Review on Medical Applications of Manganese Oxide (Mn 2 + , Mn 3 + , and Mn 4 + ) Magnetic Nanoparticles

Apart from our imagination, the nanotechnology industry is rapidly growing and promises that the substantial changes that will have signi ﬁ cant economic and scienti ﬁ c impacts be applicable to a wide range of areas, such as aerospace engineering, nanoelec-tronics, environmental remediation, and medical healthcare. In the medical ﬁ eld, magnetic materials play vital roles such as magnetic resonance imaging (MRI), hyperthermia, and magnetic drug delivery. Among them, manganese oxide garnered great interest in biomedical applications due to its different oxidation states (Mn 2 + , Mn 3 + , and Mn 4 + ). Manganese oxide nanostructures are widely explored for medical applications due to their availability, diverse morphologies, and tunable magnetic properties. In this review, cogent contributions of manganese oxides in medical applications are summarized. The crystalline structure and oxidation states of Mn oxides are highlighted. The synthesis approaches of Mn-based nanoparticles are outlined. The important medical applications of manganese-based nanoparticles like magnetic hyperthermia, MRI, and drug delivery are summarized. This review is conducted to cover the future impact of MnO x in diagnostic and therapeutic applications.


Introduction
Nanoparticles (NPs) have bloomed as a windfall in medical applications, thanks to their exclusive physical and chemical properties [1].NPs are extensively used in different biomedical applications, such as drug delivery [2], bioimaging [3], hyperthermia [4], cell labeling [5], gene delivery [6], tissue engineering [7], implants [8], antimicrobial agents [9], photothermal therapy [10], immunotherapy [11], and biosensing [12].The tunable size and shape of the NPs facilitated their usage in therapeutic applications by inflecting the blood circulation, biodistribution, and excretion of the NPs from the body [13].The quantum efficiency and magnetic properties of the NPs increased their usage in diagnostic applications like fluorescence and magnetic resonance imaging (MRI) [14].The different NPs used in the medical applications are metal NPs, metal oxide NPs, carbon-based NPs, polymer-based NPs, and magnetic nanoparticles [15].Metal NPs used in medical applications are silver, gold, platinum, titanium, ceria, palladium, cerium, zinc, copper, etc. [16].Metal oxide NPs used in medical applications are copper, iron, zinc, titanium, zirconium, and cerium oxide.Carbon-based NPs like graphene, fullerenes, carbon nanotubes, and quantum dots are extensively used in biomedical applications [17].Among these, magnetic NPs are surging as prominent NPs in various applications like hyperthermia, targeted drug delivery, tissue engineering, theranostic, and lab on a-chip by its magnetic and chemical properties and specificity.A significant boon of employing magnetic nanoparticles in medical applications is that the required magnetic properties of the NPs can be modulated by the external magnetic field [18].Magnetic NPs are used in various forms pure metals, metal oxides, and metal nanocomposites.The magnetic NPs can be prepared from pure metals Fe, Co, Ni, or a mixture of metals and polymers [19].Generally, iron oxide nanoparticles (Fe 3 O 4 , γ-Fe 2 O 3 ) are widely used magnetic particles, and the magnetic properties of the IONP can be enhanced by doping with other metals and rare earth metals [20].Iron oxide nanoparticles doped with gadolinium (Gd) [21], cobalt (Co) [22], zinc (Zn) [23], manganese (Mn) [24], and nickel (Ni) [25] expressed better magnetic properties resulting in the improved contrast effects in MRI that are prominent than bare Fe 3 O 4 NPs.Manganese oxides possess good magnetic properties and exist in the several oxides forms of MnO, MnO 2 , Mn 2 O 3 , and Mn 3 O 4 .The multifunctionality of MnO x at the nanoscale is represented in Figure 1 [26].Manganese oxides have been a spotlight in applications like biosensing, bioimaging, drug delivery, and tumor therapy by virtue of their physical and chemical properties, biocompatibility, and tunable structure and morphologies [27].The medicinal applications of manganese oxide nanomaterials are represented in Figure 2. Manganese oxides also extended their potential in various applications like batteries [28], supercapacitors [29], energy storage systems [30], water purification [31], ion exchange [32], and fertilizer [33].Besides, manganese is a vital nutrient and plays the role of a cofactor for various enzymes.Mn x O y nanoparticles are considered to be safe and showed themselves a suitable candidate T 1 weighted MRI, fluorescent imaging, CT, and theranostic applications [34].Mn NPs expressed a remarkable T 1 relaxation rate compared to available Gd-based contrast agents [35].
This review endeavors to acquaint the overview of the significant characteristics and crystal structures of manganese oxides and their medicinal applications.This review is categorized into the following sections: The first section covers the crystal structures and synthesis approaches implied for the preparation of manganese oxide nanoparticles.The second portion describes the different oxidation states of Manganese oxides.Finally, we discuss the different medical applications of manganese oxides like hyperthermia, MRI, and drug delivery.This review will certainly contribute to the research to explore much about manganese oxides, especially in the inevitable medical applications.

Manganese Oxides
2.1.Crystal Structures.Manganese is the 10 th most bounteous element in Earth's crust.It can be readily oxidized and naturally exhibits 30 different crystalline forms of oxides, hydroxides, and oxyhydroxides that possess a massive number of structural geometries.Generally, manganese oxides are termed MnO x and the fundamental building block for all the atomic structures of Mn oxide is MnO 6 octahedron [36].The different atomic structures are formed from the sharing edges or corners in the octahedra.The crystal structures of manganese have been classified as tunnel, layered, spinel, and other structures [37].A common polymorph of MnO 2 is represented in Figure 3.
