases led to improved biocompatibility by increasing adsorption of bovine serum albumin withou t hindering the formation of hydroxyapatite. The authors concluded that a 5 mol% MoO 3 substitution resulted in enhanced bioactivity and biocompat- ibility [ 255 ]. Similarly, Dang et al. [ 256 ] investigated the Fig. 5 Microcomputed tomography images showing bone regeneration in a 5-mm critical-size defect in rat calvaria after 56 days [ 233 ]. Reproduced with permission from John Wiley and Sons Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 17 of 41 3 in fl uence of MoO 3 on bioactive glass-ceramic (Mo-BGC) scaffolds for bone/interface app lications using silicate glasses of composition 70 SiO 2 – 25 CaO – 5P 2 O (mol%) with 2, 5, and 7.5 mol% of MoO 3 substituted for CaO. The sol – gel method and 3D printing technology were used to fabricate the Mo- BGC scaffolds. The fi ndings indicated that the addition of Mo to BGC scaffolds increased the compressive strength due to the formation of CaMoO 4 phase during the calcination process of Mo-BGC powder at 800 °C. In vitro degradation in Tris-HCl buffer solution of Mo-BGC scaffold resulted in a lower weight loss compared to Mo-free scaffolds. Furthermore, the rate of release of Mo ions from the scaffolds was evaluated in Tris- HCl solution for up to 28 days. A gradual release was observed during the incubation time dependent on the Mo concentration. The release pro fi les did not show a fi nal time point; therefore, after 28 days, Mo was still being released from all Mo-doped scaffolds. Moreover, in vitro ce ll experiments demonstrated that crushed scaffolds with 7.5 mol% of MoO 3 at a con- centration of 25 mg/ml increased chondrogenic differentiation of rabbit chondrocytes (RCs) and osteogenic differentiation of hBMSCs at days 3 and 7 when compared to Mo-free BGC. Interestingly, in vivo studies in rabbit osteochondral defects for 8 and 12 weeks showed that BGC scaffolds with 7.5 mol% MoO 3 considerably enhanced car tilage/bone regeneration, demonstrating bi-lineage bioactivity [ 256 ]. Furthermore, Mo- containing phosphate-based gl asses have also been investi- gated. For example, Lucacel et al. [ 257 ] reported the bioactivity and biocompatibility of melt-derived 48 P 2 O 5 – 45 CaO – 5 K 2 O – 2B 2 O 3 (mol%) glass containi ng 1, 3, 5, or 7 mol% of MoO 3 . XRD analysis con fi rmed the amorphous structure of the BGs with different amounts of Mo. The capability of HA formation of the glasses was evaluated in SBF for 15 days. In contrast to the Mo-free glass, no HA crystalline phase on the surface of molybdenum-doped calcium phosphate-based glass was detected, this might be due to the formation of dominant Mo 5 + ionic species on the surface inhibiting the migration of calcium and phosphate ions to the glass surface. Phosphate BGs containing molybdenum at 5 and 7 mol% exhibited bio- compatibility and low toxicity to HaCaT cells [ 257 ]. In drug delivery applications, molybdenum oxide has been used to modify the network of phosphate glasses in order to control the degradation rate. El-Meliegy et al. [ 258 ] investigated melt- derived phosphate glasses (50 P 2 O 5 – 30 CaO – 20 Na 2 O, mol%) incorporating MoO 3 (from 5 to 10 mol%) to tune glass dis- solution and drug release. The dissolution rate in Tris-HCl buffer solution of phosphate glas s-containing molybdenum was lower than the one of the reference phosphate glass without Mo due to the high valence of Mo oxide, which improves the bonding strength in the glass network. The surface of Mo-free phosphate glasses exhibited calcium phosphate deposits after 7 days of immersion in SBF; however, this was not the case for the Mo-doped glasses (5 and 10 mol%). Moreover, Mo- containing BGs have shown lower Vancomycin release rates than Mo-free phosphate glass, which the author s attributed to the hydrogen interactions between the hydroxyl and amino- functional groups in the drug and the hydrated P – O – Hgroups in the phosphate glass network [ 258 ]. 3.2.6 Vanadium (V) Vanadium is a trace element related to nutritional and bio- chemical functions in humans, animals, and plants [ 259 ]. Daily consumption of 10 mg of vanadium per kilogram of body mass has been reported to not have negative effects on human health [ 260 ]. Biological properties of V include the ability to stimulate insulin synthesis and mimic the effects of growth factors and biomarkers for bone-forming cell differentiation [ 259 , 261 ]; therefore, vanadium has been considered in BGs in various studies [ 253 , 262 – 265 ]. Vanadium-containing borate-based bioactive glass (13 – 93B3 with 0.15 – 3 wt.% V) scaffolds have been investigated for bone tissue engineering applications [ 266 ]. Vanadium was reported to act as a network modi fi er in the 13 – 93B3 glass system, leading to a faster degradation in SBF solution under static conditions by inhibiting tetra- hedral BO 4 units formation. Moreover, 3 wt.% V-substituted 13 – 93B3 scaffolds exhibited crystalline HA after 20 days of immersion in SBF [ 266 ]. Similarly, in another study, Marzouk et al. [ 267 ] reported the bioactivity of V-containing borate glass (57.5 B 2 O 3 – 17 CaO – 5.5 Na 2 O – 11 K 2 O – 4.5 MgO – 4.5 P 2 O 5 in wt.% with 0.5 – 1 wt. % V) after immersion in phosphate solution for 14 days. Furthermore, Deliormanli et al. [ 268 ] investigated in vivo the capacity of vanadium incorporated borate-based BG scaffolds for soft tissue applications using a mouse sub- cutaneous implantation set-up. After implantation for 4 weeks, fi brous connective tissue in fi ltrated inside V-containing scaffolds. As the concentration of vanadium increased to 3 wt.%, a reduction of tissue fi ltration was observed. In addition, V-containing scaffolds (3 wt.%) were reported to have a negative effect on angiogenesis by decreasing the vascularization area compared to V-free 13 – 93B3 BG scaffolds. Furthermore, according to a recent study, V-doped borate-based 13 – 93B3 BGs have also shown potential to be used in medical radiation applications and luminescence bioimaging [ 269 , 270 ]. Li et al. [ 271 ] used the hydrothermal synthesis technique to dope MBG in the system SiO 2 – CaO – P 2 O 5 with vana- dium in various concentrations (0, 0.71, 2.78, and 6.67 mol %) with a triblock copolymer (P123) as the structure- directing agent. The aim of the study was to modify the morphology and mesostructure of V-doped MBG to opti- mize the glass dissolution and biological behavior. Vana- dium concentration signi fi cantly in fl uenced the morphology and mesostructure of V-doped MBG. The mesopore size, total pore volume, speci fi c surface area, wall thickness, total 3 Page 18 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 micropore volume, and ordered mesostructure decreased signi fi cantly at increasing V content due to the presence of vanadate anions in solution, that could change the P123 micellization and self-assembly behavior by inducing salting-in and acidity-down effects, as well as three different forms of vanadium species located at the pore walls and/or the surface of the MBG. Clearly, the number of studies on V-containing BGs is very limited and, therefore, the potential biological bene fi ts of V in conjunction with BGs should be further investigated in systematic studies, con- sidering also different silicate glass compositions. 3.2.7 Manganese (Mn) Mn is an essential trace element, which is required for the growth, development, and maintenance of healthy bones; a lack of this element in the pre-natal and early post-natal stages has been reported to cause skeletal abnormalities [ 272 ]. Bioactive glasses containing Mn have been investi- gated due to the properties provided by this ion, such as bioactivity, biocompatibility, and antibacterial effects [ 273 – 281 ]. Miola et al. [ 282 ] reported the incorporation of Mn in a melt-derived silicate BG (45 SiO 2 – 3P 2 O 5 – 26 CaO – 7 MgO – 15 Na 2 O – 4K 2 O) substituting the molar ratio of MgO by MnO in the range of 0.25 – 0.5%. In vitro bioactivity tests in SBF revealed that Mn-doped BG showed HA formation on the surface after 28 days. Moreover, the effect of Mn- doped BG on human MG 63 cells was also evaluated, indicating that 0.25 – 0.5 mol% MnO did not show any toxic effect within 5 days of incubation. Furthermore, Mn 2 + has been shown to promote osteogenic gene expression described by the enhancement in ALP activity, type I col- lagen, osteocalcin, bone morphogenetic proteins, and solu- ble intercellular adhesion molecule-1 (sICAM-1) in osteoblasts. Since Mn-doped BGs have been shown to sti- mulate cell proliferation, cellular differentiation, and bioactivity, they are promising materials for bone tissue regeneration. In a different approach, Cañaveral et al. [ 283 ] investigated Mn-doped 58S sol – gel-based BG in which CaO was replaced by MnO (3 – 5 mol%). After calcination at 700 °C, the presence of Mn 2 + signi fi cantly in fl uenced the structure of 58S BG. XRD analysis revealed the presence of crystalline phases such as Ca 3 Mn 2 Si 3 O 12 , CaSiO 3 -MnSiO 3 , and CaSiO 3 in Mn-doped BG while Mn-free 58S BG exhibited an amorphous structure. However, the crystal- lization of the Mn-doped BG did not have a negative effect on bioactivity since the presence of Mn 2 + increased apatite formation after 2 days in SBF comparable with bare 58S BG. Similarly, Barrioni et al. [ 284 ] doped 58S sol – gel BG with Mn 2 + and evaluated the in fl uence of the doping ion on the osteogenic cell differentiation capability and cytotoxi- city of 58S BG. Interestingly, in contrast to the results previously described, XRD analysis indicated amorphous glasses with and without Mn 2 + from 2.5 to 5 mol%. Fur- thermore, MTT assays con fi rmed that the dissolution pro- ducts of Mn-doped glass (100 – 10,000 μg/ml) were not cytotoxic for osteoblast cells (for 72 h). Moreover, the antibacterial activity against B. subtilis , P. aeruginosa , and S. aureus of sol – gel Mn-doped BG (0 – 7 mol% MnO 2 ) was demonstrated in other studies by Nawaz et al. [ 285 ]. Wes- thauser et al. [ 286 , 287 ] reported the biological evaluation of sol – gel derived mesoporous bioactive glass nanoparticles (MBGNs) doped with 5 mol% MnO 2 . In vitro experiments using BMSCs demonstrated that MBGN with 5 mol% MnO 2 enhanced osteogenic differentiation by upregulating ALP, osteocalcin, osteopontin, and collagen α 1 at a con- centration of 1 mg/ml, although lower cell viability was reported at the same tested concentration. In summary, MBGNs with 5 mol% MnO 2 showed a signi fi cant cytotoxic effect at days 14 and 21. On the other hand, Mn containing MBGN at a concentration of 0.1 mg/ml increased cell via- bility from day 7 and did not show any cytotoxicity effect, demonstrating the dose-dependent effect of this material on cell behavior. Furthermore, phosphate-based BGs prepared via sol – gel synthesis (20 Na 2 O – 15 CaO – 5B 2 O 3 – 5 SiO 2 – 55 P 2 O 5 ) with 0 – 1 mol% of MnO 2 have been reported by Bragiel et al. [ 288 ]. In vitro bioactivity in SBF showed apatite formation on the glass surface after 7 days. A larger radius of Mn 2 + compared to Ca 2 + led to a faster network degradation of Mn-doped glasses, leading to a faster apatite mineralization in SBF. No cell biology studies have been reported on such phosphate Mn-BGs. 3.2.8 Gold (Au) Gold has been incorporated in BGs to explore the enhancement of features for drug delivery, wound healing, photothermal therapy, and bone regeneration [ 289 – 304 ]. Sol – gel BGs doped with gold nanoparticles (AuNPs) (60 SiO 2 – 32 CaO – 8P 2 O 5 mol% with 0 – 0.2 mol% Au 2 O) have been studied by Magyari et al. [ 305 ]. XRD patterns indi- cated Au crystalline phases, while no crystalline peaks were detected in the Au-free BGs. The presence of AuNPs in the BGs signi fi cantly affected the in vitro bioactivity and bio- compatibility. AuNPs-doped BGs exhibited apatite layer formation after immersion in SBF for 7 days. The mor- phology of apatite-like structures on the BGs surface was shown to be dependent on the amount of AuNPs, resulting in both spherical and fl ower-like shapes (0.2 mol% Au 2 O). Furthermore, BGs with 0.15 and 0.2 mol% Au 2 O promoted the proliferation of human keratinocyte cells. Similarly, Grandi et al. [ 306 ] synthesized 58S BG doped with AuNPs (0.1 and 1 wt.%). Interestingly, the antibacterial properties against S. aureus of the reference 58S BG were enhanced by the presence of Au, while no enhancing effect was observed against E. coli . Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 19 of 41 3 3.2.9 Nickel (Ni) Nickel has been incorporated in BGs to improve properties related to radiation attenuation and bone regeneration [ 307 – 312 ]. Vyas et al. [ 313 – 315 ] developed 45S5 BG and 45S5 BG-ceramic (BGC) doped with NiO at different con- centrations ranging from 0.41 to 1.65 mol% via the melt- quenching route. Compared to Ni-free 45S5 BGCs, an increase in density and mechanical properties such as microhardness, compressive, and fl exural strength was observed with increasing NiO concentration [ 313 , 315 ]. The incorporation of Ni did not have an effect on the amorphous structure of 45S5 BG, as well as no additional crystalline phases were observed for the glass-ceramics with nickel, which exhibited crystalline species characteristic of sodium calcium silicate (Na 2 Ca 2 Si 3 O 9 and Na 2 CaSi 3 O 8 ). Further- more, it was reported that the presence of Ni did not in fl uence the bioactive behavior of all tested systems that showed apatite formation after 1 day of immersion in SBF [ 313 , 315 ]. The cytotoxicity of Ni-doped 45S5 BGs to rabbit derived-osteoblast cells was directly tested. An MTT study revealed that Ni-45S5 BGCs (0 – 1.65 mol%) did not show cytotoxic behavior, resulting in higher cell prolifera- tion at 0.82 NiO mol% [ 313 ]. 3.2.10 Palladium (Pd) In the biomedical fi eld, palladium has been used in biosensors [ 316 ] and anti-cancer treatments [ 317 , 318 ]. Wu et al. [ 319 ] investigated the addition of palladium in sol – gel-derived MBG for catalytic applications to oxidize benzyl alcohol and obtain benzaldehyde, a component that is widely used in the food industry and pharmaceutics. The authors reported that by increasing the amount of PdCl 2 above 1.2%, the catalytic activity was reduced, while concentrations between 0.46 and 0.96% led to an ef fi cient catalytic activity. 3.2.11 Tungsten (W) Tungsten has been considered as non-carcinogenic and non- teratogenic, and it does not hold metabolic properties in animals and humans. In addition, under illumination, it exhibits high photocatalytic activity and antimicrobial properties [ 320 ]. Tungsten has gained interest to be incor- porated in bioactive glasses due to the potential radio- contrast properties that can be transferred to the material, for example, to visualize the bone restoration process or as radiation shielding material [ 321 , 322 ]. In this sense, Medkov et al. [ 320 ] developed sol – gel-derived BGs based on the 45S5 composition with WO 3 ranging from 0 to 4 wt. %. At increasing amounts of WO 3 , microcrystals enriched with tungsten and sodium tungstate were detected and increased radiocontrast values from 1.2 to 5.6 mm Al, respectively, which are in the adequate range values for monitoring processes. Furthermore, Deliormanli et al. [ 321 ] investigated the properties of a composite made of the borate 13 – 93B3 bioactive glass (5.5 Na 2 O, 11.1 K 2 O, 4.6 MgO, 18.5 CaO, 3.7 P 2 O 5 , 56.6 B 2 O 3 wt.%) and tungsten disul fi de (0 – 4WS 2 wt.%) for diagnostic imaging and radiotherapy applications. In terms of structure, the addition of WS 2 in the composites resulted in denser materials with the formation of tungsten trioxide phases and enhanced photon attenuation ability. 3.3 Halogens 3.3.1 Chlorine (Cl) One of the essential electrolytes in the human body is chloride. It assists in properly regulating body fl uids and the maintenance of fl uid balance inside, outside or between cells [ 323 ]. Cl has been incorporated in bioactive glasses for application as additives in toothpaste to help prevent tooth hypersensitivity and promote apatite formation [ 324 – 326 ]. Moreover, chloride has been used as an alternative to fl uoride, which has been extensively used in dental appli- cations to prevent caries; however, high content of fl uoride in BGs can lead to crystalline calcium fl uoride instead of fl uorapatite, which might cause dental fl uorosis in children [ 325 , 327 , 328 ]. Highly degradable BGs in the system SiO 2 – P 2 O 5 – CaO – CaCl 2 (with CaCl 2 in the range of 0 – 16.6 mol%) have been produced by Chen et al. [ 327 ] via the melting route. These glasses exhibited the formation of an apatite-like phase within 3 h of immersion in Tris buffer and an increasing degradation rate dependent on the amount of CaCl 2 . Similarly, mixing chloride and fl uoride in a glass composition in the form of CaF 2 and CaCl 2 has also been considered by Chen et al. [ 329 ] by the processing of melt- derived BGs in the system SiO 2 – P 2 O 5 – CaO – CaF 2 /CaCl 2 , with CaF 2 content ranging from 1.5 to 13.4 and CaCl 2 from 2.6 to 21.5 (mol%). It was reported that in terms of struc- tural properties, there was no great difference between the BGs. However, due to the difference in the size of fl uoride and chloride ions, the crystallization tendency was lower for chloride-containing BGs compared to fl uoride BGs. In comparison, a series incorporating both ions resulted in glasses with a stronger crystallization tendency. In terms of material properties, the addition of chloride ions could lead to BGs for applications in mineralizing dental toothpaste or resorbable bone substitutes, although there is still a lack of a comprehensive biological evaluation of such systems. 3.3.2 Iodine (I) Iodine has been considered an essential element in the human body since it is involved in the production, 3 Page 20 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 activation, and metabolism of the thyroid hormone [ 330 ]. The ability of iodine ions to provide borate-based BGs antibacterial properties and promote neuron regeneration has been investigated [ 114 , 331 , 332 ]. Ottomeyer et al. [ 331 ] reported the antibacterial effect against different bacteria of 13 – 93B3 BG doped with 2 wt.% iodine and compared the effect of iodine with that of other dopants such as silver and gallium. The authors reported differences in the bacteria sensitivity with all glass formulations, explained by the distinct mechanisms of the dopant ions. Iodine showed a signi fi cant antibacterial effect against V. natriegens , S. sonnei , S epidermis , and a more negligible effect than undoped 13 – 93B3 BG against E. coli MRSA and M. catarrhalis . The biological impact of iodine-containing BGs has been studied in vitro by Thyparambil et al. [ 114 ] and Gupta et al. [ 332 ]. The addition of 0.1 wt.% of I in the 13 – 93B3 composition led to an increased proliferation and migration capacity of ASC cells, resulting in a bene fi cial approach to stimulate endogenous cells and to accelerate healing processes [ 114 ]. In contrast, 0.2 wt.