**1. Introduction**

Hematite (α-Fe2O3) has been thoroughly investigated during the centuries, since it is one of the most abundant minerals in the earth's crust: on the surface as well as at the bottom of the sea [1, 2]. From the beginning of its discovery to the present days, α-Fe2O3 gained attention of the scientific community due to its magneto-structural properties, high resistance to corrosion, easy accessibility, wide distribution in natural environment, and biocompatibility. Accordingly, α-Fe2O3 is recognized as a material of significance in different scientific areas [3–12].

The usage of hematite in conventional biomedicine has been enabled by the breakthrough and development of the nanoscience. Progress in this field is achieved by detailed research of iron oxide polymorphs' physical and chemical properties on the nanoscale. Properties of nm-sized particles are significantly differed from their bulk counterparts due to various nano-size-related effects, appeared as a consequence of the changed ratio of surface and volume atoms. Approaching nanometer dimensions, the ratio of the surface atoms in the overall nanoparticle volume

drastically increased by decreasing particle size, favoring the role of the surface effects in the characteristic behavior of the nanoparticles.

Although the most attention in this chapter will be paid to magnetic properties of hematite nanoparticles, it is important to mention that overall behavior of nano-hematite is characterized by its electromagnetic response which determined biomedical application of nanoparticles. Due to coupling between nano-hematite electrical and magnetic fields, it is clear that electrical properties are contributing to the final hematite application as well as magnetic properties. Noteworthy, difference between conductivity of bulk and nano-hematite widespread biomedical application of this iron oxide polymorph application. According to the analysis of the density of electronic states, the bulk hematite showed the charge-transfer insulator nature [13]. Differed from bulk hematite, nano-hematite is an n-type semiconductor, with a bandgap of ~2.2 eV [14]. Consequently, the increase in conductivity enables the extended application of nano-hematite in different biomedical areas, such as transfer of electrical signals in biosensors, tissue engineering, neural probes, drug delivery, or diagnosis, and therapy of human diseases [15].

On the other hand, transition from bulk to nano dimensions resulted in the significant change of its magnetic behavior. Magnetic behavior of bulk hematite is determined by Neel temperature (TN) (~950 K) and Morin temperature (TM) (~260 K) that represent the temperatures upon which the hematite magnetic ordering is changed. Above TN, hematite is characterized by paramagnetic structure. In the temperature range between TN and TM, hematite showed a weak ferromagnetic ordering, while under TM it is antiferromagnetic [16]. Hematite magnetic configurations are defined by the magnetic interactions (magnetic ordering of bulk materials is mostly influenced by the exchange interaction) [17].

Magnetic structure of bulk hematite is represented by different regions of a macroscopic system broken symmetry in different ways, the so-called domains. Domains present small regions within each of which the local magnetization achieves the saturation value [17], while interface between the adjacent regions presents the domain wall. The processes of magnetization and demagnetization of materials occurred through the movement of the domain walls and change of the domain boundaries, consequently bringing to the increase/decrease of a domain size.

From the aspect of magnetic interactions, decrease of the particle size revealed a dominant role of dipole-dipole interactions in the ordering of nanoparticles' magnetic moments, which is negligible in the case of bulk hematite, since magnetic moment of bulk magnetic material is significantly lower than the moment of the nanoparticle [17]. To get a better insight in the changes in the strength ratio of bulk and nano-magnetic interactions that are responsible for maintaining of long-term ordering of magnetic moments, it is important to understand the origin of the increase in the value of nanoparticle magnetic moment. The increase of magnetic moment occurred as a consequence of lowering dimensionality of bulk materials and has been explained by the absence of multi-domain structure and appearance of single-domain nanoparticle structure. The balance between the anisotropy and exchange energies is required for formation of finite-size domain walls [18], resulting in the presence of some critical diameter size, below which nanoparticle is single-domain [18], Eq. (1):

$$\mathbf{r\_c} \approx \Re \left| \left( \mathbf{J\_{ab}} \cdot \mathbf{K\_s} \right)^{1/2} / \mu\_o \cdot \mathbf{M\_s}^2 \right| \tag{1}$$

**105**

*Preparation and Characterization of Fe2O3-SiO2 Nanocomposite for Biomedical Application*

application of magnetic properties of nano-hematite in biomedicine.