2.1.1.Tunnel structures.Tunnel Mn oxides are assembled of single, double, or triple chains of edge-sharing of MnO 6 octahedra and form a tunnel-based framework with a cross-section of square or rectangle as the chains share corners [39].The larger tunnel structures of Mn oxides are fractionally occupied with water molecules or cations.Some of the tunnel structure-based Mn oxides are pyrolusite MnO 2 , ramsdellite MnO 2 , nsutite MnO 2 , hollandite group (R.8-1.5(Mn(IV),Mn(III)) 8 O 16 , R = Ba, Pb, K, or Na), romanechite Ba 0.66 Mn(IV) 3.68 Mn(III) 1.32 O 10• 1•34H 2 O. Pyrolusite MnO 2 is the most stable and abundant polymorph of MnO 2 , which is analogous to rutile (TiO 2 ).In pyrolusite MnO 2 , framework structure contained tunnels are formed by sharing the single chains of edge-sharing Mn(IV)O 6 octahedra with neighboring chains [40].The ramsdellite structure consists of double chains of Mn(IV)O 6 octahedra, each of which comprises two neighboring single chains connected along their octahedral edges.The double chains, in turn, connect

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Journal of Nanomaterials corners to create a structure with tunnels with 1 × 2 octahedral cross-sections on each side [41].Nsutite MnO 2 , also known as gamma MnO 2 , owns an improper crystal lattice.Nsutite structures are found to be the ordered intergrowths of ramsdellite and pyrolusite.Double chains of edge-sharing MnO 6 octahedra form the hollandite structure; however, they are joined together to create tunnels with square cross-sections that are two octahedra on a side.In romanechite structures, tunnel structures are formed as rectangular cross-sections by the linkage of double and triple chains of edge-sharing MnO 6 octahedra.One of the main Mn minerals found in ocean Mn nodules is todorokite, the most likely host phase for essential metals like Ni, Co, etc.It is a significant mineral having zeolite-like tunnel structures [42,43].The tunnel-based structure is also present in the MnOOH minerals and their polymorphs.Manganite is the most stable and typical of the three naturally occurring polymorphs of MnOOH; the other two are feitknechtite and groutite.The crystal structure of manganite (γ-MnOOH) is comparable to that of pyrolusite, except all of the Mn is trivalent, and half of the O atoms are swapped out for hydroxyl anions.The hydroxyl anions in groutite (α-MnOOH) have completely replaced all of the Mn(III) and half of the O anions, much like in manganite.Naturally existing (β-MnOOH) is said to be feitknechtite [44].O structure holds edge-sharing Mn(IV)O 6 octahedra with the alternating layer of Zn cations and water molecules.The Zn cations are located above and below the unoccupied octahedral site in the Mn layer, where one-seventh of the octahedral site is unoccupied.The basic structure of the birnessite group is a MnO 6 octahedra sheet where the interlayer cations and water molecules occupy different positions and possess dominant interlayer cations between Ca and Mn(II) [42,46].
Another layered structure of MnO 2 is vernadite MnO 2 •nH 2 O, a fine grained, poorly crystalline natural Mn oxide phase.Vernadite is a variety of birnessite that is disordered in the layer-stacking direction [47].

Methods of Synthesis of Nanoparticles.
Generally, nanoparticles are prepared using broadly categorized approaches like top-down and bottom-up.In top-down approaches, the nanoparticles are fabricated by decomposing larger molecules into smaller molecules.Several examples of top-down approaches include lithographic techniques, chemical vapor deposition, physical vapor deposition, ball milling, etc.In the bottom-up approach, the nanoparticles are prepared using assembling nanostructures from smaller components like atoms or molecules.The synthesis method follows bottomup approaches sol-gel, hydrothermal, green synthesis, and biochemical synthesis.The size, shape, morphology, stability, and scalability of the nanoparticles rely on the synthesis methods.The different approaches like physical, chemical, and biosynthesis for the synthesis of MnO x -based nanoparticles are discussed in this section.

Chemical Approach.
(1) Hydrothermal Method.The hydrothermal method is the extensively employed synthesis route for the preparation of Mn oxide nanoparticles, exploits the different reaction vessel known as Teflon lined autoclave to perform the hydrothermal reaction which favors the solubility and reactivity in highpressure environment [50].Hydrothermal synthesis can be employed in a wide range of temperatures from room temperature to high temperature.The controlled morphology can be obtained by performing the reactions in low-or high-pressure conditions based on the vapor pressure of the composition involved in the reaction [51].The particle aggregation and size of the nanoparticle are controlled by using surfactants like CTAB and gelatin.The morphology and the crystal structure can be tuned by the molar composition of the precursor and the solvent involved in the reaction.Wang and Li [52] reported the preparation of α and β phases of MnO 2 by varying the concentration of the ammonium and sulfate ions in the reaction between ammonium persulphate and magnesium sulfate.Duan et al. [53] prepared MnO 2 nanostructures with different crystal phases (α-, β-, and γ-MnO 2 ) using KMnO 4 using the hydrothermal method.The different morphologies like nanorod, nanoflower, nanowall, nanosheet, and nanowire were obtained by optimizing the reaction temperature and concentration of KMnO 4 .Arkhipova et al. [54] also reported the concentration of the precursor plays an important role in obtaining different crystal structures.α-MnO 2 was prepared using 1.98 g of KMnO 4 and δ-MnO 2 using 3.96 g, the excess K + ion was required to stabilize the δ-MnO 2 .The schematic representation of hydrothermal synthesis is represented in Figure 5. Wang et al. [55] prepared α-MnO 2 , γ-MnOOH, and Mn 3 O 4 nanomaterials using manganese acetate and NaOH at 180°C for different duration of 3, 11, and 24 hr.Needle-shaped manganese oxide nanoparticle having high surface area and porous structure was prepared via one-step hydrothermal approach using KMnO 4 and H 2 SO 4 [56].Furthermore, the temperature involved in the hydrothermal reactions determines the crystal structure and influences the process of crystal growth, higher crystallinity is attained by increasing the reaction temperature.Cao et al. [57] reported the change in α-MnO 2 to β-MnO 2 as the temperature increases from 160 to 200°C, as shown in Figure 6.Hashemzadeh et al. [58] reported the comparison of manganese oxides prepared by hydrothermal and sol-gel methods.It is observed that the diameter of nanorods synthesized by the hydrothermal method was found to be around 50-100 which was smaller than the nanorods prepared by the sol-gel method.
(2) Sol-Gel.Sol-gel is a facile method employed to form refined and pure crystal structures with uniform morphology by controlling the reaction at the molecular level.This method is more favorable for the preparation of thicknesscontrolled film.Hydrolysis and condensation are the two important processes involved in this sol-gel method.The inorganic precursors are hydrolyzed with water, acid, alcohol, or base and condensed to form a 3D molecular network.The following reactions are involved. Hydrolysis: Condensation: where M refers to the Metal and R is the alkyl group.
