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lymph node imaging, esophagus, stomach, bladder/prostate/kidney, cardiology, and bone brain inflammation (not tumoral).

      In this chapter, we present the most “appealing” and trendy biomedical applications that involve the use of MNPs: Magnetic Resonance Imaging (MRI) (the first‐approved clinical application), its development Magnetic Particle Imaging (MPI) and magnetic hyperthermia (MH), which defines a research area in our group devoted to the development of MNPs with high heating powers (Iacovita et al. 2015, 2016, 2020). For each application, a short theoretical explanation of the physical phenomenon the application is based on is provided. We hope that this approach will ease their understanding, especially, in the case of the readers that are not necessarily familiarized with this topic. Due to the focused aim of this chapter, the synthesis methods developed for the MNPs of various sizes, shapes, and compositions were not included. For a detailed description of these synthesis procedures and their subsequent physical properties, please refer to the following literature (Lu et al. 2007; Reddy et al. 2012; Wu et al. 2016).

2.2 Biomedical Applications

      According to the underlying interaction mechanism of MNPs with various forms of external applied magnetic fields, we have identified three types of application that could have a major impact in nanomedicine, in the near future:

      1 Applications based on the existence of a magnetic force. The magnetic force can be defined as the force developed when MNPs, as tiny nanoscale magnets possessing a dipolar magnetic moment, interact with an external static magnetic field gradient. The acquired magnetic mobility of MNPs, due to this interaction, leads to their movement toward the higher magnetic field zones, a phenomenon known as magnetophoresis. Magnetophoresis can be used in some specific applications such as magnetic drug targeting, magnetic cell targeting, magnetofection, magnetic purification/separation of the cell or its constituents (molecules, exosomes, and organelles), controllable in vivo genome editing, or induction into apoptosis.

      2 Applications based on magnetic relaxation of protons. In this case, the non‐uniform local dipolar magnetic fields generated by MNPs, in their vicinity, significantly modify the longitudinal (T1) and transversal (T2) relaxation times of protons. This is the main mechanism involved in the use of MNPs as contrast agents for MRI applications. So far, MRI has been successfully used in diagnostic imaging, cell tracking, molecular imaging, and image‐guided drug delivery.

      3 Applications based on magnetic heating. The conversion of electromagnetic energy, resulted from the interaction of MNPs with an external alternating (AC) radiofrequency (RF) magnetic field, into thermal energy, is exploited in MH for different purposes as: apoptosis induction in cancer cells, thermal ablation of tumors, nanowarming, magnetogenetics, or controlled drug release.

      In the following section, we will address the use of MNPs as contrast agents in MRI, which represented their first biomedical application introduced in clinical practice. Afterward, we will introduce the Magnetic Particles Imaging (MPI) technique, which is a transverse to the static magnetic field and irradiating recent imaging technique possessing a much higher resolution as compared to MRI. Lastly, we will present a short overview of recent advancements reported in the field of MH.

      2.2.1 MNPs as Contrast Agents in MRI

The use of the MNPs as contrast agents in MRI was the first application for which Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved their use in clinical practice (see Table 2.1). MRI is based on the Nuclear Magnetic Resonance (NMR) of the protons constituting the nucleus of the hydrogen atoms. In the human body, protons represent 63% of the body mass. NMR can occur when the proton's nuclear magnetic momentum, aligned parallel to a static external magnetic field, reverses its orientation to an antiparallel one, by resonantly absorbing a certain amount of external energy. More precisely, the energy of an external RF electromagnetic field, transverse to the static magnetic field and irradiating the proton‐containing sample, has to be equal to the energy difference between the two orientation states. Translating the space in terms of the values of the magnetic field, B, allows one to get information about the position of the protons, by using the measured resonance frequencies.

Table 2.1 Examples of the MNPs clinically approved or in the phase of clinical trials.

Commercial name	Formulation	Application	Status
Feridex (Ferumoxide)	Iron oxide coated with dextran	MRI	FDA approval discontinued in 2008
Combidex (Ferumoxtran)	Ultrasmall iron oxide coated with low Mw dextran	MRI	Approval in Europe, withdrawal in 2007
Resovist (Ferucarbotran)	Iron oxide NPs coated with carboxyldextran	MRI	Approval in Europe, production abandoned in 2009
Gastromark (Ferumoxsil)	Silicone‐coated iron oxide NPs	MRI	FDA approval, discontinued in 2012
Feraheme (Ferumoxytol)	Iron oxide coated Silicone‐coated iron oxide NPs with polyglucose sorbitol carboxymethylether	Iron replacement therapy in patients with chronic kidney failure, MRICNS imaging, macrophage imaging, blood pool agent, cellular labeling, lymph node imaging	FDA approval withdrawn from EU market
Abdoscan	Sulfonated poly(styrene‐divinylbenzene) copolymer	Oral gastrointestinal imaging	Clinical trial
Nanotherm	Iron oxide NPs with aminosilane coating	Hyperthermia in solid tumors	Clinical trial
Magtrace Sienna+	Superparamagnetic iron oxide particles	Sentinel lymph node mapping	Clinical trials

      In MRI, the measurements are performed in pulses of RF electromagnetic field, which has the “role” to perturb the orientation states of the nuclear spins. The perturbed orientation will relax by the end of the pulse, a phenomenon that is known as spin relaxation. There are two mechanisms that are responsible for this phenomenon: the spin–lattice relaxation and the spin–spin relaxation.

      The spin–lattice relaxation process is characterized by the time interval (time constant) in which the magnetization along the direction of the static magnetic field decreases to zero, when the static field is inactivated. This time constant is called the longitudinal relaxation time and usually is denoted as T₁. On the other hand, the spin–spin relaxation mechanism is characterized by the time interval (also called transverse relaxation time, T₂) in which the magnetization in the direction perpendicular to the external magnetic field B₀ decreases to zero. The spin–spin relaxation process is also strongly correlated with the existence of inhomogeneities in the magnetic field the protons feel that leads to a decorrelation in their rotation frequencies around the axis of B₀.

      Human tissues have different values of both relaxation times due to their different proton concentrations and structure (environment). These differences are responsible for the “quality” of the

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