materials Review A Short Review on Biomedical Applications of Nanostructured Bismuth Oxide and Related Nanomaterials Mattia Bartoli 1,2 , Pravin Jagdale 3 and Alberto Tagliaferro 1,2,* 1 Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin, Italy; [email protected] 2 Italian Institute of Technology, Via Livorno 60, 10144 Torino, Italy 3 Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali (INSTM), Via G. Giusti 9, 50121 Florence, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-011-0907347 Received: 28 October 2020; Accepted: 18 November 2020; Published: 19 November 2020 Abstract: In this review, we reported the main achievements reached by using bismuth oxides and related materials for biological applications. We overviewed the complex chemical behavior of bismuth during the transformation of its compounds to oxide and bismuth oxide phase transitions. Afterward, we summarized the more relevant studies regrouped into three categories based on the use of bismuth species: (i) active drugs, (ii) diagnostic and (iii) theragnostic. We hope to provide a complete overview of the great potential of bismuth oxides in biological environments. Keywords: bismuth oxide; nanoparticles; radiopacity; chemotherapy; theragnostic 1. Introduction Recently, the concerns for human healthiness have risen day by day. Pharma industries and the research community have committed themselves to improve both the knowledge and on-field real application of newly designed drugs and protocols. Despite the numerous available established treatments, there is still an urgent need to develop new and innovative technologies that could help to delineate tumor margins, identify residual tumor cells and eventually eliminate them [1–3]. Furthermore, the development of new antimicrobial agents able to overcome antibiotic resistance rising has become critical [4]. All of these issues have been deeply investigated by nanoscience and material technology. Among all the promising nanostructured or nanosized materials, bismuth-based ones, although rather neglected, are full of unexpressed potential [5]. Bismuth has been used in plenty of applications since the 19th century for the treatment of bacterial infections but its use slowed down in the middle of the 20th century after the reversible bismuth encephalopathy occurred in France and Australia [6,7]. Nonetheless, bismuth-based medical formulations are still being used for stomach issues treatments as bismuth subsalicylate [8,9], colloidal bismuth subcitrate [10–12] or bioactive conjugated as ranitidine bismuth citrate [13]. Organo-bismuth derivatives are not the only species of great interest as nanosized oxides and related materials have raised more and more interest in the scientific community due to their cost-effective fabrication processes [14,15], high stability [16] and versatility in terms of morphology [17,18]. Furthermore, the high atomic number of bismuth brings about a high energy radiation attenuation larger than that of lead at an almost negligible risk of toxicity [19]. The combinations of bismuth properties represent a unique chance to exploit singularly or Materials 2020, 13, 5234; doi:10.3390/ma13225234 www.mdpi.com/journal/materials Materials 2020, 13, 5234 2 of 17 Materials 2020, 13, x FOR PEER REVIEW 2 of 17 simultaneously cytotoxicity and diagnostic effects. In this paper, we overview the literature providing acomprehensive synthetic although discussion comprehensive on the main discussion achievemen on thets mainreached achievements by using bismuth reached oxide by using and bismuth related oxidematerials and for related biological materials applications. for biological After applications. presenting After the main presenting chemical the mainand physical chemical properties and physical of propertiesbismuth, we of bismuth,regroup the we regroupstudies in the three studies main in threecategories main dealing categories respectively dealing respectively with (i) biological with (i) biologicalactivity, (ii) activity, use for (ii) the use production for the production of biomaterials of biomaterials and diagnostic and diagnostic agents agents and and(iii) (iii)production production of oftheragnostic theragnostic platforms. platforms. 