Initially, the precursor is dissolved in the solvent to form a homogenous solution.Then, stable sols are formed from the agglomerates due to the interaction of solute and solvent or interaction between the solute.After evaporation sols are converted into gels, and oxides are formed followed by the sintering of gels at a required temperature.The reaction involved in the sol-gel method can be optimized by the different parameters like temperature, pH, reaction time, and concentration of the solution.Birnessite manganese dioxide of lamellar type was produced from mixed oxides, A-MnO (A = K + , Na + ) by sol-gel route.The manganese oxides are formed from the reduction of aqueous permanganate solutions using organic reducing agents followed by drying and calcination.The ternary oxides are formed by the reaction of alkaline cations (K + and Na + ) with manganese oxides [63].Siddique et al. [64] prepared manganese oxide nanoparticles using the redox reaction of glycerol and potassium, calcined at two different temperatures at 400-700°C.The surface morphology of the MnO 2 calcined at 700°C shows less aggregation than 400°C.Yarbrough et al. [65] reported the effect of solvent and concentration of precursor on the morphology of Mn 3 O 4 nanoparticles.The Mn 3 O 4 nanoparticles were formed by the hydrolysis and condensation of manganese acetate in the presence of  Journal of Nanomaterials sodium hydroxide in three different solvents water, 70% ethanol, DMF, and toluene.It is reported that the Mn 3 O 4 NPs prepared using the solvent water, ethanol, and toluene yielded hexagonal structures, whereas DMF resulted in irregular nanoparticles.The average diameter of the Mn 3 O 4 NPs ranged from 100 to 200 nm for the solvent water, ethanol, and toluene irrespective of the different molar concentrations.Though the sol-gel approach is a facile technique possibility of agglomeration is more [66].
(3) Electrochemical Synthesis.The electrochemical synthesis method is an inexpensive technique widely used for the deposition of metal and metal oxide.The morphologies of the deposited materials can be optimized by the different parameters like bath composition, temperature, and current.This method results in the deposition of highly pure material on a conducting substrate, i.e., stainless steel, graphite, titanium, etc.The reactions involved in the electrodeposition of manganese oxide nanoparticles are as follows: Electrochemical deposition of manganese oxide nanoparticles prepared from different precursors like manganese acetate, manganese chloride, manganese sulfate, etc.The structure, surface area, and oxidation state of the manganese nanoparticles depend on the deposition potential and conditions.The working electrode utilized for the deposition of material must be cleaned with nitric acid and water and blow dried in the steam of nitrogen for the pure deposition.Lee et al. [67] reported the anodically electrodeposited manganese oxide nanoparticles using manganese acetate aqueous solution in a three-cell system consisting of a platinum plate, gold plate, and Ag/Agcl at three different modes, constant potential (CP) at 1 V for 900 s, pulse potential (PP) at 1 and 0 V with 0.5/0.5 s on-off time for 10,000 s, and pulse reverse potential (PRP) at 1 and 1 V with 0.5/0.5 s interval time for 10,000 s.It is reported that the morphology of the manganese oxide nanostructures varies according to the pattern of applied potential, traditional bulk film composed of a large agglomerate particle was obtained in CP mode, flower petal shaped MnO x particles were obtained in PP mode, more defined nanostructure was obtained in PRP mode.Li and Park [68] reported that the coating of manganese oxides over vertically aligned carbon nanotubes by the depositing the aqueous mixture of 0.1 M Na 2 SO 4 and 0.02 M MnSO 4 .It is stated that the 5 mA of deposition current was utilized for the high nucleation density without anodic oxygen evolution.Nakayama et al. [69] reported the electrodeposition of layered manganese oxide nanocomposites by applying 1.0 V with a charge of 330 mC/cm 2 .Broughton and Brett [70] ðaÞ ðbÞ ðcÞ ðdÞ demonstrated the efficiency of the deposition of MnO 2 relays on both anions and cations.It is reported that the acetate ion expressed the controllable effect on the deposition potential of MnO 2 produced from the mixture of manganese sulfateand acetate-based electrolyte.Acetate ions also reduce the reduction potential required for the eletrodeposition [70].
(4) Precipitation Method.The chemical precipitation method is a simple, inexpensive technique used in the synthesis of various nanomaterials at low temperatures.The formation of nanoparticles by precipitation method depends on the different parameters like pH, reaction temperature, and concentration of the reacting precursor.Kanha and Saengkwamsawang [71] prepared α-MnO 2 nanostructures using KMnO 4 and Tris (2-hydroxyethyl)amine in different stirring times (0.5, 1, 2, and 3 hr).The results indicated that the crystallite size and strain of α-MnO 2 is less as the stirring time is increased and the increase in calcination duration resulted in the increase in particle size.Chen et al. [72] reported the shape-controlled synthesis of 1D MnO 2 of different crystallographic forms and morphologies using MnCl 2 •4H 2 O and KMnO 4 .It is observed that the ratio of DI water/Isopropanol and the concentration of KMnO 4 play an important role in morphology.The ratio of DI water/Isopropanol contributes to the structural differences of the intermediate species for crystal growth owing to the discrepant coordinate abilities between DIwater and isopropanol with MnO 6 octahedron units and the concentration of KMnO 4 inducing the stacking behavior of the nuclei during the crystal growth period.Wang et al. [73] reported the preparation of different crystallographic phases γ-MnO 2 , Mn 2 O 3 , and Mn 3 O 4 at different calcination temperatures.Some of the manganese-based nanocomposites prepared using the coprecipitation method are MnO x -CeO 2 [74], MnO x -ZrO 2 [75], and Fe-Mn [76].Thus, the size and morphology of nanoparticles prepared using coprecipitation method rely on the different reaction parameters like concentration of the precursor, ratio, and proportion of the solvent, temperature, stirring duration, calcination temperature, and duration.

Physical Approach.