% of NaI in 13 – 93B3 BGs had a signi fi cant negative effect on neuron survival and regrowth compared to other dopants such as Cu or Ga. 3.4 Other elements 3.4.1 Germanium (Ge) Germanium is a trace element present in plants, animals, and humans [ 333 ]. It has been considered for the treatment of cancer, arthritis, and senile osteoporosis due to the therapeutic attributes such as immune enhancement, oxygen enrichment, and heavy metal detoxi fi cation [ 334 ]. Germanium containing silicate BGs have been investigated for applications as bone fi lling materials [ 335 , 336 ]. Mokhtari et al. [ 336 ] investigated the structural properties of 45S5 BGs containing Zn, Sr, and Ge ions (48 SiO 2 – 6CaO – 8SrO – 36 ZnO – 2P 2 O 5 with 6 and 12 mol% GeO 2 ) to be used as injectable polyalkenoate cement glasses for applications in spinal orthopedic procedures. Amorphous Ge-BGs showed enhanced bioactive behavior compared to the reference glass after immersion in SBF for 4 days, demonstrating that the formation of apatite-like struc- tures was dependent on the amount of GeO 2 .Furthermore,the nuclear radiation shielding beha vior of Ge containing glasses has been studied by Saddeek et al. [ 337 ] using computational tools. Alkaline phosphate glasses in the system P 2 O 5 – Na 2 O – K 2 O – BaO – Al 2 O 3 – Sb 2 O 3 – La 2 O 3 – Nb 2 O 5 – Y 2 O 3 – - Yb 2 O 3 (with 0 – 84 Mol% GeO 2 ) were evaluated in terms of the effect of GeO 2 on the glass mass attenuation parameter and the effective atomic number. Such values resulted increasingly dependent on the amount of GeO 2 and indicated the possible use of these materials for gamm a shielding applications. In addition, there was a mechanical reinforcement effect with the incorporation of Ge, evidenced in the stronger glass network identi fi ed for higher concentrations of germanium oxide. 3.4.2 Bismuth (Bi) Bismuth is a heavy metal ion that possesses antibacterial properties and has been widely used in pharmaceutical applications for the treatment of syphilis, gastrointestinal affections, cancer, and wound infections [ 338 – 340 ]. Aver- age Bi consumption in humans is reported to be between 5 and 20 μg per day [ 341 ]. Bismuth-reinforced BGs have shown potential applications for radiation shielding and bone regeneration [ 63 , 251 , 342 , 343 ]. Bismuth ferrite (BF) has been considered as an effective reinforcement agent in bioactive glasses for stimulating bone tissue formation and accelerating ALP activity [ 344 ]. Under the application of magnetic fi elds of 350 mT during 30 min per day, the in vitro bioactivity and bone mineralization of a BF- containing bioactive glass (BF-BG) facilitated bone like- apatite deposition in SBF after 21 days [ 344 ]. The addition of 2 wt.% BF to BG led to two-fold and three-fold greater ALP activity of MC3T3-E1 cells after 7 and 14 days, respectively, compared to the original glass composition (57 SiO 2 – 10 Na 2 O – 22 CaO – 6P 2 O 5 – 2 TiO 2 – 3Bi 2 O 3 in wt.%) [ 344 ]. Furthermore, Bi-doped phosphosilicate bioactive glasses (Bi-PBGs) have also shown photothermal effects when exposed to an 808 nm laser diode demonstrating the potential effect of killing bone tumor cells and enhancing hydroxyapatite mineralization in SBF solution [ 345 ]. This study reported cell viability higher than 80% for different cell lines, namely, mouse fi broblasts (L929), MC3T3-E1, rat osteosarcoma-derived cells (UMR106), and human osteosarcoma cells (U2OS) [ 345 ]. Prasad et al. [ 346 ] investigated in vitro cell proliferation of mouse fi broblast (NIH3T3) and antibacterial properties of Bi containing S53P4 BG against E. coli . After 11 days, the percentage of cell proliferation exposed to Bi containing S53P4 BG (1 and 2 wt.%) became higher compared to the non-doped S53P4 glass. In terms of antibacterial properties, 1, 2, 4, and 8 wt. %Bi 2 O 3 -containing S53P4 glass demonstrated anti- microbial effect against E. coli with glass powder con- centrations of 100 mg/ml incubated at 37 °C for 1 and 2 h. In addition, bismuth oxide-doped 45S5 BG nanoparticles showed potential properties for applications as dental root canal sealers [ 347 ] and radio-opaque Bi-doped 45S5 BGs produced by pyrolysis of organic solutions have been pro- posed to control the process of bone regeneration [ 168 ]. 3.4.3 Tin (Sn) Tin is a trace micronutrient for living organisms reported to be in lower amounts bene fi cial for cancer treatment [ 348 , 349 ]. A couple of studies have considered the Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 21 of 41 3 incorporation of Sn into the structure of glasses for bio- medical applications [ 350 ]. Recently, Alfadhli et al. [ 350 ] reported the gamma ray interaction parameters of glasses in the system PbCl 2 – SnCl 2 – P 2 O 5 (with SnCl 2 content from 40 to 60 mol%) for applications in nuclear medicine. The BG of composition 35 PbCl 2 – 45 SnCl 2 – 20 P 2 O 5 exhibited the lowest free path, tenth-value layer, and half-value layer showing superior ef fi ciency to absorb gamma rays. 3.4.4 Nitrogen (N) Nitrogen has been reported to enhance the mechanical behavior, antibacterial effect, and the photon attenuation of BGs [ 351 – 354 ]. Bachar et al. [ 355 , 356 ] studied the in fl u- ence of nitrogen on the density, hardness, and elastic modulus of melt-derived BGs (55 SiO 2 – 13.5 CaO – 31.5 Na 2 O, mol.%) at various concentration of Si 3 N 4 from 0 to 4 mol% [ 355 ] and 55 SiO 2 – 8.5 CaO – 31.5 Na 2 O – 5 CaF 2 mol% (with Si 3 N 4 in concentrations of 0 – 4 mol%) [ 356 ]. The incorporated N atoms into the original tetrahedral SiO 4 structure led to a stronger glass network. Consequently, properties such as density, hardness, glass transition tem- perature, and elastic modulus of N-doped BG signi fi cantly increased at higher N concentrations, while the bioactive behavior decreased [ 355 , 357 ]. Similarly, bioactive oxyni- tride glasses (55 SiO 2 – 13.5 CaO – 29 Na 2 O – 2.5 P 2 O 5 mol%) with increasing concentration of Si 3 N 4 (up to 4 mol%) were studied [ 357 ]. In addition to the previously mentioned mechanical properties and bioactivity, these BGs exhibited nontoxic behavior to epithelial cells (L132 cells) at glass powder concentrations of 25 – 400 mg/l. [ 357 ]. Moreover, Marin et al. [ 358 ] investigated in vitro the biological behavior of 45S5 BGs doped with Si 3 N 4 (5 and 10 mol%). The results revealed that the incorporation of Si 3 N 4 into 45S5 BG had a stimulatory effect on the proliferation of SaOS-2 cells and enhanced osteogenic expression for col- lagen, osteocalcin, and osteopontin [ 358 ]. 3.4.5 Tellurium (Te) Tellurium is a trace element found in the human body, mainly in bones (90%), muscles (3%), fat (3%), and liver (1.2%) [ 359 ]. Besides, Te has been used to enhance bio- compatibility [ 360 ], bioactivity [ 361 ], and radiation shielding properties [ 362 , 363 ] of materials for medical applications [ 364 , 365 ]. Damrawi et al. [ 361 ] investigated the bioactivity of tellurite and silicate glass for bioactive implants and dental materials. In vitro bioactivity tests on tellurite glass (50 TeO 2 – 26 Na 2 O – 21 CaO – 3P 2 O 5 mol%) and silicate glass (50 SiO 2 – 26 Na 2 O – 21 CaO – 3P 2 O 5 mol %) demonstrated that TeO 2 led to accelerated hydro- xyapatite nucleation and crystallization compared to the silicate BG after being soaked in SBF for 5 days [ 361 ]. In another research, Miola et al. [ 366 ] investigated the effects of tellurium (0 – 5 mol%) on bioactivity and biolo- gical behavior of BGs in the melt-derived system SiO 2 – Na 2 O – CaO – P 2 O 5 for infection and in fl ammatory response regulation and to improve bone tissue regenera- tion. In terms of structural information, Raman spectra of the BGs indicated that Te-incorporated BGs consist of TeO 4 and TeO 3 structural units. Furthermore, XRD analysis demonstrated that Te had no in fl uence on the amorphous nature of the glasses. The addition of 1 mol% TeO 2 resulted in the precipitation of HCA in SBF after 3 days, whereas 5 mol% Te-containing BG delayed the bioactive behavior in SBF considerably. Compared to Te-free BG, Te-containing glasses demonstrated signi fi cant antibacterial and anti- oxidant effects. Furthermore, the viability of hBMSCs was not negatively affected by the presence of Te in the BGs. Besides, due to tellurium ’ s capacity to prevent the genera- tion of harmful oxygen and nitrogen active species, the metabolic activity of cells in contact with Te-BG under H 2 O 2 stress was also evaluated, demonstrating the protect- ing effect of Te ions to cells. Antibacterial tests revealed that Te-containing glasses had a strong antibacterial effect, inhibiting bio fi lm formation of S. aureus and S. epidermi- dis . After 48 and 72 h inoculation, 5 mol% Te-doped BG had a signi fi cant effect on bio fi lm reduction compared to 1 mol% Te-containing BG [ 366 ]. 3.4.6 Selenium (Se) Selenium is an important element for humans in the form of selenocysteine, which is used in enzyme catalysis [ 367 ]. Se is particularly vital for the brain, since its lack could lead to irreversible brain damage [ 367 ]. In addition, it has been shown that Se intake might be used as a chemopreventive treatment in patients at high risk of pancreatic cancer [ 368 ]. Se-doped BGs have shown signi fi cant properties for radia- tion shielding and bone regeneration applications [ 369 – 373 ]. MBGs (80 SiO 2 – 15 CaO – 5P 2 O 5 in mol%) incor- porating 5 mol% of selenium (Se-MBGs) have been shown to induce in vitro apatite-forming ability (after 1 days immersion in SBF) [ 374 ]. Moreover, Se-MBG was suc- cessfully used as a drug delivery system for bone tissue therapy. Thanks to the higher surface area (242 m 2 /g) compared to MBG without Se dopants (235 m 2 /g), certain oxygen voids and lattice defects caused by the replacement of Si 4 + with Se 6 + allowed Se-MBG to provide a high DOX- loading ef fi ciency (50%) [ 374 ]. The hardness and in vitro biological behavior of selenium oxide-doped 45S5 BG (0.75 – 6 wt.% Se) have been investigated by Karakuzu- Ikizler et al. [ 375 ]. Se incorporation improved the Vickers hardness of the BG. Moreover, cell viability of up to 80% was observed in 45S5 BGs modi fi ed with 0.75, 1.5, 3, and 6 wt.% of SeO 2 after 24 h and 7 days of incubation with 3 Page 22 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 SAOS-2 osteoblast-like cells using extracts concentration of 5 mg/ml [ 375 ]. Besides, compared to 45S5 BG, Se-doped 45S5 BG accelerated the mineralization process in vitro but presented lower APL activity [ 375 ]. Hu et al. [ 376 ] eval- uated the cytotoxic effect of selenium doping in mesopor- ous bioactive glass nanospheres (60 SiO 2 – (36 – x ) CaO – 4 P 2 O 5 – x SeO 2 with x = 0, 1, 3, and 5 in mol%). MG 63 osteosarcoma and MC3T3-E1 preosteoblast cells were incubated for 48 h with Se-MBG supernatants. All the Se- MBG-containing nanospheres were signi fi cantly toxic for MG 63 cells. However, the Se 4 + ion concentrations (0, 1, and 3 in mol%) in MBG nanospheres were nontoxic to MC3T3-E1 cells, while 5 mol% Se (5Se-MBG)-containing nanospheres were signi fi cantly toxic for MC3T3-E1 cells at concentrations higher than 20 μg/ml [ 376 ]. 3Se-MBG and 5Se-MBG nanospheres showed a signi fi cant apoptosis effect on MG 63 cells compared to the control. The Se-free MBG and other Se-MBG nanospheres showed no obvious ability to induce apoptosis [ 376 ]. Alternatively, DOX was successfully loaded into Se-MBG nanospheres to improve the viability of MG 63 cells resulting in slightly higher viability than the positive control (free DOX). Moreover, selenium has shown antibacterial effects. This antibacterial activity has been demonstrated incorporating Se-doped borosilicate glass nanoparticles (80 SiO 2 – 18 B 2 O 3 – 2 SeO 2 mol%) in alginate-agarose polymeric blends designed for wound healing applications. The presence of Se-doped borosilicate glass in the polymer showed a signi fi cant antibacterial effect against S. aureus and Candida albicans compared to only alginate-agarose blend [ 377 ]. 4 Discussion Bioactive glasses are attrac ting considerable attention for regenerative medicine and tissue engineering applications due to their excellent features in te rms of bioactivity, biodegrad- ability [ 378 ], osteogenesis [ 51 ], angiogenesis [ 11 ], antibacterial [ 95 ], anti-in fl ammatory [ 379 ], and immunomodulatory effects [ 380 , 381 ]. The fi eld of ion releasing BGs for biomedical applications has been growing in the last 20 years, and several comprehensive reviews on different aspects of ion releasing BGs for biomedical use are available [ 39 – 41 , 49 , 53 , 54 ]. More recently, BG compositions incorporating exotic ( “ exotic ” in the sense that such ions are not obviously linked to a biomedical use due to a possible biological a ctivity) or less-common ions have started to be investigated. Numerous studies have shown the use of those ions in silicate-based systems; however, pro- gress has also been made in borate and phosphate glasses. The potential application of BGs reli es on their synthesis method, structure, and composition. The incorporation of various ther- apeutic elements into bioactive glasses has the aim to enhance not only the physical and mechanical properties of the material but, specially, to impart additional features such as bioactivity, biodegradability, oste ogenesis, angiogenesi s, and antibacterial properties [ 41 ]. As can be seen in Table 1 , BGs doped with “ less-common ” ions, namely, rare earth elements and other less obvious ions for biomedical use, have been produced by both the conventional melting-quench and sol – gel methods and have been shaped or processed to achieve several morpholo- gies. Mesoporous BGs produced by sol – gel have shown out- standing characteristics to be use dindrugdeliveryapplications [ 53 ]. Furthermore, BGs are used for the production of 3D- porous scaffolds ful fi lling certain properties such as adequate porosity, mechanical stability, pore interconnectivity, and bio- compatibility to facilitate nutrient supply and they can act as suitable signaling templates for bone and soft tissue regenera- tion [ 51 ]. These materials have also been applied as particles or granules to be directly implanted inside a defect [ 382 ]. More- over, BG fi bers can exhibit well-ordered structures (e.g., par- allel fi bers), leading to higher mech anical properties and high bioactivity in SBF [ 383 ] as well as suitable properties for drug delivery [ 59 ]. The ability of BGs to promote the formation of hydro- xyapatite on their surfaces is important as this determines their tissue bonding capability, particularly to hard tissue. The in vitro apatite formation can partially predict the bone formation capacity of doped bioactive glasses. The tun- ability and control of ion release overtime during the dis- solution of BGs have been increasingly investigated to develop bioactive glasses capable of supporting (hard and soft) tissue regeneration by tailored release of biologically active ions. The formation of new bone promoted by BGs can be linked to their chemical durability and dissolution rate in biological fl uids. For example, BGs containing less- common metal ions have gained special attention due to the positive effect of such ions on the material (BG) bioactive character. For example, the substitution of Eu, Sm, Y, La, Rb, Bi, Se, Zr, and Ta has been shown to lower chemical durability, which favors apatite formation when the BGs are immersed in SBF solution. On the other hand, glass dis- solution decreased in the case of Gd-doped bioactive silicate glass in the system SiO 2 – Na 2 O – CaO – P 2 O 5 with 2.5 wt.% Gd 2 O 3 . Still, Gd-doped BGs exhibited high bioactivity after soaking in SBF, indicating that the slow glass dissolution of that particular BG composition had no negative effect on bioactivity in terms of hydroxyapatite formation [ 85 ]. In vitro degradation studies in SBF or Tris-HCl buffer solutions have shown that the incorporation of Ba 2 + ,Cr 3 + (in silicate BGs), and V 5 + (in borate BGs) enhanced the degradation rate of BGs, resulting in superior bioactive behavior. Moreover, increasing concentrations of oxides of Ba (0 – 10 mol% [ 154 ]), Cr (0 – 1 mol% [ 241 ]), and V (0.15 – 3 wt.