Noteworthy, macroscopic magnetic properties of nanoparticles are mostly influenced by Zeeman energy, thermal energy, and anisotropy energy. The relations of mentioned energies [19] enable the appearance of a new magnetic state in nanomaterials, characterized by a presence of single-domain particles—superparamagnetic nanoparticles. The main characteristic of superparamagnetic nanoparticle system is the absence of coercivity and remanence at room temperature, which enables the

Considering the fact that nanomaterials possesses high surface-to-volume ratio and increased surface activity [11], it is obvious that hematite nanoparticles show various magnetic behavior dependent on the size and shape of the particles [12, 20]. Also, it is important to notice that observation of dependence of magnetic or electric properties of nano-hematite on synthesis conditions is enabled by the change of particle size, carrier density (that is dependent on the particle size), domain size, and structure of the synthesized nanoparticles. Furthermore, alteration of synthesis conditions enabled tailoring of their magneto-structural properties and a variety

When we are dealing with potential usage of nano-hematite particles in biomedicine, it should be emphasized that biomedical application requires utilization of nanocomposite materials. For preparation of nanocomposites containing α-Fe2O3 nanoparticles convenient for this purpose, silica is recognized as a suitable

In order to get deeper insight in the magnetic behavior of the nanocomposites, samples that contained hematite nanoparticles in silica matrix are often prepared by sol-gel method that involves formation of hematite nanoparticles by the phase transformations of the Fe2O3 polymorph (maghemite (γ-Fe2O3) and epsilon phases (ε-Fe2O3)). Due to the presence of particle size distribution in the nanomaterials, special attention should be addressed to the problem of coexistence of different iron

Usually the goal of the synthesis is the preparation of the samples characterized by high purity, containing only one iron oxide phase. In some cases the usage of precisely one phase of the iron oxide polymorph is not of crucial importance. For example, magnetite and maghemite nanoparticles are characterized by similar magneto-structural properties and thus could be used together for the preparation of the magnetic ferrofluids. Noteworthy, synthesis of the nanocomposite materials containing this type of iron oxide nanoparticles is so common in literature that the scientific community accepted the abbreviation "SPION" (superparamagnetic iron

Comparing the magnetic behavior of hematite nanoparticles with the magnetic properties of the other iron oxides (spinel or epsilon phase), it is certain that α-Fe2O3 cannot be used together with spinel phases due to very different magnetic properties. On the other side, at the moment it is not possible to claim with certainty whether it could be used together with the epsilon phase or not. This is a consequence of the insufficient knowledge about magnetic properties of these two iron oxide phases. Literature data revealed that pure hematite nanoparticles are characterized by the intrinsic coercivity field (Hci) value of 1.7 kOe [23], although nano-sized α-Fe2O3 in silica matrix can achieve coercivity of 4.3 kOe [24]. Under the certain size limit, hematite nanoparticles showed superparamagnetic (SPM) behavior [12]. The presence of the other ions significantly alters hematite coercivity. Even bulk hematite doped with alumina ions reached coercivity of >8 kOe [25]. It is similar with the lack of the knowledge regarding epsilon Hc value: dependent on the synthesis conditions, epsilon nanoparticles showed different coercivity. This phase is characterized by high

oxide nanoparticles) to describe spinel iron oxide species [21, 22].

*DOI: http://dx.doi.org/10.5772/intechopen.81926*

of new applications.

oxide species within the silica matrix.

material.

where Jab is the exchange integral, Ka is the anisotropy constant, and Ms is the saturation magnetization.

#### *Preparation and Characterization of Fe2O3-SiO2 Nanocomposite for Biomedical Application DOI: http://dx.doi.org/10.5772/intechopen.81926*

Noteworthy, macroscopic magnetic properties of nanoparticles are mostly influenced by Zeeman energy, thermal energy, and anisotropy energy. The relations of mentioned energies [19] enable the appearance of a new magnetic state in nanomaterials, characterized by a presence of single-domain particles—superparamagnetic nanoparticles. The main characteristic of superparamagnetic nanoparticle system is the absence of coercivity and remanence at room temperature, which enables the application of magnetic properties of nano-hematite in biomedicine.

Considering the fact that nanomaterials possesses high surface-to-volume ratio and increased surface activity [11], it is obvious that hematite nanoparticles show various magnetic behavior dependent on the size and shape of the particles [12, 20]. Also, it is important to notice that observation of dependence of magnetic or electric properties of nano-hematite on synthesis conditions is enabled by the change of particle size, carrier density (that is dependent on the particle size), domain size, and structure of the synthesized nanoparticles. Furthermore, alteration of synthesis conditions enabled tailoring of their magneto-structural properties and a variety of new applications.

When we are dealing with potential usage of nano-hematite particles in biomedicine, it should be emphasized that biomedical application requires utilization of nanocomposite materials. For preparation of nanocomposites containing α-Fe2O3 nanoparticles convenient for this purpose, silica is recognized as a suitable material.