In the physical approach, pulsed laser deposition was employed to prepare specific nanomaterials with controlled size using the high power density laser with narrow frequency.Initially, the manganese target material is heated in a vacuum by the pulsed laser to melt and ablate the surface.Then the atoms ablated or vaporized from the surface of the target deposited on the substrate.Lacerda et al. [77] reported the preparation of manganese oxide nanofoam from a metallic Mn target in a 5 Torr pressure O 2 buffer atmosphere.The Mn metallic target ablation was attained by the Nd:YAG laser of 1,064 nm wavelength, pulse duration of 7 ns, and 10 Hz repetition rate.The morphological analysis of the Mn Nanofoam obtained by SEM and TEM is represented in Figure 7. Corrales et al. [78] reported the preparation of MnO 2 nanoparticles by Nd: YAG laser of 1,064 nm, 9 ns, and 10 Hz from the target MnO 2 .Xia et al. [79] reported the manganese oxide thin film of different oxidation states from a metallic Mn target using an excimer laser of 240 nm, laser fluence of 2 Jcm −2 , and repetition rate of 10 Hz.The chamber was evacuated below the pressure of 10 −5 Torr before the deposition followed by the introduction of high-purity oxygen and thin film was deposited at 600°C.The different oxidation states of manganese oxides are obtained by varying the partial oxygen pressures from 0 to 700 mTorr.XRD patterns revealed that the face-centered cubic phase of MnO in the no oxygen atmosphere, a pure tetragonal hausmannite Mn 3 O 4 phase is obtained at 200 mTorr, as the oxygen content increased to 700 mTorr, a pure orthorhombic Mn 2 O 3 phase is obtained.The different phase composition of the manganese oxides can be attained by varying the oxygen partial pressure.The morphology of the manganese oxide film at different oxygen partial pressure is represented in Figure 8.The different oxidation states of the manganese oxides can be obtained by changing the substrate temperature.Isber et al. [80] reported that the Mn 2 O 3 phase is obtained until the temperature of 700°C and phase transformation of Mn 3 O 4 occurred above the temperature of 700°C.The structure and phase of the nanoparticle can be varied with the temperature of the substrate, oxygen partial pressure, metallic target, deposition duration, and wavelength of the laser.
Another physical approach adapted for the synthesis of MnO x nanoparticles is ball milling.Ochirkhuyag et al. [81] reported that the MnO x nanostructures are prepared by milling MnCl 2 •4H 2 O and KMnO 4 with 0.09 M of sodium hydroxide and 5 mL of water using stainless grinding balls.It is also worth mentioning that the milling speed could tailor the crystal structure and the oxidation states of the manganese.Villanueva et al. [82] reported that the manganese oxide perovskite for the hyperthermia was synthesized by milling in an agitate mill and fired at 1,400°C.In some cases, microwave-assisted ball milling was used to prepare Mn-based ferrites.There are several factors like milling duration and speed, ball-to-powder weight ratio, and type of milling balls and containers influence the shape, size, and structure of the MnO x -based nanoparticles [83].
(1) Biogenic Synthesis.Biogenic synthesis involves the synthesis of nanoparticles using microorganisms or plant extract.This approach is a boon to the nanotechnology, thanks to its features like environmentally friendly, nontoxic, and less expensive.The preparation of manganese NPs using plant extract is based on the reduction and stabilization of manganese metal into Mn NPs.The phytochemicals of plant extracts like alkaloids, flavonoids, phenolic, and terpenoids are involved in the process of reduction and also act as a capping agent to control the size of the nanoparticles.In many cases, size and shape of the nanoparticles are controlled using the extract and the amount of phytochemicals involved in the reduction of metal ions matters for the optimization of the size of the nanoparticles.
Khan et al. [84] reported the preparation of MnO NPs of ∼85 nm using the leaf extract of Abutilon indicum leaf extract.The phytomolecules like flavonoids, phenolics, and carbohydrates present in the A. indicum leaf extract reduced the Mn + into their zero valent species Mn 0 by donating electrons through a redox reaction and other phytomolecules like alkaloids, proteins, etc., contributed in the stabilization of Mn 0 .The mechanism of formation of MnO NPs involved the reduction of Mn + into their zero valent species.FTIR results of the A. indicum leaf extract and MnO nanoparticles endorsed that the phytomolecules present in the extract were involved in the reduction of Mn ions and stabilization of Mn NPs.The schematic representation of the preparation of MnO NPs using A. indicum leaf extract is represented in Figure 9. Souri et al. [85] reported that an increase in the concentration of extract prepared from the aerial parts of Dittrichia graveolens resulted in an increased synthesis rate in the production of MnO.MnO 2 NPs were prepared using the leaf extract of Viola betonicifolia expressed better antioxidant, antimicrobial, and cytotoxic effects than the pure leaf extract.Also, the physical characterization revealed that highly crystalline, spherically shaped, homogeneously dispersed MnO 2 NPs were obtained with a particle size of 10.5 AE 0.85 nm [86].The physical characterization of MnO 2 NPs synthesized using V. betonicifolia is represented in Figure 10.Prasad and Patra [87] reported the synthesis of MnO 2 nanorods in the diameter of 100-200 nm using phyllanthus amarus as a reducing agent and curcumin as a stabilizing agent.Several studies reported the preparation of MnO 2 nanoparticles using various extracts like Caryota mitis Lour.(Fishtail palm) flower [88], Leucaena Leucocephala [89], and green tea [90].Diallo et al. [91] prepared Mn 3 O 4 NPs in the diameter of 18-28 nm by Aspalathus linearis extract using the precursor, manganese chloride.The formation mechanism of Mn 3 O 4   NPs using A. linearis extract is represented in Figure 11.