% [ 266 ]) boosted the crystallization of hydro- xyapatite on BG surfaces. Furthermore, there is no agree- ment in the literature on the effect of Mo oxide on the Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 23 of 41 3 bioactivity of BGs. Ponta et al. [ 255 ] reported that the incorporation of Mo oxide (5 mol%) resulted in a silicate- based BG exhibiting bioactive behavior after 10 days of immersion in SBF; however, Lucacel et al. [ 257 ] and El- Meliegy et al. [ 258 ] reported that BGs containing Mo 6 + (1 – 10 mol% [ 257 , 258 ]) did not induce hydroxyapatite formation after 15 days in SBF. This result was explained by the presence of dominant Mo 5 + ionic species on the surface inhibiting the migration of Ca 2 + and PO 4 3 − groups to the glass surface [ 257 ]. Moreover, the addition of Ba to borosilicate glasses might improve the radiation shielding ability of the materials, described by the fact that increasing amount of BaO in the glass system produces an increase of the glass density resulting in enhanced resistance to gamma radiation [ 160 ]. Materials intended to be implanted in the body or in contact with open wounds must exhibit a number of proper- ties linked to their biocompatible characteristics. Toxic effects can cause harm to the host tissue and should be prevented. The addition of less-common ions, which are not obviously considered for their cell biology activity, must include an assessment of biotolerance as function of concentration. As a result, the possible toxic effects of incorporating different ions in BGs require careful investigation both in vitro and in vivo. In this context, the in fl uence of doping BGs with Eu, Gd, La, Bi, Se, Zr, and Nb on living cells, such as mouse fi broblasts L929 [ 384 ], macrophages (RAW 264.7) [ 69 ], osteoblasts (MC3T3-E1) [ 60 ], BHK fi broblasts [ 118 ], rat osteosarcoma- derived (UMR106) [ 345 ], and human osteosarcoma (U2OS) cells [ 201 ], has been investigated and always an ion dose- dependent response has been found. Results have shown that dissolution products of BGs containing the mentioned ions are nontoxic at low concentrations. Similarly, bioactive glasses with doping ions such as Ba 2 + ,Mo 6 + ,andTe 4 + did not show any cytotoxicity effect on different cell lines, for example, on glioblastoma cells and granulocytic 466 cells (at 1.35 mol% Ba-doped BG) [ 9 ], L929 mouse fi broblast (0 – 10 mol% Ba [ 154 ]), human bone marrow-derived stem cells (0 – 5mol%Te[ 366 ]), as well as RCs and human bone marrow-derived stem cells (7.5 mol% Mo [ 256 ]). Even though progress has been made on investigating cytotoxicity, to the authors ’ knowledge, no speci fi c studies on the cyto- toxicity of Sm-, Y-, Cr-, V-, and Rb-containing bioactive glasses have been reported so far and this is an important aspect that should be investigated in more detail to take advantage of the therapeutic properties that these ions could provide for tissue regeneration. A challenge for tissue engineering is to devise an effective approach to use biomaterials that are not only suitable in terms of mechanical stability (according to the host tissue) but also promote the relevant healing and regenerative processes including angiogenesis as a key requirement for both soft and bone tissue engineering. Adding “ less-common ” ions to BGs is an approach that is becoming highly considered in parallel to the use of the more “ standard ” ions such as Sr, Cu, Zn, Ag, Mg, and Co. For example, the use of Eu, La, and Rb in silicate-based bioactive glasses led to improved osteogenic and angio- genic responses in mouse bone marrow stromal cells, hBMSCs, and endothelial-like cells (HUVECs). Further- more, fi nding the right concentration of doping ions is important to gain information on their toxic levels and also to determine the minimum amount necessary to provide a therapeutic effect. Therefore, in vitro studies have been carried out using different ionic concentrations. For exam- ple, Eu 3 + (in the range of 6.25 – 25 mg/ml) [ 70 ], La 3 + (50 mg/ml) [ 117 ], and Rb + (100 mg/ml) [ 141 ] incorporated in different BGs have been shown to activate the Wnt/ β -catenin, and HIF-1 α signaling pathways to upregulate the secretion of osteogenic genes (RUNX2, ALP, OPN, OSX, and BSP and COL I) as well as the promotion of angiogenic growth factors (b-FGF, VEGF, PDGF and, CD31, PDGFR α / β , VEGFR1/2, and MMP9). High concentrations of doping ions, on the other hand, resulted in being harmful to cells [ 70 ]. Other elements, such as Gd [ 89 , 90 ], Zr [ 198 ], and Nb [ 230 ], have been shown to enhance osteoblast activity when tested in vitro with rBMSCs, MC3T3-E1, and BMSCs cells, respectively. Photoluminescence features of rare earth ions have been investigated in MBG fi bers doped with europium and samarium. These rare earth ion-doped BGs have the potential to be used in bioimaging, for instance, for the in vivo mon- itoring of new bone growth in bone defects [ 70 ]andin applications where monitoring the material degradation is desired [ 96 ] or as drug delivery carriers [ 56 , 58 ]. Furthermore, the inhibitory activity of Eu-doped MBGs on the expression of pro-in fl ammatory factors such as IL-18, IL-6, IL-1, OSM MyD88, Ticam1, TNF- α , and Ticom2 has also been investi- gated [ 69 , 379 ]. Clearly, such ions offer an interesting com- bination of functional properties and biological effects, which cannot be obtained by the classical doping ions. Infection is a major cause of implant failure, being bac- terial adhesion and bio fi lm formation the main causes of infection [ 385 ]. Bioactive glasses doped with metal cations such as rubidium [ 141 ], selenium [ 377 ], and zirconium [ 183 ] have been shown to impart high antibacterial activity against S. aureus , E. coli ,and P. aeruginosa . Likewise, tellurium has been described as a doping ion that promotes antibacterial effects and antioxidant effects on BGs. Antibacterial proper- ties against S. aureus and S. epidermidis have been reported for BGs with high TeO 2 concentrations (5 mol%) [ 361 ]. Furthermore, Rb-doped mesoporous glass scaffolds have been developed as promising templates for drug loading [ 141 ]. Indeed, the long-term consequences of bacterial resistance to antib iotics give future perspectives for the development of new antibiotic-free materials for 3 Page 24 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 Table 3 Effects “ less-common ” ions incorporated in bioactive glasses Ion Effects Ref. Barium Apatite-forming bioactivity [ 9 ] Biocompatible behavior [ 9 ] Anti-in fl ammatory properties [ 9 ] Gamma radiation properties [ 160 ] Increases density transmission and optical bandgap [ 160 ] Bismuth Apatite-forming bioactivity [ 344 ] Increases the expression of ALP [ 344 ] Biocompatible behavior [ 345 ] Antibacterial property against gram-negative bacteria [ 346 ] Chlorine Increases apatite-forming bioactivity [ 324 – 327 ] Decreases glass durability [ 327 ] Chromium Decreases glass durability [ 241 ] Bioactive behavior [ 241 ] Dysprosium Controlling drug release [ 133 ] Europium Photoluminescence properties [ 58 , 59 , 69 , 70 ] Controlling drug release [ 57 – 59 ] Promoting osteogenesis and angiogenesis potential [ 69 ] Increases cell viability [ 57 ] Increases apatite-forming bioactivity [ 60 ] Increases the expression of ALP, COL1, and Runx2 genes and promoted osteogenic differentiation of BMSCs [ 70 ] Decreases glass durability [ 70 ] Gadolinium or Ytterbium or Thulium Increases glass durability [ 85 ] Biocompatible behavior [ 85 ] Promoting proliferation and differentiation of rBMSCs cells and human exfoliated deciduous teeth (SHED) [ 85 , 89 , 90 ] Promoting newly formed bone and collagen deposition in rats, calvarial defect model, after 12 weeks post surgery [ 90 ] Decreases the average particle size [ 91 ] Photoluminescence properties [ 91 ] Germanium Increases apatite-forming bioactivity [ 336 ] Nuclear radiation shielding behaviors [ 337 ] Increase bulk modulus and Young ’ s modulus [ 337 ] Gold Antibacterial property against gram-positive and gram- negative bacteria [ 306 ] Apatite-forming bioactivity [ 305 ] Holmium Promoting preosteoblast cell proliferation [ 78 ] Biocompatible behavior [ 78 ] Bioactive behavior [ 78 , 79 ] Iodine Increases proliferation and migration capacity of ASC cells [ 114 ] Antibacterial properties against V. natriegens , S. sonnei , S epidermis , E. coli MRSA , and M. catarrhalis [ 331 ] Negative effect on neuron survival and regrowth [ 332 ] Lanthanum Decreases polymerizing silica network [ 124 ] Increases compressive strength [ 124 ] Manganese Increases apatite-forming bioactivity [ 282 ] Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 25 of 41 3 Table 3 (continued) Ion Effects Ref. Promoting osteogenic properties in vitro [ 282 ] Biocompatible behavior [ 284 ] Antibacterial properties against gram-positive and gram- negative bacteria [ 285 ] Molybdenum Increases mechanical strength [ 255 ] Biocompatible behavior [ 255 ] Decreases glass durability [ 256 ] Controlling drug release [ 257 ] Nickel Increase density, microhardness compressive strength, and fl exural strength [ 313 – 315 ] Biocompatible behavior [ 314 ] Niobium Increases apatite-forming bioactivity [ 230 ] Biocompatible behavior [ 229 , 230 , 233 ] Increases chemical durability [ 229 ] Increases Vickers microhardness and compressive strength [ 229 ] Promoting osteogenic and osteostimulative properties [ 230 , 232 , 233 ] Nitrogen Increase density, hardness, glass transition temperature, and elastic modulus [ 355 – 357 , 394 ] Biocompatible behavior [ 357 ] Increase osteogenic expression for collagen, osteocalcin, and osteopontin [ 358 ] Palladium High catalytic activity on benzyl alcohol oxidation [ 319 ] Rubidium Biocompatible behavior [ 118 , 123 ] Increases apatite-forming bioactivity [ 346 ] Promoting angiogenesis and osteogenesis of hBMSCs [ 118 ] Antibacterial property against gram-positive and gram- negative bacteria [ 140 , 346 ] Increases density and tensile strength [ 141 , 142 ] Antibacterial properties against gram-negative bacteria [ 346 , 395 ] Samarium Increases density, Young ’ s modulus, bulk modulus, and shear modulus [ 97 ] Increases apatite-forming bioactivity [ 97 , 98 ] Photoluminescence properties [ 93 ] Controlling drug release [ 98 ] Selenium Increases apatite-forming bioactivity [ 375 , 376 , 390 ] Controlling drug release [ 376 ] Increases Vickers microhardness [ 375 ] Biocompatible behavior [ 375 ] Tantalum Increases apatite-forming bioactivity [ 173 ] Antibacterial properties against gram-positive and gram- negative bacteria [ 173 ] Biocompatible behavior [ 162 ] Promoting hemostasis [ 162 ] Tellurium Apatite-forming bioactivity [ 366 ] Antibacterial properties against gram-positive and gram- negative bacteria [ 366 ] Antioxidant properties [ 366 ] Terbium and Erbium Biocompatible behavior [ 59 , 130 ] 3 Page 26 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 use in medicine. Bioactive glasses have great potential in this fi eld, especially when antibacterial ions are incor- porated in the right amount and can be released in a controlled manner represe nting an alternative anti- bacterial technology. In this context, the dual release of antibiotics and antibacterial ions from MBGs is a pow- erful emerging approach, as recently discussed [ 386 ], exploiting synergies that ca n emerge by the simultaneous release of ions and biomolecules. Since bioactive glasses have shown drawbacks in terms of mechanical properties and fracture resistance, research focusing on altern atives to improve such prop- erties is being increasingly carried out. The mechanical strengthofBGscanbetailoredbyadjustingthechemical composition and by induci ng crystallization [ 387 ]. As a result, several ions, includ ing selenium and zirconium, have effectively been incorporated into bioactive glasses to enhance their mechanical properties. The development of new crystalline phases such as ZrSiO, ZrSiO 4 ,Zr 2 O (PO 4 ), and Ca(ZrO 3 ) has been shown to increase the compressive strength of Zr-containing BGs. However, the controlled crystallizatio n of BGs incorporating less- common ions as an strategy to obtain better mechanical properties has not been extensively exploited so far. Based on the results reported in the literature, which have been summarized and discussed in this review, it can be stated that there is still a lack of studies evaluating the long- term performance of BGs incorporating less-common ions, especially with an assessment of their biological behavior in vivo, including long-term studies to assess possible delayed cytotoxic effects of such ions. In addition, more studies need to be carried out considering the applications of ion-doped BGs in the production of 3D constructs and scaffolds since most of the reported studies have considered BGs in particulate form. In comparison to the much higher amount of data on BGs containing “ classical ” ions such as Cu, Sr, B, Li, Mg, K, Co, studies on BGs incorporating “ less- common ” ions discussed in this review are scarce; however, the fi eld is highly promising and is expanding, with new research continuously generating data to complete our understanding about the properties and applications of such BGs. 5 Conclusions According to this literature review, research is increasingly focusing on improving the properties of bioactive glasses by Table 3 (continued) Ion Effects Ref. Photoluminescence properties [ 59 , 396 ] Increases apatite-forming bioactivity [ 59 , 130 , 396 ] Tin High gamma rays ef fi ciency [ 350 ] Tungsten Increases radiocontrast values [ 320 ] Increases density, Vickers microhardness, and compressive strength [ 321 ] Enhancing photon attenuation ability [ 321 ] Vanadium Decreases glass durability [ 266 ] Apatite-forming bioactivity [ 266 ] Photoluminescence properties [ 269 ] Gamma radiation properties [ 270 ] Yttrium Increases glass durability [ 112 , 113 ] Increase apatite-forming bioactivity [ 105 ] Promoting proliferation and migration of adipose stem cells (ASCs) [ 114 ] Zirconium Increases apatite-forming bioactivity [ 175 , 197 ] Decreases glass durability [ 197 ] Decreases polymerizing silica networks [ 197 ] Increases density, Vickers microhardness, compressive strength, and fracture toughness [ 175 , 183 , 197 , 198 ] Antibacterial properties against gram-positive and gram- negative bacteria [ 175 , 198 ] Biocompatible behavior [ 175 ] Promoting proliferation and activity of osteoblast- like cells [ 198 ] Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 27 of 41 3 doping them with less common dopants, including rare-earth elements. The addition of these dopants alters the bioactive glass properties imparting novel functionalities and induces speci fi c biological effects. The use of rare earth elements in bioactive glasses also expands their medical applications, considering the achieved therapeutic effects combined with functional properties (e.g., for imaging applications). In this paper, we have reviewed and discussed current knowledge on the effects of less-common ions on the properties of bioactive glasses, as summarized in Table 3 . We anticipate further expansion of research on this particular class of BGs and propose this review as a timely addition to the literature for the bene fi t of those researchers entering the fi eld. Acknowledgements UP acknowledges the Royal Thai Government scholarship (Ministry of Higher Education, Science, Research and Innovation). Support by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), project number BO1191/26-1, is acknowledged. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Con fl ict of interest The authors declare no competing interests. Publisher ’ s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional af fi liations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article ’ s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article ’ s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/ . References 1. Boccaccini AR, Brauer DS, Hupa L, editors. Bioactive glasses (Smart Materials Series). Cambridge: Royal Society of Chemistry; 2016. p. P001 – 530. https://doi.org/10.1039/9781782622017 . 2. Jones JR. Review of bioactive glass: from hench to hybrids. Acta Biomater. 2013;9:4457 – 86. https://linkinghub.elsevier.com/ retrieve/pii/S1742706112003996 . 3. Kim J-J, El-Fiqi A, Kim H-W. Synergetic cues of bioactive nanoparticles and nano fi brous structure in bone scaffolds to sti- mulate osteogenesis and angiogenesis. ACS Appl Mater Inter- faces. 2017;9:2059 – 73. https://doi.org/10.1021/acsami.6b12089 . 4. Yan L, Li H, Xia W. Bioglass could increase cell membrane fl uidity with ion products to develop its bioactivity. Cell Prolif. 2020;53:1 – 16. https://doi.org/10.1111/cpr.12906 . 5. Saha S, Bhattacharjee A, Rahaman SH, Ray S, Marei MK, Jain H, et al. Prospects of antibacterial bioactive glass nano fi bers for wound healing: an in vitro study. Int J Appl Glas Sci. 2020;11:320 – 8. https://doi.org/10.1111/ijag.15029 . 6. Dai LL, Mei ML, Chu CH, Lo ECM. Antibacterial effect of a new bioactive glass on cariogenic bacteria. Arch Oral Biol. 2020;117:104833. https://doi.org/10.1016/j.archoralbio.2020. 104833 . 7. Zheng K, Dai X, Lu M, Hüser N, Taccardi N, Boccaccini AR. Synthesis of copper-containing bioactive glass nanoparticles using a modi fi ed Stöber method for biomedical applications. Colloids Surf B Biointerfaces. 2017;150:159 – 67. https://doi.org/ 10.1016/j.colsurfb.2016.11.016 . 8. Kargozar S, Montazerian M, Hamzehlou S, Kim H-W, Baino F. Mesoporous bioactive glasses (MBGs): promising platforms for antibacterial strategies Saeid. Acta Biomater. 2018;81:1 – 19. https://doi.org/10.1016/j.actbio.2018.09.052 . 9. Majumdar S, Hira SK, Tripathi H, Kumar AS, Manna PP, Singh SP, et al. Synthesis and characterization of barium-doped bioactive glass with potential anti-in fl ammatory activity. Ceram Int. 2021;47:7143 – 58. https://doi.org/10.1016/j.ceramint.2020. 11.068 . 10. Björkenheim R, Jämsen E, Eriksson E, Uppstu P, Aalto-Setälä L, Hupa L, et al. Sintered S53P4 bioactive glass scaffolds have anti- in fl ammatory properties and stimulate osteogenesis in vitro. Eur Cells Mater. 2021;41:15 – 30. https://www.ecmjournal.org/pa pers/vol041/pdf/v041a02.pdf . 11. Kargozar S, Baino F, Hamzehlou S, Hill RG, Mozafari M. Bioactive glasses: sprouting angiogenesis in tissue engineering. Trends Biotechnol. 2018;36:430 – 44. https://linkinghub.elsevier. com/retrieve/pii/S0167779917303244 . 12. Miguez-Pacheco V, Hench LL, Boccaccini AR. Bioactive glas- ses beyond bone and teeth: emerging applications in contact with soft tissues. Acta Biomater. 2015;13:1 – 15. https://linkinghub. elsevier.com/retrieve/pii/S1742706114004966 . 13. Hench LL, Splinter RJ, Allen WC, Greenlee TK. Bonding mechanisms at the interface of ceramic prosthetic materials. J Biomed Mater Res. 1971;5:117 – 41. 14. Mubina MSK, Shailajha S, Sankaranarayanan R, Saranya L. In vitro bioactivity, mechanical behavior and antibacterial proper- ties of mesoporous SiO2-CaO-Na2O-P2O5 nano bioactive glass ceramics. J Mech Behav Biomed Mater. 2019;100:103379. https://doi.org/10.1016/j.jmbbm.2019.103379 . 15. Balasubramanian P, Büttner T, Miguez Pacheco V, Boccaccini AR. Boron-containing bioactive glasses in bone and soft tissue engineering. J Eur Ceram Soc. 2018;38:855 – 69. https:// linkinghub.elsevier.com/retrieve/pii/S0955221917307409 . 16. Schuhladen K, Wang X, Hupa L, Boccaccini AR. Dissolution of borate and borosilicate bioactive glasses and the in fl uence of ion (Zn, Cu) doping in different solutions. J Non Cryst Solids. 2018;502:22 – 34. https://linkinghub.elsevier.com/retrieve/pii/ S0022309318305003 . 17. Elgayar I, Aliev AE, Boccaccini AR, Hill RG. Structural analysis of bioactive glasses. J Non Cryst Solids. 2005;351:173 – 83. https://linkinghub.elsevier.com/retrieve/pii/ S0022309304004557 . 18. Arango-Ospina M, Hupa L, Boccaccini AR. Bioactivity and dissolution behavior of boron-containing bioactive glasses under static and dynamic conditions in different media. Biomed Glas. 2019;5:124 – 39. https://doi.org/10.1515/bglass-2019-0011/html . 19. Westhauser F, Hohenbild F, Arango-Ospina M, Schmitz SI, Wilkesmann S, Hupa L, et al. Bioactive glass (BG) ICIE16 shows promising osteogenic properties compared to crystallized 45S5-BG. Int J Mol Sci. 2020;21:1639 https://www.mdpi.com/ 1422-0067/21/5/1639https://www.mdpi.com/1422-0067/21/5/ 1639https://www.mdpi.com/1422-0067/21/5/1639 . 3 Page 28 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 20. Brink M, Turunen T, Happonen R-P, Yli-Urpo A. Compositional dependence of bioactivity of glasses in the system Na2O-K2O- MgO-CaO-B2O3-P2O5-SiO2. J Biomed Mater Res. 1997;37:114 – 21. 21. Brink M. The in fl uence of alkali and alkaline earths on the working range for bioactive glasses. J Biomed Mater Res. 1997;36:109 – 17. 22. Deilmann L, Winter O, Cerrutti B, Bradtmüller H, Herzig C, Limbeck A, et al. Effect of boron incorporation on the bioac- tivity, structure, and mechanical properties of ordered mesopor- ous bioactive glasses. J Mater Chem B. 2020;8:1456 – 65. http:// xlink.rsc.org/?DOI = C9TB01805K . 23. Prasad SS, Datta S, Adarsh T, Diwan P, Annapurna K, Kundu B, et al. Effect of boron oxide addition on structural, thermal, in vitro bioactivity and antibacterial properties of bioactive glasses in the base S53P4 composition. J Non Cryst Solids. 2018;498:204 – 15. https://doi.org/10.1016/j.jnoncrysol.2018.06. 027 . 24. Houaoui A, Lyyra I, Agniel R, Pauthe E, Massera J, Boissière M. Dissolution, bioactivity and osteogenic properties of composites based on polymer and silicate or borosilicate bioactive glass. Mater Sci Eng C. 2020;107:110340. https://doi.org/10.1016/j. msec.2019.110340 . 