In order to get deeper insight in the magnetic behavior of the nanocomposites, samples that contained hematite nanoparticles in silica matrix are often prepared by sol-gel method that involves formation of hematite nanoparticles by the phase transformations of the Fe2O3 polymorph (maghemite (γ-Fe2O3) and epsilon phases (ε-Fe2O3)). Due to the presence of particle size distribution in the nanomaterials, special attention should be addressed to the problem of coexistence of different iron oxide species within the silica matrix.

Usually the goal of the synthesis is the preparation of the samples characterized by high purity, containing only one iron oxide phase. In some cases the usage of precisely one phase of the iron oxide polymorph is not of crucial importance. For example, magnetite and maghemite nanoparticles are characterized by similar magneto-structural properties and thus could be used together for the preparation of the magnetic ferrofluids. Noteworthy, synthesis of the nanocomposite materials containing this type of iron oxide nanoparticles is so common in literature that the scientific community accepted the abbreviation "SPION" (superparamagnetic iron oxide nanoparticles) to describe spinel iron oxide species [21, 22].

Comparing the magnetic behavior of hematite nanoparticles with the magnetic properties of the other iron oxides (spinel or epsilon phase), it is certain that α-Fe2O3 cannot be used together with spinel phases due to very different magnetic properties. On the other side, at the moment it is not possible to claim with certainty whether it could be used together with the epsilon phase or not. This is a consequence of the insufficient knowledge about magnetic properties of these two iron oxide phases. Literature data revealed that pure hematite nanoparticles are characterized by the intrinsic coercivity field (Hci) value of 1.7 kOe [23], although nano-sized α-Fe2O3 in silica matrix can achieve coercivity of 4.3 kOe [24]. Under the certain size limit, hematite nanoparticles showed superparamagnetic (SPM) behavior [12]. The presence of the other ions significantly alters hematite coercivity. Even bulk hematite doped with alumina ions reached coercivity of >8 kOe [25]. It is similar with the lack of the knowledge regarding epsilon Hc value: dependent on the synthesis conditions, epsilon nanoparticles showed different coercivity. This phase is characterized by high

*Mineralogy - Significance and Applications*

drastically increased by decreasing particle size, favoring the role of the surface

Although the most attention in this chapter will be paid to magnetic properties of hematite nanoparticles, it is important to mention that overall behavior of nano-hematite is characterized by its electromagnetic response which determined biomedical application of nanoparticles. Due to coupling between nano-hematite electrical and magnetic fields, it is clear that electrical properties are contributing to the final hematite application as well as magnetic properties. Noteworthy, difference between conductivity of bulk and nano-hematite widespread biomedical application of this iron oxide polymorph application. According to the analysis of the density of electronic states, the bulk hematite showed the charge-transfer insulator nature [13]. Differed from bulk hematite, nano-hematite is an n-type semiconductor, with a bandgap of ~2.2 eV [14]. Consequently, the increase in conductivity enables the extended application of nano-hematite in different biomedical areas, such as transfer of electrical signals in biosensors, tissue engineering, neural probes,

On the other hand, transition from bulk to nano dimensions resulted in the significant change of its magnetic behavior. Magnetic behavior of bulk hematite is determined by Neel temperature (TN) (~950 K) and Morin temperature (TM) (~260 K) that represent the temperatures upon which the hematite magnetic ordering is changed. Above TN, hematite is characterized by paramagnetic structure. In the temperature range between TN and TM, hematite showed a weak ferromagnetic ordering, while under TM it is antiferromagnetic [16]. Hematite magnetic configurations are defined by the magnetic interactions (magnetic ordering of bulk materi-

Magnetic structure of bulk hematite is represented by different regions of a macroscopic system broken symmetry in different ways, the so-called domains. Domains present small regions within each of which the local magnetization achieves the saturation value [17], while interface between the adjacent regions presents the domain wall. The processes of magnetization and demagnetization of materials occurred through the movement of the domain walls and change of the domain boundaries, consequently bringing to the increase/decrease of a

From the aspect of magnetic interactions, decrease of the particle size revealed a dominant role of dipole-dipole interactions in the ordering of nanoparticles' magnetic moments, which is negligible in the case of bulk hematite, since magnetic moment of bulk magnetic material is significantly lower than the moment of the nanoparticle [17]. To get a better insight in the changes in the strength ratio of bulk and nano-magnetic interactions that are responsible for maintaining of long-term ordering of magnetic moments, it is important to understand the origin of the increase in the value of nanoparticle magnetic moment. The increase of magnetic moment occurred as a consequence of lowering dimensionality of bulk materials and has been explained by the absence of multi-domain structure and appearance of single-domain nanoparticle structure. The balance between the anisotropy and exchange energies is required for formation of finite-size domain walls [18], resulting in the presence of some critical diameter size, below which