Several studies have reported the formation of Mn 3 O 4 using various extracts prepared from Costus woodsonii flower [92], Adalodakam [93], Ananas comosus (L.) peel [94], Azadirachta indica [95], Simarouba Glauca leaf [96], Green gram powder [97], etc. Premakumari et al. [98] reported the synthesis of dimanganese trioxide nanoparticles, Mn 2 O 3 using different concentrations of (0.1, 0.2, and 0.3 g) tamarind seed powder.In the preparation of manganese oxide nanoparticles, the concentration of extract: precursor ratio, temperature, and time play an effective role than pH [99].Apart from the plant extract, microorganisms also expressed high potential in the preparation of Mn NPs.Microorganisms like yeast, bacteria, and fungi are employed in the synthesis of NPs.The reductase enzymes present in microorganisms are responsible for the reduction of Mn salts into Mn NPs with a limited size distribution.Sinha et al. [100] reported the synthesis of orthorhombic MnO 2 NPs by Bacillus sp.cells.In another study, the preparation of Mn 2 O 3 by isolated aerobic bacterium from Persian Gulf water for the first time.The acinetobacter bacteria was grown aerobically in K medium along with MnCl 2 at 28°C for 14 days followed by the centrifugation of Mn oxide suspension [101].Salunke et al. [102] reported the synthesis of MnO 2 NPs using the marine bacterium Saccharophagus degradans and yeast Saccharomyces cerevisiae as a reducing agent for the precursor of potassium permanganate.It is reported that the rapid reduction of KMnO 4 solution was accomplished by the supernatant of 96-hr-old S. cerevisiae culture broth and yeast extract.Some of the recently prepared various Mn-based oxides and their properties are presented in Table 1.
The synthesis approaches of the nanoparticles substantially affect the efficacy of nanoparticles in biomedical applications.The different properties like size, surface area, stability, and surface functionalization required for the medical applications rely on the synthesis approaches, precursors, and parameters involved in the synthesis.The optimization of surface area and size of the nanoparticles mostly rely on the synthesis and the parameters which are highly imperative to be used in both diagnostic and therapeutic effects as the smaller nanoparticles often exhibit enhanced cellular uptake and can penetrate tissues more effectively [115,116].The stability of the nanoparticles is essential to increase the stable performance and prolonged circulation without aggregation and which can be controlled by the synthesis [117].The biocompatibility of the nanomaterial is a great concern to be used in medical applications and hence suitable approaches and chemicals should be used to enhance the biocompatibility and the functionalization of the surface of the nanoparticles will improve the biocompatibility and its performance resulting in efficient therapeutic and diagnostic effect [118].
3. Manganese-Different (Mn 2+ , Mn 3+ , and Mn 4+ ) Oxidation States Manganese, a transition metal that subsists in different oxidation states includes +2, +3, +4, +6, and +7.Journal of Nanomaterials  10 Journal of Nanomaterials 3.1.Mn 2+ Ion.Mn 2+ ion known as manganese ion with a +2 oxidation state indicates the loss of two electrons.Manganese possesses a d 5 electron configuration in its +2 oxidation state that makes it a stable ion and is capable of forming a variety of coordination complexes with ligands.Mn 2+ is a common oxidation state for manganese and has a d 5 electron configuration in which two of the d electrons occupy the t 2g orbitals that possess spherical shape and lower energy, and the other three d electrons occupy the e g orbitals that own more elongated shape and higher energy.The electronic configuration of Mn 2+ can be indicated as (Ar) 3d 5 .The coordination number of Mn 2+ is 6, indicating that it is surrounded by six ligands or atoms in a complex.The most prevalent coordination geometry for Mn 2+ is octahedral, in which the central Mn 2+ ion is surrounded by the six ligands at the vertices of an octahedron.The ligands can be either neutral molecules or anions and they interact with the Mn 2+ ion through coordinate covalent bonds.Ligands are usually water molecules, chloride ions, or other small anions in Mn 2+ ions.
3.2.Mn 3+ Ion.Mn 3+ ion is another oxidation state of manganese with a charge of +3, formed when neutral manganese atoms lose three electrons.The electronic configuration of Mn 3+ ion is (Ar) 3d 4 obtained from the neutral state of Mn, (Ar) 3d 5 4 s 2 by the loss of three electrons.Mn 3+ ions are known for their intriguing magnetic properties and are widely utilized in the production of steel.Mn 3+ ions can be oxidized to a higher oxidation state or reduced to a lower oxidation state by redox reactions.This ionic form exists in minerals or rocks and is also employed as a catalyst for various chemical reactions.

Mn 4+
Ions.Mn 4+ ion possesses an oxidation state of +4 formed when neutral manganese atoms lose four electrons.It follows the electronic configuration of (Ar) 3d 3 4s 2 and expresses good magnetic properties because of the unpaired electrons in 3d orbitals.Generally, Mn 4+ ion is found in the form of a complex ion in an aqueous solution with the different electronic structure because of its interaction with ligands.In a simple octahedral complex with six ligands, the Mn 4+ ion would lose all four of its valence electrons from the 3d orbital, leaving only the 4 s electrons with the electronic configuration (Ar) 4 s 2 .The electronic structure of Mn 4+ ions is different in complex ligand environments like tetrahedral or square planar complexes.In some cases, some of the 3d electrons are involved in bonding with the ligands resulting in the partially filled 3d subshell and a modified electronic structure.Thus, the electronic structure of Mn 4+ ions mainly relies on the particular ligand environment and the nature of the bonding interactions with those ligands.Mn 4+ ion is found to be highly oxidizing which can accept electrons from other atoms or ions which makes them more suitable in various chemical reactions.Besides, the Mn 4+ ion is known to be stable under certain conditions and can also be reduced into a lower oxidation state by other species resulting in the formation of other compounds.The oxidation states of the manganese influence the biocompatibility, imaging, and therapeutic effect by its reactivity, redox properties, and stability [119].Mn 2+ ions are considered to be safe than other oxidation states due to their involvement in the enzymatic reactions in the body.The higher oxidation might have increased reactivity which will influence the biocompatibility and also can induce antioxidant behavior [120].Mn 2+ ions are good in providing T 1 relaxation enhancement which is favorable for enhancing the signal intensity in MRI.Mn 3+ is considered to be active in therapeutic effect due to its reactivity in producing reactive oxygen species to scavenge free radicals [121].

Medical Applications
Nanoparticles are widely used in different medical applications like drug delivery, imaging, biosensors, MRI, vaccine delivery, antimicrobial applications, wound healing, photothermal therapy, gene therapy, and hyperthermia.In this section, few important medical applications of MnO x like hyperthermia, MRI, and drug delivery are discussed.