25. Moonesi Rad R, Atila D, Evis Z, Keskin D, Tezcaner A. Development of a novel functionally graded membrane con- taining boron-modi fi ed bioactive glass nanoparticles for guided bone regeneration. J Tissue Eng Regen Med. 2019;13:1331 – 45. https://doi.org/10.1002/term.2877 . 26. Xia L, Ma W, Zhou Y, Gui Z, Yao A, Wang D, et al. Stimulatory effects of boron containing bioactive glass on osteogenesis and angiogenesis of polycaprolactone: in vitro study. Biomed Res Int. 2019;2019:8961409. https://hindawi.com/journals/bmri/ 2019/8961409/ . 27. Chen S, Michálek M, Galusková D, Michálková M, Š vancárek P, Talimian A, et al. Multi-targeted B and Co co-doped 45S5 bioactive glasses with angiogenic potential for bone regenera- tion. Mater Sci Eng C. 2020;112:110909. https://doi.org/10. 1016/j.msec.2020.110909 . 28. Haro Durand LA, Vargas GE, Romero NM, Vera-Mesones R, Porto-López JM, Boccaccini AR, et al. Angiogenic effects of ionic dissolution products released from a boron-doped 45S5 bioactive glass. J Mater Chem B. 2015;3:1142 – 8. http://xlink.rsc. org/?DOI = C4TB01840K . 29. Balasubramanian P, Grünewald A, Detsch R, Hupa L, Jokic B, Tallia F, et al. Ion release, hydroxyapatite conversion, and cytotoxicity of boron-containing bioactive glass scaffolds. Int J Appl Glas Sci 2016;7:206 – 15. https://onlinelibrary.wiley.com/ doi/10.1111/ijag.12206 . 30. Stanic V. Chapter 8 – Boron-containing bioactive glasses for bone regeneration. In: Kaur G, editor. Biomedical, therapeutic and clinical applications of bioactive glasses. Elsevier; 2019. p. 219 – 49. https://linkinghub.elsevier.com/retrieve/pii/B9780081 021965000082 . 31. Lapa A, Cresswell M, Jackson P, Boccaccini AR. Phosphate glass fi bres with therapeutic ions release capability – a review. Adv Appl Ceram. 2020;119:1 – 14. https://doi.org/10.1080/ 17436753.2018.1564413 . 32. Sharmin N, Rudd CD. Structure, thermal properties, dissolution behaviour and biomedical applications of phosphate glasses and fi bres: a review. J Mater Sci. 2017;52:8733 – 60. https://doi.org/ 10.1007/s10853-017-0784-4 . 33. Araujo MS, Silva AC, Bartolomé JF, Mello-Castanho S. Struc- tural and thermal behavior of 45S5 Bioglass ® -based composi- tions containing alumina and strontium. J Am Ceram Soc. 2020;103:3620 – 30. https://doi.org/10.1111/jace.17061 . 34. Yeliz BE, Burcu KI, Serpil KD, Sevil Y, Ismail A. Investigation of alumina doped 45S5 glass as a bioactive fi ller for experimental dental composites. Int J Appl Glas Sci. 2021;12:313 – 27. https:// doi.org/10.1111/ijag.16043 . 35. Dey P, Pal SK, Sarkar R. Effect of alumina addition on 45S5 bioglass. Trans Indian Ceram Soc. 2014;73:105 – 9. https://doi. org/10.1080/0371750X.2014.922423 . 36. Melchers S, Uesbeck T, Winter O, Eckert H, Eder D. Effect of aluminum ion incorporation on the bioactivity and structure in mesoporous bioactive glasses. Chem Mater. 2016;28:3254 – 64. https://doi.org/10.1021/acs.chemmater.5b04117 . 37. Thompson KH. Boon and bane of metal ions in medicine. Sci- ence. 2003;300:936 – 9. https://doi.org/10.1126/science.1083004 . 38. Spadaro JA, Becker RO, Bachman CH. The distribution of trace metal ions in bone and tendon. Calcif Tissue Res. 1970;6:49 – 54. https://doi.org/10.1007/BF02196183 . 39. Rabiee SM, Nazparvar N, Azizian M, Vashaee D, Tayebi L. Effect of ion substitution on properties of bioactive glasses: a review. Ceram Int. 2015;41:7241 – 51. https://doi.org/10.1016/j. ceramint.2015.02.140 . 40. O ’ Neill E, Awale G, Daneshmandi L, Umerah O, Lo KWH. The roles of ions on bone regeneration. Drug Disco Today. 2018;23:879 – 90. https://doi.org/10.1016/j.drudis.2018.01.049 . 41. Hoppe A, Güldal NS, Boccaccini AR. A review of the biological response to ionic dissolution products from bioactive glasses and glass-ceramics. Biomaterials. 2011;32:2757 – 74. https://doi.org/ 10.1016/j.biomaterials.2011.01.004 . 42. Hoppe A, Mouriño V, Boccaccini AR. Therapeutic inorganic ions in bioactive glasses to enhance bone formation and beyond. Biomater Sci. 2013;1:254 – 6. http://xlink.rsc.org/?DOI = C2BM00116K . 43. Kaur G, Pandey OP, Singh K, Homa D, Scott B, Pickrell G. A review of bioactive glasses: their structure, properties, fabrication and apatite formation. J Biomed Mater Res Part A. 2014;102:254 – 74. https://onlinelibrary.wiley.com/doi/10.1002/ jbm.a.34690 . 44. Bohner M, Santoni BLG, Döbelin N. β -tricalcium phosphate for bone substitution: synthesis and properties. Acta Biomater. 2020;113:23 – 41. https://linkinghub.elsevier.com/retrieve/pii/ S1742706120303524 . 45. Adzila S, Murad M, Sopyan I. Doping metal into calcium phosphate phase for better performance of bone implant mate- rials. Recent patents. Mater Sci. 2012;5:18 – 47. https://www. eurekaselect.com/94895/article/doping-metal-calcium-phospha te-phase-better-performance-bone-implant-materials . 46. Laskus A, Kolmas J. Ionic substitutions in non-apatitic calcium phosphates. Int J Mol Sci. 2017;18:2542 http://www.mdpi.com/ 1422-0067/18/12/2542 . 47. Naseri S, Lepry WC, Nazhat SN. Bioactive glasses in wound healing: hope or hype? J Mater Chem B. 2017;5:6167 – 74. http:// xlink.rsc.org/?DOI = C7TB01221G . 48. Westhauser F, Arango-Ospina M, Losch S, Wilkesmann S, Lehner B, Ali MS, et al. Selective and caspase-independent cytotoxicity of bioactive glasses towards giant cell tumor of bone derived neoplastic stromal cells but not to bone marrow derived stromal cells. Biomater. 2021;275:120977 https://linkinghub. elsevier.com/retrieve/pii/S0142961221003331 . 49. Schatkoski VM, Larissa do Amaral Montanheiro T, Canuto de Menezes BR, Pereira RM, Rodrigues KF, Ribas RG, et al. Current advances concerning the most cited metal ions doped bioceramics and silicate-based bioactive glasses for bone tissue engineering. Ceram Int. 2021;47:2999 – 3012. https://linkinghub. elsevier.com/retrieve/pii/S0272884220329175 . 50. Mehrabi T, Mesgar AS, Mohammadi Z. Bioactive glasses: a promising therapeutic ion release strategy for enhancing wound Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 29 of 41 3 healing. ACS Biomater Sci Eng. 2020;6:5399 – 430. https://doi. org/10.1021/acsbiomaterials.0c00528 . 51. El-Rashidy AA, Roether JA, Harhaus L, Kneser U, Boccaccini AR. Regenerating bone with bioactive glass scaffolds: a review of in vivo studies in bone defect models. Acta Biomater. 2017;62:1 – 28. https://doi.org/10.1016/j.actbio.2017.08.030 . 52. Balasubramanian P, Strobel LA, Kneser U, Boccaccini AR. Zinc-containing bioactive glasses for bone regeneration, dental and orthopedic applications. Biomed Glas. 2015;1:51 – 69. https:// doi.org/10.1515/bglass-2015-0006/html . 53. Wu C, Chang J. Multifunctional mesoporous bioactive glasses for effective delivery of therapeutic ions and drug/growth factors. J Control Release. 2014;193:282 – 95. https://doi.org/10.1016/j. jconrel.2014.04.026 . 54. Mouriño V, Vidotto R, Cattalini JP, Boccaccini AR. Enhancing biological activity of bioactive glass scaffolds by inorganic ion delivery for bone tissue engineering. Curr Opin Biomed Eng. 2019;10:23 – 34. https://doi.org/10.1016/j.cobme.2019.02.002 . 55. Koeberl C, Bayer PM. Concentrations of rare earth elements in human brain tissue and kidney stones determined by neutron activation analysis. J Alloy Compd. 1992;180:63 – 70. https:// linkinghub.elsevier.com/retrieve/pii/092583889290363E . 56. Fan Y, Huang S, Jiang J, Li G, Yang P, Lian H, et al. Lumi- nescent, mesoporous, and bioactive europium-doped calcium silicate (MCS: Eu3 + ) as a drug carrier. J Colloid Interface Sci. 2011;357:280 – 5. https://linkinghub.elsevier.com/retrieve/pii/ S0021979711001639 . 57. Zhang Y, Hu M, Wang X, Zhou Z, Liu Y. Design and evaluation of europium containing mesoporous bioactive glass nanospheres: doxorubicin release kinetics and inhibitory effect on osteo- sarcoma MG 63 cells. Nanomaterials. 2018;8:961. http://www. mdpi.com/2079-4991/8/11/961 . 58. Fan Y, Yang P, Huang S, Jiang J, Lian H, Lin J. Luminescent and mesoporous europium-doped bioactive glasses (MBG) as a drug carrier. J Phys Chem C. 2009;113:7826 – 30. https://doi.org/ 10.1021/jp900515x . 59. Huang S, Kang X, Cheng Z, Ma P, Jia Y, Lin J. Electrospinning preparation and drug delivery properties of Eu3 + /Tb3 + doped mesoporous bioactive glass nano fi bers. J Colloid Interface Sci. 2012;387:285 – 91. https://linkinghub.elsevier.com/retrieve/pii/ S002197971200896X . 60. Xue Y, Du Y, Yan J, Liu Z, Ma PX, Chen X, et al. Monodisperse photoluminescent and highly biocompatible bioactive glass nanoparticles for controlled drug delivery and cell imaging. J Mater Chem B. 2015;3:3831 – 9. http://xlink.rsc.org/?DOI = C5TB00204D . 61. Niu W, Guo Y, Xue Y, Wang M, Chen M, Winston DD, et al. Biodegradable multifunctional bioactive Eu-Gd-Si-Ca glass nanoplatform for integrative imaging-targeted tumor therapy- recurrence inhibition-tissue repair. Nano Today. 2021;38:101137 https://linkinghub.elsevier.com/retrieve/pii/ S1748013221000621 . 62. Chen M, Wang M, Niu W, Cheng W, Guo Y, Wang Y, et al. Multifunctional protein-decorated bioactive glass nanoparticles for tumor-speci fi c therapy and bioimaging in vitro and in vivo. ACS Appl Mater Interfaces. 2021;13:14985 – 94. https://pubs.acs. org/doi/abs/10.1021/acsami.1c01337 . 63. Divina R, Naseer KA, Marimuthu K, Alajerami YSM, Al-Bur- iahi MS. Effect of different modi fi er oxides on the synthesis, structural, optical, and gamma/beta shielding properties of bis- muth lead borate glasses doped with europium. J Mater Sci Mater Electron. 2020;31:21486 – 501. https://doi.org/10.1007/ s10854-020-04662-3 . 64. Miao G, Chen X, Mao C, Li X, Li Y, Lin C. Synthesis and characterization of europium-containing luminescent bioactive glasses and evaluation of in vitro bioactivity and cytotoxicity. J Sol-Gel Sci Technol. 2014;69:250 – 9. https://doi.org/10.1007/ s10971-013-3209-0 . 65. Srinivasa Rao C, Upendra Kumar K, Jayasankar CK. Lumines- cence properties of Eu3 + ions in phosphate-based bioactive glasses. Solid State Sci. 2011;13:1309 – 14. https://doi.org/10. 1016/j.solidstatesciences.2011.03.027 . 66. Krebs JK, Brownstein JM. Site-selective spectroscopy of Eu3 + in bioactive glass. J Lumin. 2007;124:257 – 9. https://linkinghub. elsevier.com/retrieve/pii/S002223130600442X . 67. Krebs JK, Brownstein JM, Gibides JT. Decay dynamics of europium excited states in bioactive glasses. J Lumin. 2008;128:780 – 2. https://linkinghub.elsevier.com/retrieve/pii/ S0022231307004656 . 68. Zaki RM, Strutynski C, Kaser S, Bernard D, Hauss G, Faessel M, et al. Direct 3D-printing of phosphate glass by fused deposition modeling. Mater Des. 2020;194:108957. https:// linkinghub.elsevier.com/retrieve/pii/S0264127520304913 . 69. Shi M, Xia L, Chen Z, Lv F, Zhu H, Wei F, et al. Europium- doped mesoporous silica nanosphere as an immune-modulating osteogenesis/angiogenesis agent. Biomaterials 2017;144:176 – 87. https://doi.org/10.1016/j.biomaterials.2017.08.027 . 70. Wu C, Xia L, Han P, Mao L, Wang J, Zhai D, et al. Europium- containing mesoporous bioactive glass scaffolds for stimulating in vitro and in vivo osteogenesis. ACS Appl Mater Interfaces. 2016;8:11342 – 54. https://pubs.acs.org/doi/10.1021/acsami. 6b03100 . 71. Baranowska A, Lesniak M, Kochanowicz M, Zmojda J, Miluski P, Dorosz D. Crystallization kinetics and structural properties of the 45S5 bioactive glass and glass-ceramic fi ber doped with Eu3 + . Materials (Basel) 2020;13:1281. https://pubmed.ncbi.nlm.nih. gov/32178342/ . 72. Borak B, Krzak J, Ptak M, Strek W, Lukowiak A. Spherical nanoparticles of europium-doped silica – calcia glass and glass- ceramic: spectroscopic characterization. J Mol Struct. 2018;1166:48 – 53. https://linkinghub.elsevier.com/retrieve/pii/ S0022286018304502 . 73. Li F, Wang M, Pi G, Lei B. Europium doped monodispersed bioactive glass nanoparticles regulate the osteogenic differ- entiation of human marrow mesenchymal stem cells. J Biomed Nanotechnol. 2018;14:756 – 64. http://www.ingentaconnect.com/ content/10.1166/jbn.2018.2504 . 74. Li G, Liang G, Zhao S, Ma K, Feng W, Zhou D, et al. Synthesis and characterisation of porous luminescent glass ceramic scaf- folds containing europium for bone tissue engineering. Adv Appl Ceram 2015;114:164 – 74. https://www.tandfonline.com/doi/abs/ 10.1179/1743676114Y.0000000210 . 75. Rim KT, Koo KH, Park JS. Toxicological evaluations of rare earths and their health impacts to workers: a literature review. Saf Health Work. 2013;4:12 – 26. https://doi.org/10.5491/SHAW. 2013.4.1.12 . 76. Poniedzialek B, Rzymski P, Piet M, Niedzielski P, Mleczek M, Wilczak M, et al. Rare-earth elements in human colostrum milk. Environ Sci Pollut Res. 2017;24:26148 – 54. http://link.springer. com/10.1007/s11356-017-0359-6 . 77. Nogueira LB, Campos TPR. Synthesis, chemical characterization and radiological response of Ho and HoZr bioglass seeds. J Sol- Gel Sci Technol. 2016;77:688 – 98. https://link.springer.com/a rticle/10.1007/s10971-015-3900-4 . 78. Delpino GP, Borges R, Zambanini T, Joca JFS, Gaubeur I, de Souza ACS, et al. Sol-gel-derived 58S bioactive glass containing holmium aiming brachytherapy applications: a dissolution, bioactivity, and cytotoxicity study. Mater Sci Eng C. 2021;119:111595 https://doi.org/10.1016/j.msec.2020.111595 . 79. Zambanini T, Borges R, de Souza ACS, Justo GZ, Machado J, de Araujo DR, et al. Holmium-containing bioactive glasses dispersed in poloxamer 407 hydrogel as a theragenerative 3 Page 30 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 composite for bone cancer treatment. Materials (Basel) 2021;14:1459 https://www.mdpi.com/1996-1944/14/6/1459 . 80. Hosseini SH, Enferadi M, Sadeghi M. Dosimetric aspects of 166Ho brachytherapy biodegradable glass seed. Appl Radiat Isot. 2013;73:109 – 15. https://linkinghub.elsevier.com/retrieve/ pii/S0969804312005830 . 81. Zaichick S, Zaichick V, Karandashev V, Nosenko S. Accumu- lation of rare earth elements in human bone within the lifespan. Metallomics. 2011;3:186 – 94. https://academic.oup.com/meta llomics/article/3/2/186-194/6016253 . 82. Tedeschi E, Caranci F, Giordano F, Angelini V, Cocozza S, Brunetti A. Gadolinium retention in the body: what we know and what we can do. Radio Med. 2017;122:589 – 600. https://doi.org/ 10.1007/s11547-017-0757-3 . 83. Feng L, He X, Xiao H, Li Z, Li F, Liu N, et al. Ytterbium and trace element distribution in brain and organic tissues of off- spring rats after prenatal and postnatal exposure to ytterbium. Biol Trace Elem Res. 2007;117:89 – 104. https://doi.org/10.1007/ BF02698086 . 84. Borges R, Schneider JF, Marchi J. Structural characterization of bioactive glasses containing rare earth elements (Gd and/or Yb). J Mater Sci. 2019;54:11390 – 9. https://doi.org/10.1007/s10853- 019-03715-1 . 85. Zambanini T, Borges R, Faria PC, Delpino GP, Pereira IS, Marques MM, et al. Dissolution, bioactivity behavior, and cytotoxicity of rare earth-containing bioactive glasses (RE = Gd, Yb). Int J Appl Ceram Technol. 2019;16:2028 – 39. https://doi. org/10.1111/ijac.13317 . 86. Borges R, Menezes NDR, Marchi J. The in fl uence of gadolinium on the thermal properties of bioactive glasses. Biomed Glas. 2019;5:193 – 202. https://doaj.org/article/ccdbd47fb35d48c0bfea 69b40a6914ce . 87. Mariselvam K. Gamma-ray interactions with ytterbium ions doped BLFB glasses for shielding applications. Optik. 2021;240:166808. https://linkinghub.elsevier.com/retrieve/pii/ S0030402621005167 . 88. Li X, Li Q, Wang C, Ni J, Zhang M, Chang J, et al. Fabrication and up-conversion fl uorescence property of Er3 + /Yb3 + co- doped Ca-Si-Ti biomaterials. Mater Res Express. 2019;6:045205 https://iopscience.iop.org/article/10.1088/2053-1591/aafb41 . 89. Zhu DY, Lu B, Yin JH, Ke QF, Xu H, Zhang CQ, et al. Gadolinium-doped bioglass scaffolds promote osteogenic dif- ferentiation of hBMSC via the Akt/GSK3 β pathway and facil- itate bone repair in vivo. Int J Nanomed. 2019;14:1085 – 100. https://www.dovepress.com/gadolinium-doped-bioglass-sca ffolds-promote-osteogenic-differentiation-peer-reviewed-article- IJN . 90. Liao F, Peng XY, Yang F, Ke QF, Zhu ZH, Guo YP. Gadoli- nium-doped mesoporous calcium silicate/chitosan scaffolds enhanced bone regeneration ability. Mater Sci Eng C. 2019;104:109999 https://doi.org/10.1016/j.msec.2019.109999 . 91. Halubek-Gluchowska K, Szymanski D, Tran TNL, Ferrari M, Lukowiak A. Upconversion luminescence of silica – calcia nanoparticles Co-doped with Tm3 + and Yb3 + ions. Materials (Basel). 2021;14:937 https://www.mdpi.com/1996-1944/14/4/ 937/htm . 92. Chellan P, Sadler PJ. The elements of life and medicines. Philos Trans R Soc A Math Phys Eng Sci. 2015;373:20140182 https:// doi.org/10.1098/rsta.2014.0182 . 93. Baranowska A, Kochanowicz M, Zmojda J, Miluski P, Wajda A, Lesniak M, et al. Biological properties of rare-earth doped bioactive glass. In: Romaniuk RS, Dorosz J, editors. Optical fi bers and their applications 2020. Bialowieza: SPIE; 2020. p. 10. https://www.spiedigitallibrary.org/conference-proceedings-of- spie/11456/2566347/Biological-properties-of-rare-earth-doped- bioactive-glass/10.1117/12.2566347.full . 94. Roberto WS, Pereira M, Campos TPR. Dosimetric analysis and characterisation of radioactive seeds produced by the sol-gel method. Key Eng Mater. 2003;240 – 242:579 – 82. https://www. scienti fi c.net/KEM.240-242.579 . 95. Roberto WS, Pereira MM, Campos TPR. Structure and dosi- metric analysis of biodegradable glasses for prostate cancer treatment. Artif Organs. 2003;27:432 – 6. https://pubmed.ncbi. nlm.nih.gov/12752203/ . 96. Baranowska A, Kochanowicz M, Dorosz J, Dabrowski JR. Effect of biodegradation on spectroscopic properties of Sm3 + doped 45S5 bioglass. In: Romaniuk RS, Linczuk M, editors. Photonics applications in astronomy, communications, industry, and high- energy physics experiments 2018. Wilga: SPIE; 2018. p. 18. https://www.spiedigitallibrary.org/conference-proceedings-of- spie/10808/2500274/Effect-of-biodegradation-on-spectroscopic- properties-of-Sm3-doped-45S5/10.1117/12.2500274.full . 97. Ershad M, Vyas VK, Prasad S, Ali A, Pyare R. Effect of Sm2O3 substitution on mechanical and biological properties of 45S5 bioactive glass. J Aust Ceram Soc. 2018;54:621 – 30. https://doi. org/10.1007/s41779-018-0190-7 . 98. Zhang Y, Wang X, Su Y, Chen D, Zhong W. A doxorubicin delivery system: Samarium/mesoporous bioactive glass/alginate composite microspheres. Mater Sci Eng C. 2016;67:205 – 13. https://doi.org/10.1016/j.msec.2016.05.019 . 99. Morais DS, Coelho J, Ferraz MP, Gomes PS, Fernandes MH, Hussain NS, et al. Samarium doped glass-reinforced hydro- xyapatite with enhanced osteoblastic performance and anti- bacterial properties for bone tissue regeneration. J Mater Chem B. 2014;2:5872 – 81. http://xlink.rsc.org/?DOI = C4TB00484A . 100. Simon S, Cacaina D, Vasilescu M, Ylänen H, Hupa M. MAS- NMR support for Hench model in the case of bioactive glass microspheres. J Mater Sci. 2017;52:8998 – 9005. https://doi.org/ 10.1007/s10853-017-1058-x . 101. Ben-Arfa BAE, Salvado IMM, Ferreira JMF, Pullar RC. The effect of functional ions (Y3 + ,F − , Ti4 + ) on the structure, sintering and crystallization of diopside-calcium pyrophosphate bioglasses. J Non Cryst Solids. 