> /μo · Ms 2

where Jab is the exchange integral, Ka is the anisotropy constant, and Ms is the

] (1)

effects in the characteristic behavior of the nanoparticles.

drug delivery, or diagnosis, and therapy of human diseases [15].

als is mostly influenced by the exchange interaction) [17].

nanoparticle is single-domain [18], Eq. (1):

saturation magnetization.

rc ≈ 9[(Ја<sup>b</sup> · Ka)1/2

**104**

domain size.

room temperature coercivity (10–20 kOe) [26, 27]. Nevertheless, some literature reports depicted the lowered epsilon Hc value (8 or 2.4 kOe [28, 29]). As well, epsilon nanoparticles could be prepared in order to display SPM behavior [30]. Although hematite nanoparticles cannot achieve coercivity of 10–20 kOe, there is a certain interval of Hci values during which the hematite and epsilon phase coercivities could overlap. Likewise, it is important to point out that coercivity of the samples containing both phases, hematite and epsilon, significantly varies dependent on the synthesis conditions.

The aim of this chapter was to examine in more detail the correlation between synthesis parameters and magnetic properties of nanocomposites containing pure hematite phase or hematite phase in combination with the SPM epsilon phase. A better insight in the measured magnetic field (which is in literature usually denoted as coercivity field) variations dependence on the synthesis conditions is of importance for improvement of the current efforts in understanding of the magnetic properties of hematite phase. Also, some difficulties inherent in studying influence of the variation of synthesis conditions onto the magnetic behavior of the examined samples are highlighted. Results summarized in this chapter could facilitate application of nano-hematite in biomedicine.

## **2. Overview of nano-hematite applications in biomedicine**

Plenty of synthesis pathways for production of the nano-hematite enabled formation of hematite nanoparticles characterized by different properties, which determine their application. There are a lot of reasons for a biomedical application of nano-sized α-Fe2O3: low cost, long-term chemical stability, and nontoxicity. Up until today, nano-hematite is mostly used as a starting material for preparation of multifunctional nanocomposite particles that found application in different areas of biomedicine. In order to obtain appropriate candidate for biomedical application, nanocomposite materials containing hematite nanoparticles are prepared by a few steps of synthesis procedures.

Some of the biomedical applications of *α-Fe2O3* nanoparticles are listed below.

Nano-hematite could be used as a starting material for the synthesis of platforms, presenting promising functional nanomaterials for drug delivery and hyperthermia treatments. Liu et al. synthesized α-Fe2O3 nanoparticles by hydrothermal method [31]. Particles were further coated with a nonporous silica (Fe2O3@ SiO2) and subsequently treated with an organosilicate-incorporated silica by simultaneous sol-gel polymerization of tetraethoxysilane (TEOS) and n-octadecyltrimethoxysilane (C18TMS). Final step of the synthesis considered reduction of the hematite cores to magnetite. Obtained nanocomposite platforms are used as smarttargeted drug delivery materials for further in vivo evaluation of cancer therapies [31]. Another application of the platforms based on the usage of nano-hematite as a starting material is considered a preparation of asymmetric hematite-silica nanocomposites (JFSNs) as multifunctional peroxidase mimetics that found application in glucose colorimetric biosensing [32].

On the other hand, a combination of mesoporous nano-hematite with carbon quantum dots enabled preparation of the nanomaterial that showed promising properties for the application in visible photo-light photocatalysis [33]. Due to very good photocatalytic properties, excellent biocompatibility, and high chemical stability, carbon quantum dots/mesoporous hematite nanocomposites could be used in numerous biomedical applications, such as photodynamic therapy for cancer treatment, drug delivery systems, cell imaging, biosensors for biological assay, and genetic engineering [34].

**107**

acid (DNA) [38].

**particles**

*Preparation and Characterization of Fe2O3-SiO2 Nanocomposite for Biomedical Application*

tissues) performed by using magnetically labeled binding members [38].

It is important to notice that SPM hematite nanoparticles also could be utilized for biomedical applications, in fabrication of biomolecular sensor system, used for detection of intravenously introduced nanoparticles. Litvinov showed that α-Fe2O3 nanoparticles could be used as magnetoresistive nanosensors designed for sensing biomolecule-conjugated nanoparticles (different targets could be detected, such as cell surface receptor, protein, nucleic acid, mRNA, genomic DNA, etc.) [37].