4.1.Hyperthermia.Hyperthermia is an effective therapeutic approach in which the body tissue is exposed to high temperatures ranging from 40 to 45°C for a certain duration.Hyperthermia ruins cancer cells by damaging their protein and DNA leading to cell death.It can enhance the sensitivity of cancer cells to radiation therapy and chemotherapy and provoke the immune system to decimate the cancer cells by the natural defense mechanism.Mn NPs have been explored for their potential in hyperthermia applications, thanks to their unique magnetic and thermal properties.They have the ability to engender heat on exposure to an alternating magnetic field, a property named magnetic hyperthermia.Mn NPs exhibit several advantages over other materials due to their high magnetic moment and biocompatible nature.
Magnetic hyperthermia efficiency is investigated by the specific absorption rate (SAR), which relies on the size, shape, composition, concentration of NPs, and applied magnetic field.A higher SAR value is more favorable as it reduces the dosage and duration of treatment.The necessary therapeutic temperature depends on the size, saturation magnetization (M s ), amplitude, frequency, and time of the applied magnetic field.Generally, ferrites, magnetite, and maghemite are very much employed in hyperthermia studies.Among different ferrites, manganese ferrites are more pertinent for hyperthermia owing to their chemical stability, low inherent toxicity, simple synthesis approach, and exquisite magnetic properties.Besides it is very much suited for MRI and contrast agents.Mn NPs are used as either dopants or combined with other magnetic NPs in hyperthermia studies.Andrade et al. [122] prepared calcium-doped manganese nanoparticles coated with citrate in the range of 10-20 nm by sol-gel approach.It is reported that Ca 0.2 Mn 0.8 Fe 2 O 4 expressed the highest SAR value of 36.3W/g at low frequency and attained a temperature variation ∼7°C in 120 s and corroborated cytocompatibility over 0-250 µg/mL range with good internalization after 24 hr making them more suitable for hyperthermia agent.The magnetic hyperthermia measurements of MnFe 2 O 4 and Ca 0.2 Mn 0.8 Fe 2 O 4 are shown in Figure 12.Silveira-Alves Jr. et al. [123] reported the preparation of MnFe 2 O 4 , coupled with meso-tetrakis(N-methylpyridinium-4-yl) porphyrin (TMPyP) and their zinc complex (ZnTMPyP) and coated with citrate (CA), dimercaptosuccinicnate (DMSA), tripolyphosphate (TPP) anions.The colloidal stability and saturation magnetization of different surfactant-coated MnFe 2 O 4 NPs are represented in Figure 13.M s of CA, DMSA, and TPP coated MnFe 2 O 4 values were found to be 49.6, 45.8, and 43.9 emu/g, respectively.The mild variation in the M s for different surfactants is because interaction between the capping and the nanoparticles surface alters the spin canting and magnetic order of the nanoparticles.In another work, MnFe 2 O 4 NPs were modified with polyethylene glycol (PEG) loaded with glucose oxidase and exhibited good magnetic susceptibility with M s of ∼75 emu/g and SAR of 296 W/g [124].Joshi et al. [125] developed Core@Shell NPs, i.e., γ-Fe 2 O 3 @Mn x O y @SiO 2 by thermolysis of iron and manganese oleate.The hyperthermia studies of the prepared on γ-Fe 2- O 3 @Mn x O y @SiO 2 MCF-7 and A549 cell lines revealed that cell viability is decreased after treating the cells with an AC magnetic field.Gupta and Sharma [126] reported Mn-doped magnetic nanoclusters by hydrothermal synthesis route with SAR value ∼600 W/g MNC observed at 250 µg/mL.Phalake et al. [127] stated that Mn 0.75 Fe 0.25 Fe 2 O 4 demonstrated a remarkable SAR value of 153.76 W/g which is due to the substitution of Mn 2+ in A or B position in the Fe 3 O 4 structure.Recently, Shah et al. [128] investigated the lauric acid coated Mn-Zn-based ferrofluid for hyperthermia against HeLa and MG-63.Singh et al. [129] reported that the substitution of Mn 2+ ions in magnetite distinctly boosted the SAR value (SAR: 510 kW/kg).Hence, the efficiency of manganese-based hyperthermia agents relies on the concentration of Mn 2+ substitution, site of substitution, particle size, morphology, saturation magnetization, applied magnetic field, frequency, and the dosage of NPs [130].Some of the manganese-based hyperthermia agents and their SAR values are represented in Table 2.  [137][138][139], Fe-based alloy [140], Mn [141][142][143], and gadolinium-based materials [144][145][146] are used in MRI as contrast agents.Manganese ions are explored as contrast agents in MRI due to the unpaired electron, making them paramagnetic [147,148].This paramagnetic behavior distorts the local magnetic field, inducing a contrast effect in the MRI Image.Furthermore, Mn ions have a prolonged relaxation time than water molecules allowing longer imaging windows, improved signal intensity, and specificity [149,150].Mn can impact relaxation times but can act as either a T 1 or T 2 contrast agent, based on its oxidation state and the surrounding environment.This versatility allows manganese to provide contrast in both T 1 and T 2 weighted images, whereas gadolinium-based materials alter the relaxation times by nearby water protons and enhance signal intensity in T 1 weighted images [151,152].Besides, Mn 2+ ions are dominant in the brain cells mitochondria, making them a more suitable candidate for imaging neurodegenerative diseases [153].Mn can involve in cellullar processes and possess the potential to present insights into functional behavior of tissues and organs, making it favorable for functional MRI (fMRI) applications while Gd-based materials can provide imformation only on structural abnormalites and not the functional aspects of tissues and organs [141,154].Mn-based contrast agents are considered to be safe than the other traditional contrast agensts.Mo et al. [155] reported polydopamine-manganese dioxide MRI-guided photodynamic therapy.As shown in Figure 14, in vitro T 1 weighted imaging studies revealed that the concentration of Mn is in a linear relationship in both acidic and neutral conditions.The brightness of the image was dominant in the acidic state pH = 6.5, then neutral.The T 1 relaxation rate at pH = 6.5 was 4.58 mm −1 s −1 , more significant than that in a normal environment.Lopes et al. [156] developed the MnO 2 -based hydrogel made of gelatin gum and hyaluronic acid as a contrast agent for MRI.Mn-based MRI techniques are not constrained to diagnosis but could be used as guidance for the therapy.For instance, Hou et al. [157] reported ovalbumin-loaded Mn 3 O 4 NPs for dendritic cells-based immunotherapy utilizing the direction of T 1 MRI.The developed system revealed enhanced T 1 -MR imaging, ameliorated tumor accumulation, and efficacy in monitoring the real-time treatment procedure.MRI properties and T 1 -weighted imaging of ovalbuminloaded Mn 3 O 4 NPs are shown in Figure 15.Mn-based oxides, chelates, and coordination complexes are used as dopants to alter the relaxation times for the improved signal intensity resulting in better image contrast.Cai et al. [158] reported Mn doped silica materials of different dimensions for the MRI visualization.Mn-doped Fe 3 O 4 is found to be a strong candidate for resonance imaging techniques; Mn doping decreases the hydrodynamic size and increases the saturation magnetization and magnetic moments resulting in higher r 2 and r 1 due to tenacious spin-spin interactions [159].PEG-coated Mn-doped Fe 3 O 4 NPs possessed hydrophilicity and biocompatibility.It is reported that the prepared ratio of 1 : 20 (Mn : IONP) exhibited harmonious longitudinal and transversal relaxivity of r 1 = 7.1 mM −1 s −1 and r 2 = 120.9mM −1 s −1 , respectively, signified that it could be a superior T 1 /T 2 dualcontrast MRI [160].In Mn-doped ZnSe quantum dots on mesoporous silica NPs, improved Mn 2+ concentration increased T 1 MR contrast resulting in the enriched MRI signal [161].In some cases, manganese oxide nanoparticles are used as a coating for enhanced MRI.Zhao et al. [162] coated MnO 2 over gold nanorods covered by silica dioxide (SiO 2 ) and camouflaged myeloid-derived suppressor cells on the surface.Recently, nanodiamonds doped with Mn were reported by Kunuku et al. [164].The doping of Mn on nanodiamonds improved the relaxivity, i.e., longitudinal and transversal relaxivity was 5 and 17 times higher than the pure nanodiamond.Thus, manganese can be used as a dopant, coating for enhanced resonance imaging.It can be combined with other magnetic materials for better T 1 /T 2 contrast images.Drug loading and surface modification of manganese oxides make them more suitable for live diagnosing guidance for the treatment.The stability and the dosage of the Mn-based material are required to explore more Mn-based materials for MRI.biocompatibility, high surface area, redox activity, stimuliresponsive, and tunable surface [121,165,166].The Mn oxides are used in drug delivery in different forms like MnO 2 [167], MnO [168], Mn 2 O 3 [169], Mn 3 O 4 [34], and Mn-based composites [170,170].Mn NP is used in different structures like rods [171], spheres [166], wires [172], sheets [173], platelets [174], mesoporous [166], hollow [175], etc.The redox ability of MnO 2 makes it more favorable for the triggered drug release by the reversible redox reaction [176].Mn-based NPs are capable of undergoing a Fenton reaction, where Mn ions initiate the decomposition of H 2 O 2 present in the tumor environment and generate oxygen and increase the reactive oxygen species in cancer cells resulting in the activation of oxidative stress which ruins cancer cells [177].Xu et al. [178] reported the doxorubicin (DOX) loaded hollow MnO 2 NPs (HMDN) functionalized with polyethyleneimine (PEI) and polylysine (PLL) (DOX@HMDN-PEI-PLL(cit)) for chemohemodynamic cancer therapy.It is reported that the decomposition of hollow manganese oxide nanoparticles into Mn 2+ ion under acidic conditions and high glutathione (GSH) concentration provoked the release of DOX and Fenton like reaction for the augmented therapeutic effect.The TEM image and drug release behavior of DOX@HMDN-PEI-PLL at different pH and GSH is represented in Figures16 and 17.C6 cell membrane coated DOX conjugated MnO 2 system is used for the treatment of glioma by inducing oxidative stress for the destruction of cancer cells via the Fenton reaction [179].He et al. [180] prepared the honeycomb-structured hollow MnO 2 carrier of ∼93 nm using template-assisted synthesis approach for the delivery of DOX.The hollow MnO 2 carrier comprised some MnO 2 platelets which facilitates the adsorption of DOX by the van der Waals interaction between drug   [186] reported that Mn 2 O 3 nanoparticles are used as templates to prepare the dopamine loaded hyaluronic acid and chitosan hydrogels.Mn-based composites and hybrid nanoparticles gained much attention to extend the drug-loading ability, the optimized drug release, site-specific delivery to enhance biocompatibility.Manganese oxides are combined with mesoporous organosilica (TMON) for the delivery of DOX and to improve the biodegradability and biocompatibility.It is reported that the Mn-based hybrid with silica particles facilitates the cell membrane crossing and delivers the drug resulting in improved cancer cell death [187].The cytotoxic activity of TMON-MnO 2 and TMON-MnO 2 -DOX are shown in Figure 18.Mn is combined with upconversion nanoparticles and metal-organic framework for the delivery of 3-F-10-OHevodiamine (FOE), an antitumor agent [188].Recently, Sabaghi et al. [189] prepared chitosan crosslinked tripolyphosphatecoated MnO 2 rod to achieve the biocompatibility and labeled with fluorescein isothiocyanate for the targeted delivery of doxorubicin to the tumor microenvironment.Mn-based materials are high potential in delivering drugs to the targeted site and are capable of enhancing the therapeutic effect by combined therapy and MRI-guided therapy.The improved therapeutic effect of Mn-based drug delivery depends on the size and morphology of the carrier, drug-loading capacity, redox reaction, Fenton reaction, stimuli-responsive behavior, and biocompatibility, etc.More attention has to be given to controlling the dosage level, surface functionalization, and controlled drug release behavior.Some of the recently prepared Mn-based oxides as a drug delivery carriers are presented in Table 3 [109,155,178,179,181,184,187,188,[190][191][192][193][194][195][196][197].