2016;443:162 – 71. https://doi.org/ 10.1016/j.jnoncrysol.2016.04.028 . 102. Cacaina D, Ylänen H, Udvar DA, Simon S, Kogalniceanu M. EPR study of gamma irradiated yttrium bioactive glasses and yttrium silica sol-gel microspheres. J Optoelectron Adv Mater. 2007;9:675 – 9. https://www.semanticscholar.org/paper/EPR- study-of-gamma-irradiated-yttrium-bioactive-and-Cacaina-Yl% C3%A4nen/3d1d046ad5cff84229996c046891e3adda8f83ed . 103. Cacaina D, Ylänen H, Simon S, Hupa M. The behaviour of selected yttrium containing bioactive glass microspheres in simulated body environments. J Mater Sci Mater Med. 2008;19:1225 – 33. https://pubmed.ncbi.nlm.nih.gov/ 17701304/ . 104. Lee EMR, Borges R, Marchi J, Paula Eduardo C, Marques MM. Bioactive glass and high-intensity lasers as a promising treatment for dentin hypersensitivity: an in vitro study. J Biomed Mater Res Part B Appl Biomater. 2020;108:939 – 47. https://pubmed. ncbi.nlm.nih.gov/31381257/ 105. Hadush Tesfay A, Chou YJ, Tan CY, Fufa Bakare F, Tsou NT, Huang EW, et al. Control of dopant distribution in yttrium-doped bioactive glass for selective internal radiotherapy applications using spray pyrolysis. Materials (Basel). 2019;12:986 https://www.mdpi.com/1996-1944/12/6/986 . 106. Cacaina D, Viitala R, Jokinen M, Ylänen HO, Hupa M, Simon S. In vitro behavior of yttrium silica sol-gel microspheres. Key Eng Mater. 2005;284 – 286:411 – 4. https://www.scienti fi c.net/KEM. 284-286.411 . 107. Vasanthavel S, Meenakshi K, Nivedha V, Ballamurugan AM, Kannan S. Tuning the structural and mechanical properties in ZrO2-SiO2 binary system through Y3 + inclusions. Mater Sci Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 31 of 41 3 Eng C. 2018;84:230 – 5. https://pubmed.ncbi.nlm.nih.gov/ 29519433/ . 108. Placek LM, Keenan TJ, Wren AW. Bioactivity of Y2O3 and CeO2 doped SiO2-SrO-Na2O glass-ceramics. J Biomater Appl. 2016;31:165 – 80. https://pubmed.ncbi.nlm.nih.gov/27231265/ . 109. Farmakis E-TR, Kozyrakis K, Khabbaz MG, Schoop U, Beer F, Moritz A. In vitro evaluation of dentin tubule occlusion by denshield and neodymium-doped yttrium-aluminum-garnet laser irradiation. J Endod. 2012;38:662 – 6. https://pubmed.ncbi.nlm. nih.gov/22515897/ . 110. Christie JK, Tilocca A. Integrating biological activity into radioisotope vectors: molecular dynamics models of yttrium- doped bioactive glasses. J Mater Chem. 2012;22:12023 http:// xlink.rsc.org/?DOI = c2jm31561k . 111. Erbe EM, Day DE. Chemical durability of Y2O3-Al2O3-SiO2 glasses for thein vivo delivery of beta radiation. J Biomed Mater Res. 1993;27:1301 – 8. https://onlinelibrary.wiley.com/doi/10. 1002/jbm.820271010 . 112. Christie JK, Malik J, Tilocca A. Bioactive glasses as potential radioisotope vectors for in situ cancer therapy: investigating the structural effects of yttrium. Phys Chem Chem Phys. 2011;13:17749 http://xlink.rsc.org/?DOI = c1cp21764j . 113. Arafat A, Samad SA, Titman JJ, Lewis AL, Barney ER, Ahmed I. Yttrium doped phosphate-based glasses: structural and degra- dation analyses. Biomed Glas 2020;6:34 – 49. https://www. degruyter.com/document/doi/10.1515/bglass-2020-0004/html . 114. Thyparambil NJ, Gutgesell LC, Hurley CC, Flowers LE, Day DE, Semon JA. Adult stem cell response to doped bioactive borate glass. J Mater Sci Mater Med. 2020;31:13. https://doi.org/ 10.1007/s10856-019-6353-4 . 115. Bronner F. Chapter 25 – Metals in bone: aluminum, boron, cadmium, chromium, lanthanum, lead, silicon, and strontium. In: Bilezikian J, Raisz L, Martin TJ, editors. Principles of bone biology. Elsevier; 2008. p. 515 – 31. https://linkinghub.elsevier. com/retrieve/pii/B9780123738844000446 . 116. Youness RA, Taha MA, Ibrahim M, El-Kheshen A. FTIR spectral characterization, mechanical properties and anti- microbial properties of La-doped phosphate-based bioactive glasses. Silicon. 2018;10:1151 – 9. https://doi.org/10.1007/ s12633-017-9587-0 . 117. Zhu D, Lu B, Yang Q, Yu H, Liu P, Yin J, et al. Lanthanum- doped mesoporous bioglasses/chitosan composite scaffolds enhance synchronous osteogenesis and angiogenesis for aug- mented osseous regeneration. Chem Eng J. 2021;405:127077 https://doi.org/10.1016/j.cej.2020.127077 . 118. El-Meliegy E, Farag MM, El-Kady AM, Mohamed MS, Abdelhakim HK, Moaness M. Evaluation of solubility and cytotoxicity of lanthanum-doped phosphate glasses nanoparticles for drug delivery applications. J Non Cryst Solids. 2017;475:59 – 70. https://doi.org/10.1016/j.jnoncrysol.2017.08.034 . 119. Liying L, Zhao D, Zhang Z, Zhang X. Adsorption and photo- catalyst of methylene blue on mesoporous bioactive glass with La and Ti dopants. Glas Phys Chem. 2021;47:143 – 53. https:// doi.org/10.1134/S1087659621020073 . 120. Ben – Arfa BAE, Miranda Salvado IM, Ferreira JMF, Pullar RC. The effects of Cu2 + and La3 + doping on the sintering ability of sol-gel derived high silica bioglasses. Ceram Int. 2019;45:10269 – 78. https://linkinghub.elsevier.com/retrieve/pii/ S0272884219303815 . 121. Khoshsima S, Alshemary A, Tezcaner A, Surdem S, Evis Z. Impact of B2O3 and La2O3 addition on structural, mechanical and biological properties of hydroxyapatite. Process Appl Ceram. 2018;12:143 – 52. http://www.doiserbia.nb.rs/Article. aspx?ID = 1820-61311802143K . 122. Ershad M, Ali A, Mehta NS, Singh RK, Singh SK, Pyare R. Mechanical and biological response of (CeO2 + La2O3)- substituted 45S5 bioactive glasses for biomedical application. J Aust Ceram Soc. 2020;56:1243 – 52. https://link.springer.com/10. 1007/s41779-020-00471-3 . 123. Ben-Arfa BAE, Palamá IE, Miranda Salvado IM, Ferreira JMF, Pullar RC. Cytotoxicity and bioactivity assessments for Cu 2 + and La 3 + doped high-silica sol-gel derived bioglasses: the complex interplay between additive ions revealed. J Biomed Mater Res Part A. 2019;107:2680 – 93. https://onlinelibrary. wiley.com/doi/10.1002/jbm.a.36772 . 124. Ben – Arfa BAE, Neto S, Miranda Salvado IM, Pullar RC, Fer- reira JMF. Robocasting of Cu2 + & La3 + doped sol – gel glass scaffolds with greatly enhanced mechanical properties: com- pressive strength up to 14 MPa. Acta Biomater. 2019;87:265 – 72. https://linkinghub.elsevier.com/retrieve/pii/ S1742706119300704 . 125. Jodati H, Güner B, Evis Z, Keskin D, Tezcaner A. Synthesis and characterization of magnesium-lanthanum dual doped bioactive glasses. Ceram Int. 2020;46:10503 – 11. https://linkinghub. elsevier.com/retrieve/pii/S0272884220300511 . 126. Deliormanli AM, Issa SAM, Al-Buriahi MS, Rahman B, Zakaly HMH, Tekin HO. Erbium (III)- and Terbium (III)-containing silicate-based bioactive glass powders: physical, structural and nuclear radiation shielding characteristics. Appl Phys A. 2021;127:463. https://link.springer.com/article/10.1007/s00339- 021-04615-5 127. Lopez-Iscoa P, Ojha N, Pugliese D, Mishra A, Gumenyuk R, Boetti NG, et al. Design, processing, and characterization of an optical core-bioactive clad phosphate fi ber for biomedical applications. J Am Ceram Soc. 2019;102:6882 – 92. https://cera mics.onlinelibrary.wiley.com/doi/full/10.1111/jace.16553 128. Li Q, Xing M, Chen Z, Wang X, Zhao C, Qiu J, et al. Er 3 + /Yb 3 + co-doped bioactive glasses with up-conversion luminescence prepared by containerless processing. Ceram Int. 2016;42:13168 – 75. https://linkinghub.elsevier.com/retrieve/pii/ S0272884216307155 . 129. Li X, Li Y, Chen X, Li B, Gao B, Ren Z, et al. Optically monitoring mineralization and demineralization on photo- luminescent bioactive nano fi bers. Langmuir. 2016;32:3226 – 33. https://pubs.acs.org/doi/pdf/10.1021/acs.langmuir.6b00290 130. Wang X, Zhang Y, Lin C, Zhong W. Sol-gel derived terbium- containing mesoporous bioactive glasses nanospheres: In vitro hydroxyapatite formation and drug delivery. Colloids Surf B Biointerfaces. 2017;160:406 – 15. https://doi.org/10.1016/j. colsurfb.2017.09.051 . 131. Li Q, Xing M, Chang L, Ma L, Chen Z, Qiu J, et al. Upcon- version luminescence Ca – Mg – Si bioactive glasses synthesized using the containerless processing technique. Front Mater Sci. 2019;13:399 – 409. http://link.springer.com/10.1007/s11706-019- 0484-x . 132. Deliormanli AM, Rahman B, Oguzlar S, Ertekin K. Structural and luminescent properties of Er3 + and Tb3 + -doped sol – gel- based bioactive glass powders and electrospun nano fi bers. J Mater Sci. 2021;56:14487 – 504. https://link.springer.com/10. 1007/s10853-021-06203-7 . 133. Conzone SD, Day DE. Preparation and properties of porous microspheres made from borate glass. J Biomed Mater Res Part A 2009;88:531 – 42. https://doi.org/10.1002/jbm.a.31883 . 134. Day DE, White JE, Brown RF, McMenamin KD. Transforma- tion of borate glasses into biologically useful materials. Glas Technol. 2003;44:75 – 81. https://scholarsmine.mst.edu/biosci\_fa cwork/42/ . 135. Patcas L, Vanea E, Tamasan M, Eniu D, Simon V. Nanos- tructural changes induced by thermal treatment of calcium-sili- cate glasses containing dysprosium and iron. Optoelectron Adv Mater Rapid Commun. 2014;8:989 – 92. https://oam-rc.inoe.ro/a rticles/nanos-tructural-changes-induced-by-thermal-treatment-of- 3 Page 32 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 calcium-silicate-glasses-containing-dysprosium-and-iron/ fulltext . 136. Soetan KO, Olaiya CO, Oyewole OE. The importance of mineral elements for humans, domestic animals and plants: a review. Afr J Food Sci. 2010;4:200 – 22. https://www.google.com/url?sa = t&rct = j&q = &esrc = s&source = web&cd = &cad = rja&uact = 8&ved = 2ahUKEw iLqrWjlvT0AhXDxDgGHbAEBkcQFnoECAIQAQ&url = https %3A%2F%2Facademicjournals.org%2Farticle%2Fa rticle1380713863_Soetan%2520et%2520al.pdf&usg = AOvVaw 1J2YpTgMuY_nTzKtBDfeLj . 137. Yukawa M, Suzuki-Yasumoto M, Amano K, Terai M. Dis- tribution of trace elements in the human body determined by neutron activation analysis. Arch Environ Heal Int J. 1980;35:36 – 44. http://www.tandfonline.com/doi/abs/10.1080/ 00039896.1980.10667459 . 138. Yamagata N. The concentration of common cesium and rubi- dium in human body. J Radiat Res. 1962;3:9 – 30. https://aca demic.oup.com/jrr/article-lookup/doi/10.1269/jrr.3.9 . 139. Tan YN, Chen WJ, Wei W, Huang QL, He X. Rubidium-mod- i fi ed bioactive glass-ceramics with hydroxyapatite crystals for bone regeneration. Trans Nonferrous Met Soc China. 2021;31:521 – 32. https://linkinghub.elsevier.com/retrieve/pii/ S1003632621655140 140. Ouyang S, Zheng K, Huang Q, Liu Y, Boccaccini AR. Synthesis and characterization of rubidium-containing bioactive glass nanoparticles. Mater Lett. 2020;273:127920. https://doi.org/10. 1016/j.matlet.2020.127920 . 141. He X, Ding Y, Duan S, Luo S, Song J, Peng C, et al. Wound dressings based on rubidium-doped bioactive glass nanospheres promote diabetic wound healing. J Biomed Nanotechnol. 2019;15:2059 – 71. https://www.ingentaconnect.com/content/10. 1166/jbn.2019.2849 . 142. He X, Liu Y, Tan Y, Grover LM, Song J, Duan S, et al. Rubi- dium-containing mesoporous bioactive glass scaffolds support angiogenesis, osteogenesis and antibacterial activity. Mater Sci Eng C. 2019;105:110155 https://doi.org/10.1016/j.msec.2019. 110155 . December 2018 143. Schroeder HA, Tipton IH, Nason AP. Trace metals in man: strontium and barium. J Chronic Dis. 1972;25:491 – 517. https:// linkinghub.elsevier.com/retrieve/pii/0021968172901506 . 144. Oskarsson A. Barium. In: Nordberg GF, Fowler BA, Nordberg M, editors. Handbook on the toxicology of metals. Elsevier; 2015. p. 625 – 34. https://linkinghub.elsevier.com/retrieve/pii/ B9780444594532000299 . 145. Shokrollahi H, Salimi F, Doostmohammadi A. The fabrication and characterization of barium titanate/akermanite nano-bio- ceramic with a suitable piezoelectric coef fi cient for bone defect recovery. J Mech Behav Biomed Mater. 2017;74:365 – 70. https:// pubmed.ncbi.nlm.nih.gov/28672271/ 146. Tanaka CB, Lopes DP, Kikuchi LNT, Moreira MS, Catalani LH, Braga RR, et al. Development of novel dental restorative com- posites with dibasic calcium phosphate loaded chitosan fi llers. Dent Mater. 2020;36:551 – 9. https://linkinghub.elsevier.com/ retrieve/pii/S0109564120300385 147. Hasan MS, Kehoe S, Boyd D. Temporal analysis of dissolution by-products and genotoxic potential of spherical zinc – silicate bioglass: “ Imageable beads ” for transarterial embolization. J Biomater Appl. 2014;29:566 – 81. https://pubmed.ncbi.nlm.nih. gov/24913613/ . 148. Huang TY, Su WT, Chen PH. Comparing the effects of chitosan scaffolds containing various divalent metal phosphates on osteogenic differentiation of stem cells from human exfoliated deciduous teeth. Biol Trace Elem Res.2018;185:316 – 26. https:// pubmed.ncbi.nlm.nih.gov/29399740/ . 149. Par M, Š antic A, Gamulin O, Marovic D, Mogu š -Milankovic A, Tarle Z. Impedance changes during setting of amorphous cal- cium phosphate composites. Dent Mater. 2016;32:1312 – 21. https://pubmed.ncbi.nlm.nih.gov/27524232/ . 150. Natale LC, Rodrigues MC, Alania Y, Chiari MDS, Boaro LCC, Cotrim M, et al. Mechanical characterization and ion release of bioactive dental composites containing calcium phosphate par- ticles. J Mech Behav Biomed Mater. 2018;84:161 – 7. https:// linkinghub.elsevier.com/retrieve/pii/S1751616118304429 . 151. Biland ž ic MD, Roos C, Braun A, Jansen P. Development of a radiopaque dental glass for endodontic laser applications. J Mater Res Technol. 2020;9:13994 – 4001. https://linkinghub.elsevier. com/retrieve/pii/S2238785420318172 . 152. Saeidi B, Derakhshandeh MR, Delshad Chermahini M, Doost- mohammadi A. Novel porous barium titanate/nano-bioactive glass composite with high piezoelectric coef fi cient for bone regeneration applications. J Mater Eng Perform. 2020;29:5420 – 7. https://doi.org/10.1007/s11665-020-05016-0 . 153. Arepalli SK, Tripathi H, Vyas VK, Jain S, Suman SK, Pyare R, et al. In fl uence of barium substitution on bioactivity, thermal and physico-mechanical properties of bioactive glass. Mater Sci Eng C. 2015;49:549 – 59. https://linkinghub.elsevier.com/retrieve/pii/ S0928493115000594 . 154. Yazdanpanah A, Moztarzadeh F. Synthesis and characterization of Barium – Iron containing magnetic bioactive glasses: the effect of magnetic component on structure and in vitro bioactivity. Colloids Surf B Biointerfaces. 2019;176:27 – 37. https://doi.org/ 10.1016/j.colsurfb.2018.12.036 . 155. Kaur G, Sharma P, Kumar V, Singh K. Assessment of in vitro bioactivity of SiO2-BaO-ZnO-B2O3-Al2O3 glasses: an optico- analytical approach. Mater Sci Eng C. 2012;32:1941 – 7. https:// linkinghub.elsevier.com/retrieve/pii/S0928493112002548 156. Altaie A, Bubb N, Franklin P, German MJ, Marie A, Wood DJ. Development and characterisation of dental composites con- taining anisotropic fl uorapatite bundles and rods. Dent Mater. 2020;36:1071 – 85. https://pubmed.ncbi.nlm.nih.gov/32513479/ . 157. El-Meliegy EM, Hamzawy EMA. Celsian – fl uorophlogopite porcelain based on Egyptian talc. Adv Appl Ceram. 2005;104:92 – 6. https://doi.org/10.1179/174367605X16590 . 158. Alania Y, Chiari MDS, Rodrigues MC, Arana-Chavez VE, Bressiani AHA, Vichi FM, et al. Bioactive composites contain- ing TEGDMA-functionalized calcium phosphate particles: degree of conversion, fracture strength and ion release evalua- tion. Dent Mater. 2016;32:e374 – 81. https://linkinghub.elsevier. com/retrieve/pii/S0109564116304031 159. Paliwal P, Kumar AS, Tripathi H, Singh SP, Patne SCU, Krishnamurthy S. Pharmacological application of barium con- taining bioactive glass in gastro-duodenal ulcers. Mater Sci Eng C. 2018;92:424 – 34. https://doi.org/10.1016/j.msec.2018.06.068 . 160. Zakaly HMH, Saudi HA, Issa SAM, Rashad M, Elazaka AI, Tekin HO, et al. Alteration of optical, structural, mechanical durability and nuclear radiation attenuation properties of barium borosilicate glasses through BaO reinforcement: experimental and numerical analyses. Ceram Int. 2021;47:5587 – 96. https:// doi.org/10.1016/j.ceramint.2020.10.143 . 161. Qian H, Lei T, Ye Z, Hu Y, Lei P. From the performance to the essence: the biological mechanisms of how tantalum contributes to osteogenesis. Biomed Res Int. 2020;2020:1 – 8. https://www. hindawi.com/journals/bmri/2020/5162524/ . 162. Nagrath M, Gallant R, Yazdi AR, Mendonca A, Rahman S, Chiu L, et al. Tantalum-containing mesoporous bioactive glass powder for hemostasis. J Biomater Appl. 2021;35:924 – 32. https://journa ls.sagepub.com/doi/full/10.1177/0885328220965150 . 163. Kamitakahara M, Kawashita M, Miyata N, Kokubo T, Nakamura T. Preparation of bioactive fl exible poly(tetramethylene oxide) Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 33 of 41 3 (PTMO) – CaO – Ta2O5 hybrids. J Mater Sci Mater Med. 2007;18:1117 – 24. https://doi.org/10.1007/s10856-007-0147-9 . 164. Wang A, Lin W, Ma J, Shi L, Wang W, He Y, et al. Application of tantalum-containing chitosan scaffolds for the repair of osteoporotic bone defects. Sci Adv Mater. 2018;10:1179 – 89. https://doi.org/10.1166/sam.2018.3282 . 165. Madhavi B, Reddy ASS, Prasad PS, Mohan Babu M, Rao PR, Kumar VR, et al. In-vitro bioactivity and antibacterial properties of CaF2-CaO-B2O3-P2O5 – SrO glass system-in fl uence of Ta2O5. J Non Cryst Solids. 2021;566:120881 https://linkinghub. elsevier.com/retrieve/pii/S0022309321002404 . 166. Grishchenko DN, Slobodyuk AB, Kuryavyi VG, Medkov MA. Tantalum-containing bioactive glass-ceramics: a mechanism of suppression of the biological activity of the 45S5 bioglass by doping with Ta2O5. Russ J Inorg Chem. 2020;65:1606 – 13. https://doi.org/10.1134/S0036023620100083 . 167. Nagrath M, Yazdi AR, Rafferty A, Daly D, Rahman SU, Gallant RC, et al. Tantalum-containing meso-porous glass fi bres for hemostatic applications. Mater Today Commun. 2021;27:102260 https://linkinghub.elsevier.com/retrieve/pii/ S235249282100252X 168. Medkov MA, Grishchenko DN, Dmitrieva EE, Kudryavyi VG. Obtaining bioactive glasses by the pyrolysis of organic solutions. Theor Found Chem Eng. 2020;54:1005 – 9. https://doi.org/10. 1134/S0040579520050188 . 169. Mendonca A, Rahman MS, Alhalawani A, Rodriguez O, Gallant RC, Ni H, et al. The effect of tantalum incorporation on the physical and chemical properties of ternary silicon – calcium – phosphorous mesoporous bioactive glasses. J Biomed Mater Res Part B Appl Biomater. 2019;107:2229 – 37. https://doi.org/10. 1002/jbm.b.34310 . 170. Alalawi A. Optical features and nuclear radiation shielding ef fi ciency of ZnO-B2O3-Ta2O5 glasses. Phys Scr. 2020;95:105302 https://doi.org/10.1088/1402-4896/abb49d . 171. Madanat R, Moritz N, Vedel E, Svedström E, Aro HT. Radio- opaque bioactive glass markers for radiostereometric analysis. Acta Biomater. 2009;5:3497 – 505. https://linkinghub.elsevier. com/retrieve/pii/S1742706109002591 172. Alhalawani AM, Mehrvar C, Stone W, Waldman SD, Towler MR. A novel tantalum-containing bioglass. Part II. Development of a bioadhesive for sternal fi xation and repair. Mater Sci Eng C. 2017;71:401 – 11. https://pubmed.ncbi.nlm.nih.gov/27987724/ . 173. Tabia Z, Akhtach S, El Mabrouk K, Bricha M, Nouneh K, Ballamurugan A. Tantalum doped SiO2-CaO-P2O5 based bioactive glasses: investigation of in vitro bioactivity and anti- bacterial activities. Biomed Glas. 2020;6:10 – 22. https://www. degruyter.com/document/doi/10.1515/bglass-2020-0002/html . 