Recent scientific work on *α-Fe2O3* revealed a potential application of hematite nanoparticles in genotyping, since results of scientific investigation confirmed the presence of interaction between appreciably high concentration of hematite nanoparticles and drying pattern of a sessile droplet of genomic deoxyribonucleic

**3. Prerequisite conditions for preparation of high-quality nano-hematite** 

An important step in the usage of materials that contained nano-hematite in biomedical application presents synthesis of high-quality nano-hematite particles and high control of its magnetic behavior. To use hematite nanoparticles in biomedical

The nanoparticle surface presents a key factor that determines biocompatibility and enables cell adhesion of the particle injected in the human body. Accordingly, the surface of the nano-hematite particles, predetermined for biomedical applica-

1.Biocompatibility: non-toxicity for human organism is prerequisite for the

2.Monodispersity: uniform nanoparticle size and shape minimized interparticle interactions and agglomeration. This task is not completely overcome up until today, due to the presence of the particle size and shape distribution. For that reason, different synthesis strategies are employed with the aim to improve the knowledge regarding achieving nanoparticles' monodispersity [39, 40]. Reaching monodispersity would allow improvement of the control of magnetic

3.Functionalization: particles should possess high efficiency for binding target molecules, and non-specific binding should be avoided. In order to ensure the

purposes, it is necessary first to modify the surface of nano-hematite.

tion, has to meet few basic requirements:

application in biomedicine.

behavior of the overall sample.

Mirzaei et al. investigated the usage of materials consisting nano-hematite in biosensor technologies [35]. Nanocomposite material was prepared by Pechini solgel method that involved the formation of a complex between hematite nanoparticles and citric acid, followed by an esterification reaction with ethylene glycol. Since hematite nanoparticles are displaying good electrical and sensing stability, nanocomposite material is used as a highly stable and selective biochemical sensor for detection of ethanol and monitoring alcohol consumption [35, 36]. Another biosensing application of hematite nanoparticles denoted the application of anodization method that enables synthesis of highly ordered hematite nanotube array on a patterned SiO2/Si substrate. Prepared nanomaterial showed an excellent selectivity and ppb-level detection limits toward acetone, depicting its promising application for breath analyzers to diagnose diabetes mellitus [37]. As well, nano-hematite is recognized as a suitable material for magnetically assisted binding assays (measurement of the concentration or potency of a substance by its effect on living cells or

*DOI: http://dx.doi.org/10.5772/intechopen.81926*

#### *Preparation and Characterization of Fe2O3-SiO2 Nanocomposite for Biomedical Application DOI: http://dx.doi.org/10.5772/intechopen.81926*

Mirzaei et al. investigated the usage of materials consisting nano-hematite in biosensor technologies [35]. Nanocomposite material was prepared by Pechini solgel method that involved the formation of a complex between hematite nanoparticles and citric acid, followed by an esterification reaction with ethylene glycol. Since hematite nanoparticles are displaying good electrical and sensing stability, nanocomposite material is used as a highly stable and selective biochemical sensor for detection of ethanol and monitoring alcohol consumption [35, 36]. Another biosensing application of hematite nanoparticles denoted the application of anodization method that enables synthesis of highly ordered hematite nanotube array on a patterned SiO2/Si substrate. Prepared nanomaterial showed an excellent selectivity and ppb-level detection limits toward acetone, depicting its promising application for breath analyzers to diagnose diabetes mellitus [37]. As well, nano-hematite is recognized as a suitable material for magnetically assisted binding assays (measurement of the concentration or potency of a substance by its effect on living cells or tissues) performed by using magnetically labeled binding members [38].

It is important to notice that SPM hematite nanoparticles also could be utilized for biomedical applications, in fabrication of biomolecular sensor system, used for detection of intravenously introduced nanoparticles. Litvinov showed that α-Fe2O3 nanoparticles could be used as magnetoresistive nanosensors designed for sensing biomolecule-conjugated nanoparticles (different targets could be detected, such as cell surface receptor, protein, nucleic acid, mRNA, genomic DNA, etc.) [37].

Recent scientific work on *α-Fe2O3* revealed a potential application of hematite nanoparticles in genotyping, since results of scientific investigation confirmed the presence of interaction between appreciably high concentration of hematite nanoparticles and drying pattern of a sessile droplet of genomic deoxyribonucleic acid (DNA) [38].