2. Bismuth Oxide and Related Materials: Productive Productive Strategies Strategies Nowadays, bismuth is mainly produced as a side product of lead streams and could be isolated through the Betterton–Kroll process [[20]20] or throughthrough an electrochemicalelectrochemical procedure known as Betts electrolytic processprocess [[21].21]. It is obtained in a highly purified purified form for those applications where it is used as a replacement for lead [[22].22]. Commonly, bismuthbismuth is is used used in formin form of halide, of halide, oxo-halide, oxo-halide, nitrate nitrate and oxides and derivatives.oxides derivatives. Bismuth halidesBismuth (BiX halides3,X =(BiXF, Cl,3, X Br, = F, I) areCl, Br, generally I) are generally prepared prepared by treating bybismuth treating oxidebismuth in aoxide watery in a medium watery bymedium adding by the adding specific the specific HX acid. HX Bismuth acid. Bismuth trihalides trihalides are bipyramidal are bipyramidal molecular molecular species species in the in gasthe phasegas phase with with angle angle X-Bi-X X-Bi-X in the in range the range 96–100 96–100°◦ [23]. In [2 the3]. solidIn the phase, solid theyphase, show they a varietyshow a of variety different of structuresdifferent structures based on based the halogen on the halogen present present in the crystals. in the crystals. BiF3 shows BiF3 shows a pseudo-ionic a pseudo-ionic structure structure with tricappedwith tricapped trigonal trigonal prismatic prismatic motive motive where where bismuth bismuth atoms atoms are surrounded are surrounded by nine by fluoride nine fluoride atoms, whileatoms, the while other the halides other halides show bicappedshow bicapped trigonal trigonal prism prism crystals. crystals. Bismuth Bismuth oxide oxide halides halides (BiOX) (BiOX) are formedare formed by partialby partial hydrolysis hydrolysis of bismuthof bismuth halides. halides. BiOF BiOF and and BiOI BiOI can can also also be be mademade byby heatingheating the corresponding halideshalides inin thethe air. air. BiOX BiOX have have complex complex layer layer lattice lattice structures structures [24 [24]] and, and, when when heated heated up toup 600 to 600◦C, °C, BiOCl BiOCl or BiOBror BiOBr are are decomposed decomposed by formingby forming Bi24 Bi03124X03110X[1025 [25].]. Moving on, bismuth can easily bebe producedproduced asas bismuthbismuth nitrate.nitrate. Firstly, Firstly, it is recovered as Bi(NO33)3·5H5H22OO through through crystallization crystallization after hydrolysis of Bi22O3 byby using using concentrated nitric acid. If a · diluted acidacid isis usedused is is possible possible to to recover recover the the basic basic salt salt BiO(NO BiO(NO3).3 BiO(NO). BiO(NO3) could3) could be be also also produced produced by precipitationby precipitation treating treating Bi(NO Bi(NO3)3 5H3)23·5HO at2O 150 at◦ C150 with °C butanolwith butanol forming forming road-like road-like structures structures as reported as · byreported Liu et al.by [26Liu]. Aset al. clearly [26]. enlightenAs clearly by enlighten Briand and by Burford Briand [27and] the Burford hydrolysis [27] ofthe Bi(NO hydrolysis3)3 5H 2ofO · couldBi(NO lead3)3·5H to2O a plethoracould lead of to di ffa erentplethora compounds. of different Furthermore, compounds. several Furthermore, attempts several were reportedattempts in were the literaturereported in [28 the–32 literature] pursuing [28–32] the thermal pursuing oxodehydration the thermal oxodehydration of Bi(NO3)3 5H 2ofO Bi(NO with the3)3·5H formation2O with ofthe a · seriesformation of complex of a series species of complex as summarized species as in summarized Figure1. in Figure 1. FigureFigure 1.1. ComprehensiveComprehensive schemescheme ofof chemicalchemical evolutionevolution ofof Bi(NOBi(NO3))3·55 H 2O.O. 3 3· 2 An interesting study was was reported reported by by Tanveer Tanveer et et al. al. [17] [17] about about the the transition transition from from Bi(NO Bi(NO3)3·5H)3 5H2O2 toO · toBi5O Bi75NOO73NO showing3 showing how it how is possible it is possible to isolate to a isolate species a of species Bi5O7NO of3 tailored Bi5O7NO on3 thetailored surface on with the β surface-Bi2O3. with Bismuthβ-Bi2O3. oxides are the other deeply studied class of bismuth compounds and they present four differentBismuth phases oxides [33] areas reported the other in deeply Figure studied 2. class of bismuth compounds and they present four different phases [33] as reported in Figure2. At room temperature, monoclinic α-Bi2O3 is the common stable phase with a polymeric-distorted layered structure composed of pentacoordinate bismuth atoms enclosed into pseudo-octahedral units. At a temperature higher than 710 ◦C, α phase is converted into the cubic δ phase that has a defective structure with random oxygen vacancies [34]. The β phase and several oxygen-rich forms are closely related to the δ phase. In particular, the vacancy structures of highly defected bismuth oxides some 2 sites filled with O− together with Bi(III) and Bi (V) sites. Bismuth oxide γ-phase shows also a cubic structure but it is highly unstable and hard to synthesize without supporting it onto other oxides or Materials 2020, 13, 5234 3 of 17 metallic species [35]. The other two