174. Samudrala RK, Azeem PA. Preliminary biological evaluation of tantalum containing soda lime borosilicate bioactive glasses. J Alloy Compd. 2019;810:151853 https://doi.org/10.1016/j.ja llcom.2019.151853 . 175. Babu MM, Prasad PS, Bindu SH, Rao PV, Govindan NP, Veeraiah N, et al. RETRACTED: bioactivity, antibacterial activity and functionality of zirconia doped zinc phosphate bio- glasses for application in dentistry. Mater Sci Eng C. 2020;114:111052 https://doi.org/10.1016/j.msec.2020.111052 . 176. Zhang K, Van Le Q. Bioactive glass coated zirconia for dental implants: a review. J Compos Compd. 2020;2:10 – 7. https:// jourcc.com/index.php/jourcc/article/view/jcc212 . 177. Tosiriwatanapong T, Singhatanadgit W. Zirconia-based bioma- terials for hard tissue reconstruction. Bone Tissue Regen Insights. 2018;9:1179061X1876788. https://doi.org/10.1177/ 1179061X18767886 . 178. Majhi MR, Pyare R, Singh SP. Studies on preparation and characterizations of CaO – Na2O – SiO2 – P2O5 bioglass ceramics substituted with Al2O3, TiO2 and ZrO2. J Biomater Tissue Eng. 2012;2:154 – 69. http://openurl.ingenta.com/content/xref? genre = article&issn = 2157-9083&volume = 2&issue = 2&spage = 154 179. Zohourfazeli M, Tajer MHM, Moghanian A. Comprehensive investigation on multifunctional properties of zirconium and silver co-substituted 58S bioactive glass. Ceram Int. 2021;47:2499 – 507. https://doi.org/10.1016/j.ceramint.2020.09. 093 . 180. Moghanian A, Tajer MHM, Zohourfazeli M, Miri Z, Yazdi M. Sol-gel derived silicate-based bioactive glass: Studies of syner- getic effect of zirconium and magnesium on structural and bio- logical characteristics. J Non Cryst Solids. 2021;554:120613 https://linkinghub.elsevier.com/retrieve/pii/ S0022309320307237 . 181. Kang TY, Seo JY, Ryu JH, Kim KM, Kwon JS. Improvement of the mechanical and biological properties of bioactive glasses by the addition of zirconium oxide (ZrO2) as a synthetic bone graft substitute. J Biomed Mater Res Part A. 2021;109:1196 – 208. https://onlinelibrary.wiley.com/doi/full/10.1002/jbm.a.37113 182. Babu MM, Prasad PS, Rao PV, Bindu SH, Prasad A, Veeraiah N, et al. In fl uence of ZrO2 addition on structural and biological activity of phosphate glasses for bone regeneration. Materials (Basel). 2020;13:4058 https://www.mdpi.com/1996-1944/13/18/ 4058/htm 183. Kumar P, Kumar V, Kumar R, Kumar R, Pruncu CI. Fabrication and characterization of ZrO2 incorporated SiO2 – CaO – P2O5 bioactive glass scaffolds. J Mech Behav Biomed Mater. 2020;109:103854 https://linkinghub.elsevier.com/retrieve/pii/ S1751616120304082 . 184. Zhu Y, Zhang Y, Wu C, Fang Y, Yang J, Wang S. The effect of zirconium incorporation on the physiochemical and biological properties of mesoporous bioactive glasses scaffolds. Micro- porous Mesoporous Mater. 2011;143:311 – 9. https://linkinghub. elsevier.com/retrieve/pii/S1387181111001132 . 185. Rajkumar G, Aravindan S, Rajendran V. Structural analysis of zirconia-doped calcium phosphate glasses. J Non Cryst Solids. 2010;356:1432 – 8. https://linkinghub.elsevier.com/retrieve/pii/ S0022309310001973 . 186. Ploska U, Berger G, Sahre M. Investigation of the in fl uence of zirconium content on the formation of apatite on bioactive glass- ceramics. Key Eng Mater. 2003;254 – 256:71 – 4. https://www. scienti fi c.net/KEM.254-256.71 . 187. Lubauer J, Belli R, Petschelt A, Cicconi MR, Hurle K, Lohbauer U. Concurrent kinetics of crystallization and toughening in multicomponent biomedical SiO2-Li2O-P2O5-ZrO2 glass-cera- mics. J Non Cryst Solids. 2021;554:120607 https://linkinghub. elsevier.com/retrieve/pii/S0022309320307171 . 188. Samudrala R, Reddy GVN, Manavathi B, Azeem PA. Synthesis, characterization and cytocompatibility of ZrO2 doped bor- osilicate bioglasses. J Non Cryst Solids. 2016;447:150 – 5. https:// doi.org/10.1016/j.jnoncrysol.2016.05.001 . 189. Lu X, Deng L, Du J. Effect of ZrO2 on the structure and properties of soda-lime silicate glasses from molecular dynamics simulations. J Non Cryst Solids. 2018;491:141 – 50. https:// linkinghub.elsevier.com/retrieve/pii/S002230931830200X . 190. Yin P, Yuan JW, Liu LH, Xiao T, Lei T. Effect of ZrO2 on the bioactivity properties of gel-derived CaO-P2O5-SiO2-SrO glas- ses. Ceram Int. 2017;43:9691 – 8. https://linkinghub.elsevier.com/ retrieve/pii/S0272884217307514 191. Prabhu M, Kavitha K, Sutha S, Manivasakan P, Rajendran V, Kulandaivelu P, et al. Bioactivity of zirconium-substituted nanobioactive glass particles. Synth React Inorg Met Org Chem. 2014;45:92 – 6. https://doi.org/10.1080/15533174.2013.819894 . 192. Mozafari M, Salahinejad E, Shari fi -Asl S, Macdonald DD, Vashaee D, Tayebi L. Innovative surface modi fi cation of orthopaedic implants with positive effects on wettability and in 3 Page 34 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 vitro anti-corrosion performance. Surf Eng. 2014;30:688 – 92. https://doi.org/10.1179/1743294414Y.0000000309 . 193. Tigunta S, Pisitpipathsin N, Kantha P, Eitssayeam S, Rujijanagul G, Tunkasiri T, et al. Electrical properties of calcium phosphate/ BZT bioglass-ceramics prepared by incorporation method. Fer- roelectrics. 2014;459:188 – 94. https://doi.org/10.1080/00150193. 2013.849527 . 194. Pisitpipathsin N, Kantha P, Eitsayeam S, Rujijanakul G, Guo R, Bhalla AS, et al. Effect of BCZT on electrical properties and bioactivity of 45S5 bioglass. Integr Ferroelectr. 2013;142:144 – 53. https://doi.org/10.1080/10584587.2013.780574 . 195. Mozafari M, Salahinejad E, Shabafrooz V, Yazdimamaghani M, Vashaee D, Tayebi L. Multilayer bioactive glass/zirconium titanate thin fi lms in bone tissue engineering and regenerative dentistry. Int J Nanomed. 2013;8:1665 https://www.ncbi.nlm. nih.gov/pmc/articles/PMC3639719/ . 196. Aguilar CR, Reyes EAA, Martínez MF, Patiño CAL, Anita REN. Synthesis and characterisation of β -TCP/bioglass/zirconia scaffolds. Adv Appl Ceram. 2017;116:452 – 61. https://doi.org/ 10.1080/17436753.2017.1356043 . 197. Yadav SK, Ray S, Ershad M, Vyas VK, Prasad S, Ali A, et al. Development of zirconia substituted 1393 bioactive glass for orthopaedic application. Orient J Chem. 2017;33:2720 – 30. http://www.orientjchem.org/vol33no6/development-of-zirconia- substituted-1393-bioactive-glass-for-orthopaedic-application/ . 198. Moghanian A, Zohourfazeli M, Tajer MHM. The effect of zir- conium content on in vitro bioactivity, biological behavior and antibacterial activity of sol-gel derived 58S bioactive glass. J Non Cryst Solids. 2020;546:120262. https://doi.org/10.1016/j. jnoncrysol.2020.120262 . 199. Ginebra MP, Montufar EB. Cements as bone repair materials. In: Pawelec KM, Planell JA, editors. Bone repair biomaterials. 2nd ed. Elsevier; 2019. 233 – 71. https://doi.org/10.1016/B978-0-08- 102451-5.00009-3 . 200. Bargavi P, Chitra S, Durgalakshmi D, Radha G, Balakumar S. Zirconia reinforced bio-active glass coating by spray pyrolysis: structure, surface topography, in-vitro biological evaluation and antibacterial activities. Mater Today Commun. 2020;25:101253. https://doi.org/10.1016/j.mtcomm.2020.101253 . 201. Ali A, Ershad M, Hira S, Pyare R, Singh SP. Mechanochemical and in vitro cytocompatibility evaluation of zirconia modi fi ed silver substituted 1393 bioactive glasses. Boletín la Soc Española Cerámica y Vidr. 2020. https://doi.org/10.1016/j.bsecv.2020.07. 002 . (In press). 202. Capanema NSV, Mansur AAP, Carvalho SM, Silva ARP, Ciminelli VS, Mansur HS. Niobium-doped hydroxyapatite bio- ceramics: synthesis, characterization and in vitro cytocompat- ibility. Materials (Basel). 2015;8:4191 – 209. http://www.mdpi. com/1996-1944/8/7/4191 . 203. Carneiro KK, Araujo TP, Carvalho EM, Meier MM, Tanaka A, Carvalho CN, et al. Bioactivity and properties of an adhesive system functionalized with an experimental niobium-based glass. J Mech Behav Biomed Mater. 2018;78:188 – 95. https://doi.org/ 10.1016/j.jmbbm.2017.11.016 . 204. Leal A, Carvalho C, Filho EM, Neto VM, Carmo M, Maciel A, et al. Airborne-particle abrasion with niobium phosphate bioac- tive glass on caries-affected dentin: effect on the microtensile bond strength. J Adhes Sci Technol. 2017;31:2410 – 23. https:// doi.org/10.1080/01694243.2017.1303865 . 205. Bonetti L, Altomare L, Bono N, Panno E, Campiglio CE, Draghi L, et al. Electrophoretic processing of chitosan based composite scaffolds with Nb-doped bioactive glass for bone tissue regen- eration. J Mater Sci Mater Med. 2020;31:43 https://doi.org/10. 1007/s10856-020-06378-6 . 206. DEGRAZIA, Felipe Weidenbach et al. Evaluation of an anti- bacterial orthodontic adhesive incorporated with niobium-based bioglass: an in situ study. Brazilian Oral Research [online]. 2019;33:e010. https://doi.org/10.1590/1807-3107bor-2019. vol33.0010 . 207. Carvalho EM, Lima DM, Carvalho CN, Loguercio AD, Marti- nelli JR, Bauer J. Effect of airborne-particle abrasion on dentin with experimental niobophosphate bioactive glass on the microtensile bond strength of resin cements. J Prosthodont Res. 2015;59:129 – 35. https://pubmed.ncbi.nlm.nih.gov/25659301/ 208. Bauer J, Carvalho EM, Carvalho CN, Meier MM, Souza JP de, Carvalho RM de, et al. Development of a simpli fi ed etch-and- rinse adhesive containing niobiophosphate bioactive glass. Int J Adhes Adhes. 2016;69:110 – 4. https://linkinghub.elsevier.com/ retrieve/pii/S014374961630063X . 209. Balbinot G de S, Collares FM, Visioli F, Soares PBF, Takimi AS, Samuel SMW, et al. Niobium addition to sol-gel derived bioactive glass powders and scaffolds: in vitro characterization and effect on pre-osteoblastic cell behavior. Dent Mater. 2018;34:1449 – 58. https://pubmed.ncbi.nlm.nih.gov/29929845/ . 210. Bauer J, Silva e Silva A, Carvalho EM, Carvalho CN, Carvalho RM, Manso AP. A niobophosphate bioactive glass suspension for rewetting dentin: effect on antibacterial activity, pH and resin-dentin bonding durability. Int J Adhes Adhes. 2018;84:178 – 83. https://linkinghub.elsevier.com/retrieve/pii/ S0143749618300824 . 211. Carvalho CN, Wang Z, Shen Y, Gavini G, Martinelli JR, Manso A, et al. Comparative analyses of ion release, pH and multi- species bio fi lm formation between conventional and bioactive gutta-percha. Int Endod J. 2016;49:1048 – 56. https://pubmed. ncbi.nlm.nih.gov/26443466/ . 212. Balbinot G de S, Leitune VCB, Ogliari FA, Collares FM. Nio- bium silicate particles as bioactive fi llers for composite resins. Dent Mater. 2020;36:1578 – 85. https://linkinghub.elsevier.com/ retrieve/pii/S0109564120302505 . 213. Meneses CCB, Olivi LT, Carvalho CN, Gavini G, Sipert CR. Cytotoxic effect of niobium phosphate glass – based gutta-percha points on periodontal ligament fi broblasts in vitro. J Endod. 2020;46:1297 – 301. https://linkinghub.elsevier.com/retrieve/pii/ S0099239920304271 . 214. Denry IL, Holloway JA, Nakkula RJ, Walters JD. Effect of niobium content on the microstructure and thermal properties of fl uorapatite glass-ceramics. J Biomed Mater Res Part B Appl Biomater. 2005;75B:18 – 24. https://doi.org/10.1002/jbm.b. 30295 . 215. Altmann ASP, Collares FM, Balbinot GDS, Leitune VCB, Takimi AS, Samuel SMW. Niobium pentoxide phosphate invert glass as a mineralizing agent in an experimental orthodontic adhesive. Angle Orthod. 2017;87:759 – 65. https://pubmed.ncbi. nlm.nih.gov/28686093/ . 216. Balbinot G, de S, Bahlis EA, da C, Visioli F, Leitune VCB, Soares RMD, Collares FM. Polybutylene-adipate-terephthalate and niobium-containing bioactive glasses composites: Develop- ment of barrier membranes with adjusted properties for guided bone regeneration. Mater Sci Eng C. 2021;125:112115. https:// linkinghub.elsevier.com/retrieve/pii/S092849312100254X 217. Carvalho CN, Martinelli JR, Bauer J, Haapasalo M, Shen Y, Bradaschia-Correa V, et al. Micropush-out dentine bond strength of a new gutta-percha and niobium phosphate glass composite. Int Endod J. 2015;48:451 – 9. https://pubmed.ncbi.nlm.nih.gov/ 24923365/ . 218. Altmann ASP, Collares FM, Leitune VCB, Arthur RA, Takimi AS, Samuel SMW. In vitro antibacterial and remineralizing effect of adhesive containing triazine and niobium pentoxide phosphate inverted glass. Clin Oral Investig. 2017;21:93 – 103. https://pubmed.ncbi.nlm.nih.gov/26892472/ 219. Lima CJ de, Silva IIC da, Barros LFH de, Graneiro JM, da Silva MHP. Resposta do tecido subcutâneo de camundongos à Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 35 of 41 3 implantação de um novo biovidro à base de óxido de nióbio. Matéria (Rio Janeiro). 2011;16:574 – 82. http://www.scielo.br/j/ rmat/a/bCrJG47wmpLhk6PkzQHgmfC/?lang = pt&format = html . 220. Madhavi B, Reddy ASS, Prasad PS, Prasad A, Devi PPK, Kumar VR, et al. The impact of Nb2O5 on in-vitro bioactivity and antibacterial activity of CaF2 – CaO – B2O3 – P2O5 – SrO glass system. Ceram Int. 2021;47:28328 – 37. https://linkinghub. elsevier.com/retrieve/pii/S0272884221020071 . 221. Carvalho EM, Ferreira PVC, Gutiérrez MF, Sampaio RF, Car- valho CN, Menezes AS de, et al. Development and character- ization of self-etching adhesives doped with 45S5 and niobophosphate bioactive glasses: physicochemical, mechanical, bioactivity and interface properties. Dent Mater. 2021;37:1030 – 45. https://linkinghub.elsevier.com/retrieve/pii/ S010956412100107X . 222. Kushwaha M, Pan X, Holloway JA, Denry IL. Differentiation of human mesenchymal stem cells on niobium-doped fl uorapatite glass-ceramics. Dent Mater. 2012;28:252 – 60. https://doi.org/10. 1016/j.dental.2011.10.010 . 223. Fernandes GVO, Alves G, Linhares ABR, Prado da Silva MH, Granjeiro JM. Evaluation of cytocompatibility of bioglass-nio- bium granules with human primary osteoblasts: a multi- parametric approach. Key Eng Mater. 2011;493 – 494:37 – 42. https://www.scienti fi c.net/KEM.493-494.37 . 224. Lopes JH, Magalhães A, Mazali IO, Bertran CA. Effect of nio- bium oxide on the structure and properties of melt-derived bioactive glasses. J Am Ceram Soc. 2014;97:3843 – 52. https:// doi.org/10.1111/jace.13222 . 225. Grazziotin-Soares R, Dourado L, Gonçalves B, Ardenghi D, Ferreira M, Bauer J, et al. Dentin microhardness and sealer bond strength to root dentin are affected by using bioactive glasses as intracanal medication. Materials (Basel). 2020;13:721. https:// pubmed.ncbi.nlm.nih.gov/32033430/ . 226. Balbinot G, de S, Leitune VCB, Ponzoni D, Collares FM. Bone healing with niobium-containing bioactive glass composition in rat femur model: a micro-CT study. Dent Mater. 2019;35:1490 – 7. https://doi.org/10.1016/j.dental.2019.07.012 . 227. Balbinot G, de S, Collares FM, Herpich TL, Visioli F, Samuel SMW, Leitune VCB. Niobium containing bioactive glasses as remineralizing fi ller for adhesive resins. Dent Mater. 2020;36:221 – 8. https://doi.org/10.1016/j.dental.2019.11.014 . 228. Sato PS, Watanabe T, Maeda H, Obata A, Kasuga T. Structural analysis of 65ZnO – 30P 2 O 5 – 5Nb 2 O 5 invert glass using X-ray photoelectron spectroscopy. Mater Trans. 2019;60:1707 – 10. https://www.jstage.jst.go.jp/article/matertrans/60/8/60\_ M2019070/_article 229. Samudrala R, Azeem PA, Penugurti V, Manavathi B. In vitro evaluation of niobia added soda lime borosilicate bioactive glasses. J Alloy Compd. 2018;764:1072 – 8. https://doi.org/10. 1016/j.jallcom.2018.06.069 . 230. Lopes JH, Souza LP, Domingues JA, Ferreira FV, Alencar Hausen M, Camilli JA, et al. In vitro and in vivo osteogenic potential of niobium-doped 45S5 bioactive glass: a comparative study. J Biomed Mater Res Part B Appl Biomater. 2020;108:1372 – 87. https://doi.org/10.1002/jbm.b.34486 . 231. Miguez-Pacheco V, de Ligny D, Schmidt J, Detsch R, Boccac- cini AR. Development and characterization of niobium-releasing silicate bioactive glasses for tissue engineering applications. J Eur Ceram Soc. 2018;38:871 – 6. https://doi.org/10.1016/j. jeurceramsoc.2017.07.028 . 232. Souza L, Lopes JH, Encarnação D, Mazali IO, Martin RA, Camilli JA, et al. Comprehensive in vitro and in vivo studies of novel melt- derived Nb-substituted 45S5 bioglass reveal its enhanced bioactive properties for bone healing. Sci Rep. 2018;8:12808. http://www.na ture.com/articles/s41598-018-31114-0 . 233. Souza LPL, Lopes JH, Ferreira FV, Martin RA, Bertran CA, Camilli JA. Evaluation of effectiveness of 45S5 bioglass doped with niobium for repairing critical-sized bone defect in in vitro and in vivo models. J Biomed Mater Res Part A. 2020;108:446 – 57. https://onlinelibrary.wiley.com/doi/10.1002/jbm.a.36826 . 234. Berzina L, Cimdin š R, Dobelis M, Diktenko O, Vetra J. Bio- ceramics in the system CaO-Nb2O5-P2O5. In: Andersson ÖH, Happonen RP, Yli-Urpo A, editors. Bioceramics. Elsevier; 1994. p. 151 – 7. https://linkinghub.elsevier.com/retrieve/pii/ B9780080421445500273 . 235. Lee S, Maeda H, Obata A, Ueda K, Narushima T, Kasuga T. Structures and dissolution behaviors of CaO – P2O5 – TiO 2 /Nb 2 O 5 (Ca/P ≥ 1) invert glasses. J Non Cryst Solids. 2015;426:35 – 42. https://linkinghub.elsevier.com/retrieve/pii/ S0022309315300831 . 236. Obata A, Takahashi Y, Miyajima T, Ueda K, Narushima T, Kasuga T. Effects of niobium ions released from calcium phosphate invert glasses containing Nb 2 O 5 on osteoblast-like cell functions. ACS Appl Mater Interfaces. 2012;4:5684 – 90. https://doi.org/10.1021/am301614a . 237. Sene FF, Martinelli JR, Gomes L. Synthesis and characterization of niobium phosphate glasses containing barium and potassium. J Non Cryst Solids. 2004;348:30 – 7. https://linkinghub.elsevier. com/retrieve/pii/S0022309304006647 . 238. Lim TH, Sargent T, Kusubov N. Kinetics of trace element chromium(III) in the human body. Am J Physiol Integr Comp Physiol. 1983;244:R445 – 54. https://doi.org/10.1152/ajpregu. 1983.244.4.R445 . 239. Di Bona KR, Love S, Rhodes NR, McAdory D, Sinha SH, Kern N, et al. Chromium is not an essential trace element for mam- mals: effects of a “ low-chromium ” diet. JBIC J Biol Inorg Chem. 2011;16:381 – 90. https://doi.org/10.1007/s00775-010-0734-y . 240. Bhattacharya PT, Misra SR, Hussain M. Nutritional aspects of essential trace elements in oral health and disease: an extensive review. Scienti fi ca (Cairo). 2016;2016:1 – 12. http://www.hindaw i.com/journals/scienti fi ca/2016/5464373/ . 241. Krishnamacharyulu N, Jagan Mohini G, Little Flower G, Sahaya Baskaran G, Veeraiah N. An in-vitro bioactive, structural and degradation studies on B2O3 – SiO2 – P2O5 – Na2O – CaO glass system incorporated with chromium ions. Mater Today Proc. 2018;5:26280 – 9. https://doi.org/10.1016/j.matpr.2018.08.078 . 242. Mendel RR. Cell biology of molybdenum. BioFactors. 2009;35:429 – 34. https://doi.org/10.1002/biof.55 . 243. Mendel RR. Molybdenum: biological activity and metabolism. Dalt Trans. 2005;21:3404 http://xlink.rsc.org/?DOI = b505527j . 244. Sardesai VM. MOLYBDENUM: an essential trace element in human nutrition. Nutr Clin Pr. 1993;8:277 – 81. https://doi.org/10. 1177/0115426593008006277 . 245. Odularu AT, Ajibade PA, Mbese JZ. Impact of molybdenum compounds as anticancer agents. Bioinorg Chem Appl. 2019;2019:1 – 9. https://www.hindawi.com/journals/bca/2019/ 6416198/ . 246. Zoroddu MA, Aaseth J, Crisponi G, Medici S, Peana M, Nurchi VM. The essential metals for humans: a brief overview. J Inorg Biochem. 