Magnetic Resonance Imaging (MRI). MRI is a persuasive noninvasive medical imaging technique in the diagnosis of
(1) Other Applications.Mn-based materials are also harnessed for other medical applications like wound healing, antioxidant agents, antimicrobial agents, and biosensing applications.Mn-based nanomaterials are known for their   For instance, Lu et al. [86] reported that MnO 2 nanoparticles synthesized using the extract of V. betonicifolia showed better antibacterial, antifungal, and antioxidant activity.The antibacterial activity of MnO 2 is due to the production of reactive oxygen species which induces oxidative stress in the bacterial cell and the interaction of the nanoparticles to the surface of the bacterial cells.Farhan and Mohammed [198] evaluated the efficacy of MnO 2 NPs for antioxidant and antidiabetic agents due to the production of reactive oxygen species, high surface area to volume ratio, and catalytic activity.Pardhiya et al. [199] investigated the bovine serum albumin conjugated MnO 2 nanoparticles as antioxidant nanozymes and the efficiency increased with nanoparticle concentration.Recently, Zhang et al. [200] investigated that the BSA-coated MnO 2 nanoparticles demonstrated catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase mimicking activities.The antimicrobial and antioxidant properties of Mn-based materials are improved by doping with nanoparticles like silver [201], gold [202], and functionalization with polymers [203], ligands [204], and antibodies [205].Liu et al. [206] reported that the oleic acid-coated MnO 2 eradicated biofilm formation of staphylococcus aureus and demonstrated supreme antibacterial performance compared to vancomycin and the reactive oxygen therapy of OA-MnO 2 promoted wound healing in mice.Mnbased nanomaterials are used in photodynamic therapy due to their oxidation properties which assist in mitigating the hypoxic condition of the tumor microenvironment by interacting with the H 2 O 2 found in tumors [207].Deng et al. [197] fabricated photosensitizer functionalized Mn@Co magnetic nanoparticles for photothermal therapy of gastric cancer.Ijaz Dar et al. [208] reported that the Au@Mn 3 O 4 magnetoplasmonic nanoflowers exhibited noticeable photothermal heating effect with 38% of thermal transduction efficiency than Au nanorods and nanoparticles.Moreover, Mn-based nanostructures are explored as biosensors and fluorescent quenchers.Especially 2d manganese nanostructures are good in light harvesting and conducting electrons making them more favorable for sensing in both biological and chemical applications [209].Chauhan et al. [210] reported Au coated 2d material wrapped MnO 2 nanocomposite for the sensing of neurotransmitter acetylcholine.Recently, Gao et al. [211] investigated MnO 2 nanosheetsbased sensor for the determination of staphylococcus aureus which causes food-borne diseases.Therefore, all these examples signify that manganese-based materials could hold significant promise in medicinal applications.

Issues and Challenges
Though manganese oxides are blooming in medical applications, it is challenging to ascertain the degree of toxicity associated with the various oxide phases.The biocompatibility of Mn-based material varies with the oxidation states.The accumulation and neurotoxicity of manganese are a major threat to be used in biological systems.More studies like in vivo experiments are recommended in determining the dosage of the nanoparticles to avoid toxicity and neurotoxicity.The transformation of manganese-based materials from laboratory to clinical market requires a systematic methodology for determining the correlation between the formulations of Mn-based materials and the in vivo pharmacokinetics and long-term toxicity assessment of NPs.Though the multioxidation states of the Mn-based nanoparticles are highly reactive in scavenging free radicals, stability is the major challenge.
More research has to be conducted on the optimization of surface stability by surface functionalization.Economic viability and reproducibility are the other challenges to initiating the commercialization and the utilization in the clinical market.

Conclusion
Mn-based magnetic materials hold a huge place in medicinal applications due to the biocompatibility, biological activity, magnetic nature, redox behavior, and availability.Several studies showed that they are toxic to the central nervous system.The enhancement of biocompatibility of Mn-based magnetic particles is of great concern to extend the usage widely in medical applications.The biocompatibility of the Mn-based material can be enhanced by surface functionalization or incorporating other compatible materials, reducing the dosage and optimizing the size and shape.More attention has to be given to conducting the in vivo studies of Mn-based materials in all the applications like MRI, hyperthermia, and drug delivery to optimize the dosage and concentration and analyze the suitable morphology.The development of simple approaches for the preparation of Mn NPs and Mn-based composites on a large scale has to be considered for the production of stable NPs with optimized size and structure.
In conclusion, Mn-based magnetic materials are the most promising material in medicinal applications exclusively MRI and drug delivery and more studies have to be conducted for hyperthermia.We believe that this review will serve the researchers to explore the unexplored sides of Mn-based magnetic materials for medicinal applications as they hold a preeminent place in biomedical applications.

FIGURE 8 :
FIGURE 8: FESEM images of (a) the MnO thin film, (b) the Mn 3 O 4 thin film, (c) the Mn 2 O 3 thin film, and (d) cross-section FESEM image of a Mn 3 O 4 thin film deposited on a Si substrate (reprinted with permission from [79] Elsevier, 2009).
that the release of Mn 2+ in an acidic tumor microenvironment makes it favorable for the MRI.Shi et al.[163] coated MnO 2 and AuNP on mesoporous Prussian blue for MRI and antitumor therapy, and the release of Mn 2+ ions from the degradation of MnO 2 upgraded MR relaxation.
Schematic representation of MnO x at the nanoscale.
2•8H 2 O [45].The lithiophorite structure comprises a stack of MnO 6 sheets alternated with Al(OH) 6 octahedra sheets, where one-third of the octahedral sites are vacant.Li cations occupy the vacant sites in the Al layer, and the charge is balanced by replacing an equal number of Mn(III) for Mn(IV) cations.The layers are framed by the H-bond crosslinking between the hydroxyl of the Al/Li layer and the O atoms of the Mn sheet.Chalcophanite ZnMn 3 O 7 •3H 2

TABLE 1 :
Synthesis of various manganese nanoparticles and their properties.
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18 Journal of Nanomaterials molecules and MnO 2 .It is reported that the MnO 2 carrier was withered to Mn 2+ in the GSH environment for the release of DOX via thiol-mediated reduction.Drug release studies revealed that around 100% of DOX released in 15 min in GSH.Tan et al. [181] reported DOX-loaded MnO 2 zeolitic imidazolate framework-8 for the treatment of lung cancer.The amount of drug released was varied with pH, i.e., total amount of drug released at [185].Zhou et al.[185]developed DOX-loaded Mn 3 O 4 @Au conjugated with double stranded DNA to activate the stimulator of interferon genes (STING) which synergistic antitumor activity by the combination of phagocytosis due to STING and chemotherapy due to DOX.Arjama et al.
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