2019;195:120 – 9. https://linkinghub.elsevier.com/ retrieve/pii/S0162013418306846 247. Ribeiro AM, Flores-Sahagun THS, Paredes RC. A perspective on molybdenum biocompatibility and antimicrobial activity for applications in implants. J Mater Sci. 2016;51:2806 – 16. https:// doi.org/10.1007/s10853-015-9664-y . 248. Kirakci K, Zelenka J, Rumlová M, Cvacka J, Ruml T, Lang K. Cationic octahedral molybdenum cluster complexes functiona- lized with mitochondria-targeting ligands: photodynamic antic- ancer and antibacterial activities. Biomater Sci. 2019;7:1386 – 92. http://xlink.rsc.org/?DOI = C8BM01564C . 3 Page 36 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 249. Tian X, Sun Y, Fan S, Boudreau MD, Chen C, Ge C, et al. Photogenerated charge carriers in molybdenum disul fi de quan- tum dots with enhanced antibacterial activity. ACS Appl Mater Interfaces. 2019;11:4858 – 66. https://doi.org/10.1021/acsami. 8b19958 . 250. Mukheem A, Shahabuddin S, Akbar N, Anwar A, Sarih NM, Sudesh K, et al. Fabrication of biopolymer polyhydroxyalk- anoate/chitosan and 2D molybdenum disul fi de – doped scaffolds for antibacterial and biomedical applications. Appl Microbiol Biotechnol. 2020;104:3121 – 31. https://doi.org/10.1007/s00253- 020-10416-2 . 251. Tekin HO, Abouhaswa AS, Kilicoglu O, Issa SAM, Akkurt I, Rammah YS. Fabrication, physical characteristic, and gamma- photon attenuation parameters of newly developed molybdenum reinforced bismuth borate glasses. Phys Scr. 2020;95:115703 https://doi.org/10.1088/1402-4896/abbf6e . 252. Pramanik M, Bhaumik A. Self-assembled hybrid molybdenum phosphonate porous nanomaterials and their catalytic activity for the synthesis of benzimidazoles. ChemCatChem. 2014;6:2577 – 86. https://doi.org/10.1002/cctc.201402291 . 253. Vedeanu NS, Magdas DA. The in fl uence of some transition metal ions in lead- and calcium-phosphate glasses. J Alloys Compd. 2012;534:93 – 6. https://linkinghub.elsevier.com/retrieve/ pii/S0925838812007438 . 254. Niu W, Guo Y, Xue Y, Chen M, Wang M, Cheng W, et al. Monodisperse branched molybdenum-based bioactive nano- particles signi fi cantly promote osteogenic differentiation of adi- pose-derived stem cells. Part Part Syst Charact. 2019;36:1900105 https://doi.org/10.1002/ppsc.201900105 . 255. Ponta O, Ciceo-Lucacel R, Vulpoi A, Radu T, Simon S. Molybdenum effect on the structure of SiO2-CaO-P2O5 bioac- tive xerogels and on their interface processes with simulated bio fl uids. J Biomed Mater Res Part A. 2014;102:3177 – 85. https://doi.org/10.1002/jbm.a.34989 . 256. Dang W, Wang X, Li J, Deng C, Liu Y, Yao Q, et al. 3D printing of Mo-containing scaffolds with activated anabolic responses and bi-lineage bioactivities. Theranostics. 2018;8:4372 – 92. http://www.thno.org/v08p4372.htm . 257. Lucacel RC, Ponta O, Licarete E, Radu T, Simon V. Synthesis, structure, bioactivity and biocompatibility of melt-derived P2O5- CaO-B2O3-K2O-MoO3 glasses. J Non Cryst Solids. 2016;439:67 – 73. https://linkinghub.elsevier.com/retrieve/pii/ S0022309316300424 . 258. El-Meliegy E, Farag MM, Knowles JC. Dissolution and drug release pro fi les of phosphate glasses doped with high valency oxides. J Mater Sci Mater Med. 2016;27:108 https://doi.org/10. 1007/s10856-016-5711-8 . 259. Barrio DA, Etcheverry SB. Vanadium and bone development: putative signaling pathways. Can J Physiol Pharm. 2006;84:677 – 86. https://pubmed.ncbi.nlm.nih.gov/16998531/ . 260. Rehder D. Interrelations between essential metal ions and human diseases. In: Sigel A, Sigel H, Sigel RKO, editors. Metal ions in life sciences. Vol. 13. Dordrecht: Springer Netherlands; 2013. p. 139 – 69. https://doi.org/10.1007/978-94-007-7500-8 . 261. Pal RP, Mani V, Tripathi D, Kumar R, Kewalramani NJ. In fl u- ence of feeding inorganic vanadium on growth performance, endocrine variables and biomarkers of bone health in crossbred calves. Biol Trace Elem Res. 2018;182:248 – 56. https://doi.org/ 10.1007/s12011-017-1095-y . 262. Kilcup N, Gaynard S, Werner-Zwanziger U, Tonkopi E, Hayes J, Boyd D. Stimulation of apoptotic pathways in liver cancer cells: an alternative perspective on the biocompatibility and the utility of biomedical glasses. J Biomater Appl. 2016;30:1445 – 59. https://pubmed.ncbi.nlm.nih.gov/26675751/ . 263. Ori G, Montorsi M, Pedone A, Siligardi C. Insight into the structure of vanadium containing glasses: a molecular dynamics study. J Non Cryst Solids. 2011;357:2571 – 9. https://linkinghub. elsevier.com/retrieve/pii/S0022309311001098 . 264. Kumari CV, Kumar VR, Sobhanachalam P, Rao PV, Baskaran GS, Veeraiah N. In vitro degradation studies on bioactive cal- cium fl uoroborophosphate glasses mixed with some modi fi er oxides-in fl uence of therapeutically active vanadium ions. Mater Chem Phys. 2018;205:376 – 90. https://linkinghub.elsevier.com/ retrieve/pii/S0254058417309082 . 265. Wang YM, Wu SY, Jiang SJ, Luo YJ, Zhu QS, Han M. Inves- tigations of defect structures for V4 + in CBPB glasses with distinct V2O5 contents. J Non Cryst Solids. 2021;566:120879 https://linkinghub.elsevier.com/retrieve/pii/S0022309321002386 266. Deliormanli AM. In vitro assessment of degradation and mineralisation of V 2 O 5 substituted borate bioactive glass scaffolds. Mater Technol. 2014;29:358 – 65. https://doi.org/10. 1179/1753555714Y.0000000167 . 267. Marzouk MA, ElBatal FH, Ghoneim NA. In vitro bioactivity behavior of modi fi ed multicomponent borate glasses containing dopants of Ag2O, CuO, CeO2 or V2O5. Appl Phys A. 2018;124:110 https://doi.org/10.1007/s00339-017-1526-9 . 268. Deliormanli AM, Seda Vatansever H, Yesil H, Özdal-Kurt F. In vivo evaluation of cerium, gallium and vanadium-doped borate- based bioactive glass scaffolds using rat subcutaneous implan- tation model. Ceram Int. 2016;42:11574 – 83. https://doi.org/10. 1016/j.ceramint.2016.04.033 . 269. Deliormanli AM, Oguzlar S, Ertekin K. Photoluminescence and decay characteristics of cerium, gallium and vanadium - con- taining borate-based bioactive glass powders for bioimaging applications. Ceram Int. 2021;47:3797 – 807. https://linkinghub. elsevier.com/retrieve/pii/S0272884220329552 . 270. Deliormanli AM, Al-Buriahi MS, Somaily HH, Tekin HO. Correction to: 13-93B3 Bioactive glasses containing Ce3 + , Ga3 + and V5 + : dose rate and gamma radiation characteristic for medical purposes. Appl Phys A. 2021;127:245 https://doi.org/10. 1007/s00339-021-04407-x . 271. Li J, Li X, Li J, Pu X, Wang J, Huang Z, et al. Effects of incorporated vanadium and its chemical states on morphology and mesostructure of mesoporous bioactive glass particles. Microporous Mesoporous Mater. 2021;319:111061 https:// linkinghub.elsevier.com/retrieve/pii/S1387181121001876 . 272. Bea ttie JH, Avenell A. Trace element nutrition and bone metabo- lism. Nutr Res Rev. 1992;5:167 – 88. https://www.cambridge.org/ core/product/identi fi er/S0954422492000143/type/journal_article . 273. Rau JV, De Stefanis A, Barbaro K, Fosca M, Yankova VG, Matassa R, et al. Adipogenic, chondrogenic, osteogenic, and antimicrobial features of glass ceramic material supplemented with manganese. J Non Cryst Solids. 2021;559:120709 https:// linkinghub.elsevier.com/retrieve/pii/S0022309321000685 274. Tseng CF, Fei YC, Chou YJ. Investigation of in vitro bioactivity and antibacterial activity of manganese-doped spray pyrolyzed bioactive glasses. J Non Cryst Solids. 2020;549:120336 https:// linkinghub.elsevier.com/retrieve/pii/S0022309320304488 275. Tripathi H, Pandey GC, Dubey A, Shaw SK, Prasad NK, Singh SP, et al. Superparamagnetic manganese ferrite and strontium bioactive glass nanocomposites: enhanced biocompatibility and antimicrobial properties for hyperthermia application. Adv Eng Mater. 2021;23:2000275 https://doi.org/10.1002/adem. 202000275 . 276. Liu Y, Lin R, Ma L, Zhuang H, Feng C, Chang J, et al. Meso- porous bioactive glass for synergistic therapy of tumor and regeneration of bone tissue. Appl Mater Today. 2020;19:100578 https://doi.org/10.1016/j.apmt.2020.100578 . 277. Sarin N, Singh KJ, Kaur R, Singh J. Manganese and zinc doped CaO-SiO 2 -P 2 O 5 bioceramics for recovery from bone defects. Integr Ferroelectr. 2020;204:142 – 9. https://doi.org/10.1080/ 10584587.2019.1674973 . Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 37 of 41 3 278. Barrioni BR, Norris E, Li S, Naruphontjirakul P, Jones JR, Pereira M, de M. Osteogenic potential of sol – gel bioactive glasses containing manganese. J Mater Sci Mater Med. 2019;30:86 https://doi.org/10.1007/s10856-019-6288-9 . 279. Ferreira M, Brito A, Brazete D, Pereira I, Carrilho E, Abrantes A, et al. Doping β -TCP as a strategy for enhancing the regenerative potential of composite β -TCP — alkali-free bioactive glass bone grafts. Experimental study in rats. Materials (Basel). 2018;12:4 https://pubmed.ncbi.nlm.nih.gov/30577440/ . 280. Vadera N, Ashokan A, Gowd GS, Sajesh KM, Chauhan RP, Jayakumar R, et al. Manganese doped nano-bioactive glass for magnetic resonance imaging. Mater Lett. 2015;160:335 – 8. https://doi.org/10.1016/j.matlet.2015.07.158 . 281. Srivastava AK, Pyare R, Singh SP. In vitro bioactivity and physical – mechanical properties of MnO2 substituted 45S5 bioactive glasses and glass-ceramics. J Biomater Tissue Eng. 2012;2:249 – 58. http://openurl.ingenta.com/content/xref? genre = article&issn = 2157-9083&volume = 2&issue = 3&spage = 249 . 282. Miola M, Brovarone CV, Maina G, Rossi F, Bergandi L, Ghigo D, et al. In vitro study of manganese-doped bioactive glasses for bone regeneration. Mater Sci Eng C. 2014;38:107 – 18. https:// doi.org/10.1016/j.msec.2014.01.045 . 283. Cañaveral S, Morales D, Vargas AF. Synthesis and character- ization of a 58S bioglass modi fi ed with manganese by a sol-gel route. Mater Lett. 2019;255:126575. https://linkinghub.elsevier. com/retrieve/pii/S0167577X19311966 . 284. Barrioni BR, Oliveira AC, de Fátima Leite M, de Magalhães Pereira M. Sol – gel-derived manganese-releasing bioactive glass as a therapeutic approach for bone tissue engineering. J Mater Sci. 2017;52:8904 – 27. https://doi.org/10.1007/s10853-017-0944-6 . 285. Nawaz Q, Rehman MAU, Burkovski A, Schmidt J, Beltrán AM, Shahid A, et al. Synthesis and characterization of manganese containing mesoporous bioactive glass nanoparticles for biome- dical applications. J Mater Sci Mater Med. 2018;29:64 https:// doi.org/10.1007/s10856-018-6070-4 . 286. Westhauser F, Wilkesmann S, Nawaz Q, Hohenbild F, Rehder F, Saur M, et al. Effect of manganese, zinc, and copper on the biological and osteogenic properties of mesoporous bioactive glass nanoparticles. J Biomed Mater Res Part A. 2021;109:1457 – 67. https://doi.org/10.1002/jbm.a.37136 . 287. Westhauser F, Wilkesmann S, Nawaz Q, Schmitz SI, Moghad- dam A, Boccaccini AR. Osteogenic properties of manganese- doped mesoporous bioactive glass nanoparticles. J Biomed Mater Res Part A. 2020;108:1806 – 15. https://doi.org/10.1002/ jbm.a.36945 . 288. Bragiel P, Ficek P, Prochwicz W, Radkowska I, Veeraiah N. Are the phosphorus-rich Na2O – CaO – B2O3 – SiO2 – P2O5 glasses bioactive and what is an in fl uence of doping with manganese oxide? Mater Sci. 2017;35:760 – 6. https://doi.org/10.1515/msp- 2017-0093 . 289. Aina V, Cerrato G, Martra G, Bergandi L, Costamagna C, Ghigo D, et al. Gold-containing bioactive glasses: a solid-state synthesis to produce alternative biomaterials for bone implantations. J R Soc Interface. 2013;10:20121040 https://doi.org/10.1098/rsif. 2012.1040 . 290. Lusvardi G, Malavasi G, Aina V, Bertinetti L, Cerrato G, Magnacca G, et al. Bioactive glasses containing Au nano- particles. Effect of calcination temperature on structure, mor- phology, and surface properties. Langmuir. 2010;26:10303 – 14. https://doi.org/10.1021/la100472p . 291. Mârza SM, Magyari K, Bogdan S, Moldovan M, Pe?tean C, Nagy A, et al. The impact of composites with silicate-based glasses and gold nanoparticles on skin wound regeneration. Molecules. 2021;26:620. https://www.mdpi.com/1420-3049/26/ 3/620/htm . 292. Yin C, Zhao Q, Li W, Zhao Z, Wang J, Deng T, et al. Biomi- metic anti-in fl ammatory nano-capsule serves as a cytokine blocker and M2 polarization inducer for bone tissue repair. Acta Biomater. 2020;102:416 – 26. https://linkinghub.elsevier.com/ retrieve/pii/S1742706119307664 . 293. Wang CK, Chen SH, Li WY, Lai CH, Chen WC. Bioactive glass shell growth of a Si-Na-Ca-P layer on gold nanoparticles func- tionalized with mercaptopropyltrimethyloxysilane-silicate- tetra- ethylothosilicate. Surf Rev Lett. 2009;16:37 – 42. https://doi.org/ 10.1142/S0218625X09012263 . 294. Wang G, Wu X, Cen D, He H, Fu Y, Ren Z, et al. A bifunctional scaffold for tissue regeneration and photothermal therapy. J Biomed Nanotechnol. 2018;14:698 – 706. https://doi.org/10.1166/ jbn.2018.2548 . 295. Simon S, Ciceo-Lucacel R, Radu T, Baia L, Ponta O, Iepure A, et al. Gold nanoparticles developed in sol – gel derived apatite — bioactive glass composites. J Mater Sci Mater Med. 2012;231193 – 201. https://doi.org/10.1007/s10856-012-4590-x . 296. Yao L, Wang X, Weng W, Fu Y, Cheng K. Bioactive nano- composite coatings under visible light illumination promoted surface-mediated gene delivery. Biomater Sci. 2020;8:3685 – 96. https://pubs.rsc.org/en/content/articlehtml/2020/bm/ d0bm00123f . 297. Catauro M, Papale F, Caputo P, Donnarumma G. Chemical, biological, and antibacterial characterization of silica glass con- taining silver and gold nanoparticles. Int J Appl Ceram Technol. 2017;14:108 – 16. https://doi.org/10.1111/ijac.12643 . 298. Aina V, Ghigo D, Marchis T, Cerrato G, Laurenti E, Morterra C, et al. Novel bio-conjugate materials: soybean peroxidase immobilized on bioactive glasses containing Au nanoparticles. J Mater Chem. 2011;21:10970 – 81. https://pubs.rsc.org/en/ content/articlehtml/2011/jm/c1jm10442j . 299. Regos AN, Ardelean I. Preparation, structure and bioactivity of xAu2O3·(100 − x)[P2O5·CaO] glass system. J Mol Struct. 2011;1006:312 – 7. 300. Aina V, Marchis T, Laurenti E, Diana E, Lusvardi G, Malavasi G, et al. Functionalization of sol gel bioactive glasses carrying Au nanoparticles: selective Au af fi nity for amino and thiol ligand groups. Langmuir. 2010;26:18600 – 5. https://doi.org/10.1021/la 1036647 . 301. Jayalekshmi AC, Sharma CP. Gold nanoparticle incorporated polymer/bioactive glass composite for controlled drug delivery application. Colloids Surfaces B Biointerfaces. 2015;126:280 – 7. https://linkinghub.elsevier.com/retrieve/pii/ S0927776514006985 . 302. Mârza S, Magyari K, Bogdan S, Moldovan M, Pestean C, Nagy A, et al. Skin wound regeneration with bioactive glass-gold nanoparticles ointment. Biomed Mater. 2019;14:025011. https:// pubmed.ncbi.nlm.nih.gov/30630137/ . 303. Magyari K, Tóth ZR, Pap Z, Licarete E, Vodnar DC, Todea M, et al. Insights into the effect of gold nanospheres, nanotriangles and spherical nanocages on the structural, morphological and biological properties of bioactive glasses. J Non Cryst Solids. 2019;522:119552. https://linkinghub.elsevier.com/retrieve/pii/ S0022309319304235 304. Dreanca A, Muresan-Pop M, Taulescu M, Tóth ZR, Bogdan S, Pestean C, et al. Bioactive glass-biopolymers-gold nanoparticle based composites for tissue engineering applications. Mater Sci Eng C. 2021;123:112006 https://linkinghub.elsevier.com/ retrieve/pii/S0928493121001454 305. Magyari K, Nagy-Simon T, Vulpoi A, Popescu RA, Licarete E, Stefan R, et al. Novel bioactive glass-AuNP composites for biomedical applications. Mater Sci Eng C. 2017;76:752 – 9. https://doi.org/10.1016/j.msec.2017.03.138 . 306. Grandi S, Cassinelli V, Bini M, Saino E, Mustarelli P, Arciola CR, et al. Bone reconstruction: Au nanocomposite bioglasses 3 Page 38 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 with antibacterial properties. Int J Artif Organs. 2011;34:920 – 8. https://doi.org/10.5301/ijao.5000059 . 307. Tekin HO, Kavaz E, Altunsoy EE, Kilicoglu O, Agar O, Erguzel TT, et al. An extensive investigation on gamma-ray and neutron attenuation parameters of cobalt oxide and nickel oxide sub- stituted bioactive glasses. Ceram Int. 2019;45:9934 – 49. https:// linkinghub.elsevier.com/retrieve/pii/S0272884219303335 308. Floroian L, Florescu M, Munteanu D, Badea M, Popescu-Pelin G, Ristoscu C, et al. A new concept of stainless steel medical implant based upon composite nanostructures coating. Dig J Nanomater Biostructures. 2014;9:1555 – 68. https://chalcogen.ro/ 1555_Floroian.pdf 309. Smith JM, Martin RA, Cuello GJ, Newport RJ. Structural characterisation of hypoxia-mimicking bioactive glasses. J Mater Chem B. 2013;1:1296. http://xlink.rsc.org/?DOI = c3tb00408b . 310. Kumari CV, Gandhi Y, Sobhanachalam P, Reddy ASS, Ven- katramaiah N, Rao PV, et al. Bioactive behaviour of NiO sub- stituted CaF2 – CaO – B2O3 – BaO – P2O5 glasses by means of spectroscopic studies. Opt Mater (Amst). 2019;97:109394 https://linkinghub.elsevier.com/retrieve/pii/S0925346719306147 311. Elnahrawy A, Elokr MM, Metawe F, Osman BA, el kader A. Characteristics and magnetic properties of ((80-x) P2O5: 20 SiO2: X Al2O3) and doped with Ni2O3 prepared by sol gel method. J Ovonic Res. 2016;12:253 – 9. https://www.researchga te.net/publication/309427094_Characteristics_and_magnetic_ properties_of_80-x_P2O5_20_SiO2_X_Al2O3_and_doped_w ith_Ni2O3_prepared_by_sol_gel_method . 312. Boukhris I, Alalawi A, Al-Buriahi MS, Kebaili I, Sayyed MI. Radiation attenuation properties of bioactive glasses doped with NiO. Ceram Int. 2020;46:19880 – 9. https://linkinghub.elsevier. com/retrieve/pii/S0272884220313328 313. Vyas VK, Kumar AS, Ali A, Prasad S, Srivastava P, Mallick SP, et al. Assessment of nickel oxide substituted bioactive glass- ceramic on in vitro bioactivity and mechanical properties. Boletín la Soc Española Cerámica y Vidr. 2016;55:228 – 38. https://doi.org/10.1016/j.bsecv.2016.09.005 . 314. Vyas VK, Sampath Kumar A, Singh SP, Pyare R. Effect of nickel oxide substitution on bioactivity and mechanical proper- ties of bioactive glass. Bull Mater Sci. 2016;39:1355 – 61. https:// doi.org/10.1007/s12034-016-1242-7 . 315. Vyas VK, Kumar AS, Singh SP, Pyare R. Destructive and non- destructive behavior of nickel oxide doped bioactive glass and glass-ceramic. J Aust Ceram Soc. 2017;53:939 – 51. https://doi. org/10.1007/s41779-017-0110-2 . 316. Adam V, Hanustiak P, Krizkova S, Beklova M, Zehnalek J, Trnkova L, et al. Palladium biosensor. Electroanalysis. 2007;19:1909 – 14. https://doi.org/10.1002/elan.200703953 . 317. Pranczk J, Jacewicz D, Wyrzykowski D, Chmurzynski L. Platinum (II) and Palladium(II) complex compounds as anti-cancer drugs. Methods of cytotoxicity deter mination. Curr Pharm Anal. 2014;10:2 – 9. http://www.eurekaselect. com/openurl/content.php? genre = article&issn = 1573-4129&volume = 10&issue = 1&spage = 2 . 318. Ulukaya E, Ari F, Dimas K, Ikitimur EI, Guney E, Yilmaz VT. Anti-cancer activity of a novel palladium(II) complex on human breast cancer cells in vitro and in vivo. Eur J Med Chem. 2011;46:4957 – 63. https://linkinghub.elsevier.com/retrieve/pii/ S022352341100568X . 319. Wu W, Liu ZW, Hua JJ, Lin CC, Zeng Y, Ding F. Preparation of palladium-containing mesoporous bioactive glass catalyst and evaluation of its catalytic effect on oxidation of benzyl alcohol. Mater Res Innov. 2013;17:53 – 7. https://doi.org/10.1179/ 1432891713Z.000000000180 . 320. Medkov MA, Grishchenko DN, Kuryavyi VG, Slobodyuk AB. Tungsten-containing bioactive radiocontrast glass: production and properties. Glas Ceram. 2018;75:322 – 6. https://doi.org/10. 1007/s10717-018-0079-5 . 321. Deliormanli AM, Ensoylu M, Issa SAM, Elshami W, Al-Baradi AM, Al-Buriahi MS, et al. WS2/bioactive glass composites: fabrication, structural, mechanical and radiation attenuation properties. Ceram Int. 2021;47:29739 – 47. https://linkinghub. elsevier.com/retrieve/pii/S0272884221021878 . 322. Uosif MAM, Mostafa AMA, Issa SAM, Tekin HO, Alrowaili ZA, Kilicoglu O. Structural, mechanical and radiation shielding properties of newly developed tungsten lithium borate glasses: an experimental study. J Non Cryst Solids. 2020;532:119882. https://linkinghub.elsevier.com/retrieve/pii/ S0022309319307525 . 323. Berend K, van Hulsteijn LH, Gans ROB. Chloride: the queen of electrolytes? Eur J Intern Med. 2012;23:203 – 11. https:// linkinghub.elsevier.com/retrieve/pii/S0953620511002779 . 324. Chungong LF, Swansbury LA, Mountjoy G, Hannon AC, Lee AF, Martin RA. Atomic structure of chlorine containing calcium sili- cate glasses by neutron diffraction and 29 Si solid-state NMR. Int J Appl Glas Sci. 2017;8:383 – 90. https://doi.org/10.1111/ijag.12280 . 325. Swansbury LA, Mountjoy G, Chen X, Karpukhina N, Hill R. Modeling the onset of phase separation in CaO – SiO 2 – CaCl 2 chlorine-containing silicate glasses. J Phys Chem B. 2017;121:5647 – 53. https://doi.org/10.1021/acs.jpcb.7b02986 . 326. Pedone A, Chen X, Hill RG, Karpukhina N. Molecular dynamics investigation of halide-containing phospho-silicate bioactive glasses. J Phys Chem B. 2018;122:2940 – 8. https://doi.org/10. 1021/acs.jpcb.8b00547 . 327. Chen X, Karpukhina N, Brauer DS, Hill RG. Novel highly degradable chloride containing bioactive glasses. Biomed Glas. 2015;1:108 – 18. https://doi.org/10.1515/bglass-2015-0010/html . 328. Chen X, Hill R, Karpukhina N. Chlorapatite glass-ceramics. Int J Appl Glas Sci. 2014;5:207 – 16. https://doi.org/10.1111/ijag.12082 . 329. Chen X, Chen X, Pedone A, Apperley D, Hill RG, Karpukhina N. New insight into mixing fl uoride and chloride in bioactive silicate glasses. Sci Rep. 2018;8:1316 http://www.nature.com/a rticles/s41598-018-19544-2 . 330. Abraham G, Flechas J, Hakala J. Orthoiodosupplementation: iodine suf fi ciency of the whole human body. 2007. https://hea lthfully. fi les.wordpress.com/2017/03/iod02.pdf . Accessed 20 Aug 2021. 331. Ottomeyer M, Mohammadkah A, Day D, Westenberg D. Broad- spectrum antibacterial characteristics of four novel borate-based bioactive glasses. Adv Microbiol. 2016;6:776 – 87. https://doi. org/10.4236/aim.2016.610076 . 332. Gupta B, Papke JB, Mohammadkhah A, Day DE, Harkins AB. Effects of chemically doped bioactive borate glass on neuron regrowth and regeneration. Ann Biomed Eng. 2016;44:3468 – 77. https://doi.org/10.1007/s10439-016-1689-0 . 333. Li L, Ruan T, Lyu Y, Wu B. Advances in effect of germanium or germanium compounds on animals — a review. J Biosci Med. 2017;5:56 – 73. http://www.scirp.org/journal/PaperInformation. aspx?PaperID = 77890 . 334. Goodman S. Therapeutic effects of organic germanium. Med Hypotheses. 1988;26:207 – 15. https://linkinghub.elsevier.com/ retrieve/pii/0306987788901016 . 335. Khader BA, Rodriguez O, Towler M. Incorporating germanium oxide into the glass phase of novel zinc/magnesium-based GPCs designed for bone void fi lling: evaluating their physical and mechanical properties. J Funct Biomater. 2018;9:47. http://www. mdpi.com/2079-4983/9/3/47 . 336. Mokhtari S, Krull EA, Sanders LM, Coughlan A, Mellott NP, Gong Y, et al. Investigating the effect of germanium on the structure of SiO2-ZnO-CaO-SrO-P2O5 glasses and the sub- sequent in fl uence on glass polyalkenoate cement formation, solubility and bioactivity. Mater Sci Eng C. 2019;103:109843. https://linkinghub.elsevier.com/retrieve/pii/S09284931173 48956 . Journal of Materials Science: Materials in Medicine (2022) 33:3 Page 39 of 41 3 337. Saddeek YB, Issa SAM, Guclu EEA, Kilicoglu O, Susoy G, Tekin HO. Alkaline phosphate glasses and synergistic impact of germanium oxide (GeO2) additive: mechanical and nuclear radiation shielding behaviors. Ceram Int. 2020;46:16781 – 97. https://linkinghub.elsevier.com/retrieve/pii/ S0272884220309020 . 338. Wang R, Li H, Sun H. Bismuth: environmental pollution and health effects. In: Nriagu J, editor. Encyclopedia of environ- mental health. Elsevier; 2019. p. 415 – 23. https://linkinghub. elsevier.com/retrieve/pii/B9780124095489118706 . 339. Thomas F, Bialek B, Hensel R. Medical use of bismuth: the two sides of the coin. J Clin Toxicol. 2011;3:4. https://www. omicsonline.org/medical-use-of-bismuth-the-two-sides-of-the- coin-2161-0495.S3-004.php?aid = 5343 . 340. Lin DJ, Tsai MT, Shieh TM, Huang HL, Hsu JT, Ko YC, et al. In vitro antibacterial activity and cytocompatibility of bismuth doped micro-arc oxidized titanium. J Biomater Appl. 2013;27:553 – 63. https://doi.org/10.1177/0885328211414942 . 341. Slikkerveer A, Wolff FA. Pharmacokinetics and toxicity of bis- muth compounds. Med Toxicol Advers Drug Exp. 1989;4:303 – 23. https://doi.org/10.1007/BF03259915 . 342. Boukhris I, Kebaili I, Al-Buriahi MS, Tonguc B, AlShammari MM, Sayyed MI. Effect of bismuth oxide on the optical features and gamma shielding ef fi ciency of lithium zinc borate glasses. Ceram Int. 2020;46:22883 – 8. https://linkinghub.elsevier.com/ retrieve/pii/S0272884220317089 . 343. Pazarçeviren AE, Evis Z, Keskin D, T ezcaner A. Resorbable PCEC/gelatin-bismuth doped bio glass-graphene oxide bilayer membranes for guided bone regeneration. Biomed Mater. 2019;14:035018. https://doi.org/10.10 88/1748-605X/ab007b . 344. Khatua C, Bodhak S, Kundu B, Balla VK. In vitro bioactivity and bone mineralization of bismuth ferrite reinforced bioactive glass composites. Materialia. 2018;4:361 – 6. https://doi.org/10. 1016/j.mtla.2018.10.014 . 345. Wang L, Long NJ, Li L, Lu Y, Li M, Cao J, et al. Multi-functional bismuth-doped bioglasses: combining bioactivity and photothermal response for bone tumor treatment and tissue repair. Light Sci Appl. 2018;7:1 https://doi.org/10.1038/s41377-018-0007-z . 346. Prasad SS, Ratha I, Adarsh T, Anand A, Sinha PK, Diwan P, et al. In vitro bioactivity and antibacterial properties of bismuth oxide modi fi ed bioactive glasses. J Mater Res. 2018;33:178 – 90. https://doi.org/10.1557/jmr.2017.442 . 347. Heid S, Stoessel PR, Tauböck TT, Stark WJ, Zehnder M, Mohn D. Incorporation of particulate bioactive glasses into a dental root canal sealer. Biomed Glas. 2016;2:29 – 37. https://doi.org/10. 1515/bglass-2016-0004/html . 348. Esmail SAA, Shamsi M, Chen T, Al-asbahy WM. Design, synthesis and characterization of tin-based cancer chemotherapy drug entity: In vitro DNA binding, cleavage, induction of cancer cell apoptosis by triggering DNA damage-mediated p53 phos- phorylation and molecular docking. Appl Organomet Chem. 2019;33:e4651 https://doi.org/10.1002/aoc.4651 . 349. Meng X, You L, Li S, Sun Q, Luo X, He H, et al. An ICT- based fl uorescence enhancement probe for detection of Sn 2 + in cancer cells. RSC Adv. 2020;10:37735 – 42. http://xlink.rsc. org/?DOI = D0RA07330J . 350. Alfadhli S, Kumar A, Sayyed MI, Jain A, Laariedh F, Mahmoud KA, et al. Gamma ray interaction studies of the PbCl2 – SnCl2 – P2O5 bioactive glass system for applications in nuclear medi- cine. J Aust Ceram Soc. 2021;57:635 – 42. https://doi.org/10. 1007/s41779-021-00564-7 . 351. Akin SRK, Dolekcekic E, Webster TJ. Effect of nitrogen on the antibacterial behavior of oxynitride glasses. Ceram Int. 2021;47:18213 – 7. https://linkinghub.elsevier.com/retrieve/pii/ S0272884221008270 . 352. Hani fi AR, Crowley CM, Pomeroy MJ, Hampshire S. Bioactivity potential of calcium alumino-silicate glasses and glass – ceramics containing nitrogen and fl uorine. J Mater Sci. 2014;49:4590 – 4. https://doi.org/10.1007/s10853-014-8159-6 . 353. Al-Hadeethi Y, Al-Buriahi MS, Sayyed MI. Bioactive glasses and the impact of Si3N4 doping on the photon attenuation up to radiotherapy energies. Ceram Int. 2020;46:5306 – 14. https:// linkinghub.elsevier.com/retrieve/pii/S0272884219331554 . 354. Wójcik NA, Jonson B, Möncke D, Palles D, Kamitsos EI, Ghas- semali E, et al. In fl uence of synthesis conditions on glass forma- tion, structure and thermal properties in the Na2O-CaO-P2O5 system doped with Si3N4 and Mg. J Non Cryst Solids. 2018;494:66 – 77. https://doi.org/10.1016/j.jnoncrysol.2018.04.055 . 355. Bachar A, Mercier C, Tricoteaux A, Leriche A, Follet C, Saadi M, et al. Effects of addition of nitrogen on bioglass properties and structure. J Non Cryst Solids. 2012;358:693 – 701. https://doi. org/10.1016/j.jnoncrysol.2011.11.036 . 356. Bachar A, Mercier C, Tricoteaux A, Leriche A, Follet-Houtte- mane C, Saadi M, et al. Effects of nitrogen on properties of oxy fl uoronitride bioglasses. Process Biochem. 2013;48:89 – 95. https://linkinghub.elsevier.com/retrieve/pii/ S1359511312002292 . 357. Mabrouk A, Bachar A, Atbir A, Follet C, Mercier C, Tricoteaux A, et al. Mechanical properties, structure, bioactivity and cyto- toxicity of bioactive Na-Ca-Si-P-O-(N) glasses. J Mech Behav Biomed Mater. 2018;86:284 – 93. https://doi.org/10.1016/j. jmbbm.2018.06.023 . 358. Marin E, Adachi T, Boschetto F, Zanocco M, Rondinella A, Zhu W, et al. Biological response of human osteosarcoma cells to Si3N4-doped Bioglasses. Mater Des. 2018;159:79 – 89. https:// doi.org/10.1016/j.matdes.2018.08.020 . 359. Schroeder HA, Buckman J, Balassa JJ. Abnormal trace elements in man: tellurium. J Chronic Dis. 1967;20:147 – 61. https:// linkinghub.elsevier.com/retrieve/pii/0021968167900495 . 360. Ma MG, Zhu JF, Sun RC, Chen F, Zhu YJ. Synthesis and characterization of the tellurium/calcium silicate nanocomposite. Mater Lett. 2011;65:424 – 6. https://doi.org/10.1016/j.matlet. 2010.10.083 . 361. El-Damrawi G, Doweidar H, Kamal H. Characterization of new categories of bioactive based tellurite and silicate glasses. Sili- con. 2017;9:503 – 9. https://doi.org/10.1007/s12633-014-9248-5 . 362. Tekin HO, Kassab LRP, Kilicoglu O, Magalhães ES, Issa SAM, da Silva Mattos GR. Newly developed tellurium oxide glasses for nuclear shielding applications: an extended investigation. J Non Cryst Solids. 2020;528:119763 https://doi.org/10.1016/j. jnoncrysol.2019.119763 . 363. Rammah YS. Evaluation of radiation shielding ability of boro- tellurite glasses: TeO2 – B2O3 – SrCl2 – LiF – Bi2O3. Appl Phys A. 2019;125:857 https://doi.org/10.1007/s00339-019-3154-z . 364. Wang H, Chai L, Xie Z, Zhang H. Recent advance of tellurium for biomedical applications. Chem Res Chin Univ. 2020;36:551 – 9. https://doi.org/10.1007/s40242-020-0193-0 . 365. Sredni B. Immunomodulating tellurium compounds as anti- cancer agents. Semin Cancer Biol. 2012;22:60 – 9. https://doi.org/ 10.1016/j.semcancer.2011.12.003 . 366. Miola M, Massera J, Cochis A, Kumar A, Rimondini L, Vernè E. Tellurium: a new active element for innovative multifunctional bioactive glasses. Mater Sci Eng C. 2021;123:111957. https:// linkinghub.elsevier.com/retrieve/pii/S0928493121000965 . 367. Rayman MP. Selenium and human health. Lancet. 2012;379:1256 – 68. https://doi.org/10.1016/S0140-6736(11)61452-9 . 368. Amaral AFS, Porta M, Silverman DT, Milne RL, Kogevinas M, Rothman N, et al. Pancreatic cancer risk and levels of trace elements. Gut. 2012;61:1583 – 8. https://gut.bmj.com/lookup/doi/ 10.1136/gutjnl-2011-301086 . 3 Page 40 of 41 Journal of Materials Science: Materials in Medicine (2022) 33:3 369. Elshami W, Tekin HO, Al-Buriahi MS, Hegazy HH, Abuzaid MM, Issa SAM, et al. Developed selenium dioxide-based cera- mics for advanced shielding applications: Au2O3 impact on nuclear radiation attenuation. Results Phys. 2021;24:104099. https://linkinghub.elsevier.com/retrieve/pii/ S2211379721002564 . 370. Karan R, Manna P, Maiti PK, Das K. In fl uence of selenium dioxide (SeO2) on properties of bioglass in SiO2-Na2O-CaO- P2O5 system. J Aust Ceram Soc. 2020;56:1135 – 45. https://doi. org/10.1007/s41779-020-00459-z . 371. Aksakal B, Demirel M. In vitro study of antimicrobial and cell viability on newly synthesized bioglass-based bone grafts: effects of selenium and silver additions. Proc Inst Mech Eng Part H J Eng Med. 2018;232:1039 – 47. https://doi.org/10.1177/ 0954411918797968 . 372. Lucacel RC, Radu T, Ponta O, Simon V. Novel selenium con- taining boro-phosphate glasses: preparation and structural study. Mater Sci Eng C. 2014;39:61 – 6. https://linkinghub.elsevier.com/ retrieve/pii/S0928493114001027 . 373. Coughlan A, Haddad HF, Wren AW, Hall MM. An exploratory investigation of the development and evaluation of a novel selenium containing bioactive glass. In: 2013 39th Annual Northeast Bioengineering Conference. 2013. p. 104 – 6. https:// doi.org/10.1109/NEBEC.2013.49 . 374. Wang X, Zhang Y, Ma Y, Chen D, Yang H, Li M. Selenium- containing mesoporous bioactive glass particles: physicochem- ical and drug delivery properties. Ceram Int. 2016;42:3609 – 17. https://doi.org/10.1016/j.ceramint.2015.11.024 . 375. Ikizler BK, Terzioglu P, Tekerek BSO, Yücel S. Effect of sele- nium incorporation on the structure and in vitro bioactivity of 45S5 bioglass. J Aust Ceram Soc. 2020;56:697 – 709. https://doi. org/10.1007/s41779-019-00388-6 . 376. Hu M, Fang J, Zhang Y, Wang X, Zhong W, Zhou Z. Design and evaluation a kind of functional biomaterial for bone tissue engineering: selenium/mesoporous bioactive glass nanospheres. J Colloid Interface Sci. 2020;579:654 – 66. https://doi.org/10. 1016/j.jcis.2020.06.122 . 377. El-Kady AM, Ali AA, El-Fiqi A. Controlled delivery of ther- apeutic ions and antibiotic drug of novel alginate-agarose matrix incorporating selenium-modi fi ed borosilicate glass designed for chronic wound healing. J Non Cryst Solids. 2020;534:119889 https://doi.org/10.1016/j.jnoncrysol.2020.119889 . 378. Whitlow J, Paul A, Polini A. Bioactive materials: de fi nitions and application in tissue engineering and regeneration therapy. In: Marchi J, editor. Advanced Structured Materials. Cham: Springer; 2016. p. 1 – 17. https://doi.org/10.1007/978-3-319-44249-5\_1 . 379. Zheng K, Torre E, Bari A, Taccardi N, Cassinelli C, Morra M, et al. Antioxidant mesoporous Ce-doped bioactive glass nano- particles with anti-in fl ammatory and pro-osteogenic activities. Mater Today Bio. 2020;5:100041 https://doi.org/10.1016/j. mtbio.2020.100041 . 380. Schuhladen K, Stich L, Schmidt J, Steinkasserer A, Boccaccini AR., Zinser E. Cu, Zn doped borate bioactive glasses: anti- bacterial ef fi cacy and dose-dependent in vitro modulation of murine dendritic cells. Biomater Sci. 2020;8:2143 – 55. http:// xlink.rsc.org/?DOI = C9BM01691K . 381. Lima JM, de Pinheiro Ferreira E, Bonan RF, Silva-Teixeira DN, Goulart LR, de Souza JR, et al. Cytokine regulation from human peripheral blood leukocytes cultured in vitro with silver doped bioactive glasses microparticles. Biomed Res Int. 2019;2019:1 – 9. https://www.hindawi.com/journals/bmri/2019/3210530/ . 382. Fiume E, Barberi J, Verné E, Baino F. Bioactive glasses: from parent 45S5 composition to scaffold-assisted tissue-healing therapies. J Funct Biomater. 2018;9:24 https://www.mdpi.com/ 2079-4983/9/1/24 . 383. Souza MT, Tansaz S, Zanotto ED, Boccaccini AR. Bioactive glass fi ber-reinforced PGS matrix composites for cartilage regeneration. Materials (Basel). 2017;10:83 http://www.mdpi. com/1996-1944/10/1/83 . 384. Atkinson I, A nghel EM, Petrescu S, Seciu AM, Stefan LM, Mocioiu OC, et al. Cerium-containing mes oporous bioactive g lasses: material characterization, in vitro bioactivity, biocompatibility and cytotoxi- city evaluation. Microporous Mesoporous Mater. 2019;276:76 – 88. https://doi.org/10.1016/ j.micromeso.2018.09.029 . 385. Ribeiro M, Monteiro FJ, Ferraz MP. Infection of orthopedic implants with emphasis on bac terial adhesion process and techniques used in studying bact erial-material interactions. Biomatter. 2012;2:176 – 94. https://doi.org/10.4161/biom. 22905 . 386. Zhu H, Zheng K, Boccaccini AR. Multi-functional silica-based mesoporous materials for simultaneous delivery of biologically active ions and therapeutic biomolecules. Acta Biomater. 2021;129:1 – 17. https://pubmed.ncbi.nlm.nih.gov/34010692/ . 387. Kaur G, Kumar V, Baino F, Mauro JC, Pickrell G, Evans I, et al. Mechanical properties of bioactive glasses, ceramics, glass- ceramics and composites: State-of-the-art review and future challenges. Mater Sci Eng C. 2019;104:109895. https://doi.org/ 10.1016/j.msec.2019.109895 . 388. Curcio M, De Stefanis A, De Bonis A, Teghil R, Rau JV. Pulsed laser deposited bioactive RKKP-Mn glass-ceramic coatings on titanium. Surf Coat Technol. 2019;357:122 – 8. https://doi.org/10. 1016/j.surfcoat.2018.10.004 . 389. Barrioni BR, Naruphontjirakul P, Norris E, Li S, Kelly NL, Hanna JV, et al. Effects of manganese incorporation on the morphology, structure and cytotoxicity of spherical bioactive glass nanoparticles. J Colloid Interface Sci. 2019;547:382 – 92. https://doi.org/10.1016/j.jcis.2019.04.016 . 390. Sarin N, Singh KJ, Singh D, Arora S, Singh AP, Mahajan H. Preliminary studies of strontium and selenium binary doped CaO – SiO2 – P2O5 – MgO bioceramics for faster growth of hydroxyapatite and bone regeneration applications. Mater Chem Phys. 2020;253:123329 https://doi.org/10.1016/j.matchemphys. 2020.123329 . 391. Moghanian A, Zohourfazeli M, Haji Mahdi Tajer M, Miri AK. Comprehensive in vitro studies of novel sol gel-derived Zr4 + /Zn2 + co-substituted bioactive glass with enhanced biological proper- ties for bone healing. J Non Cryst Solids. 2021;566:120887 https:// doi.org/10.1016/j.jnoncrysol.2021.120887 . 392. Ershad M, Vyas VK, Prasad S, Ali A, Pyare R. Synthesis and characterization of cerium- and lanthanum-containing bioactive glass. Key Eng Mater. 2017;751:617 – 28. https://www.scienti fi c. net/KEM.751.617 . 393. Deliormanli AM, Yildirim M. Sol-gel synthesis of 13-93 bioactive glass powders containing therapeutic agents. J Aust Ceram Soc. 2016;52:9 – 19. https://aperta.ulakbim.gov.tr/record/ 57399#.YSPDyI4zZPY . 394. Bachar A, Mercier C, Tricoteaux A, Hampshire S, Leriche A, Follet C. Effect of nitrogen and fl uorine on mechanical properties and bioactivity in two series of bioactive glasses. J Mech Behav Biomed Mater. 2013;23:133 – 48. https://doi.org/10.1016/j. jmbbm.2013.03.010 . 395. Pazarçeviren AE, Tahmasebifar A, Tezcaner A, Keskin D, Evis Z. Investigation of bismuth doped bioglass/graphene oxide nanocomposites for bone tissue engineering. Ceram Int. 2018;44:3791 – 9. https://linkinghub.elsevier.com/retrieve/pii/ S0272884217326226 . 396. Kalaivani S, Srividiya S, Vijayalakshmi U, Kannan S. Bioac- tivity and up-conversion luminescence characteristics of Yb3 + /Tb3 + co-doped bioglass system. Ceram Int. 2019;45:18640 – 7. https://doi.org/10.1016/j.ceramint.2019.06.088 . 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