**1. Introduction**

Nanotechnologies aim to ease and to satisfy the needs of regenerative medicine<sup>1</sup> by providing multifunctional, theranostic, and stimuli-responsive biomaterials [1, 2]. In particular, stimuli-responsive biomaterials such as magneto-responsive biomaterials are devices capable of reacting to an external magnetic field spatiotemporally in a specific way [3]. This powerful class of biomaterials is a promising candidate as active and therapeutic scaffolds for advanced drug delivery and tissue regeneration applications [3, 4].

Multifunctional magnetic-responsive materials can be manufactured by modifying or functionalizing traditional materials employed in tissue engineering or by

<sup>1</sup> Regenerative medicine is a tissue regeneration technique based on the replacement or repair of diseased tissue or organs to restore a lost or impaired function [1].

#### *Smart Nanosystems for Biomedicine, Optoelectronics and Catalysis*


• To provide a controlled *mechanical stimulation* of tissues and boost the healing

*Magnetic scaffolds are obtained by the combination of biomaterials and MNPs. They are multifunctional and*

• To develop a smart and reliable *magnetic drug delivery system* (MDD)

*theranostic nanocomposites. The potential biomedical applications of MagS are shown.*

*Biomedical Applications of Biomaterials Functionalized with Magnetic Nanoparticles*

*DOI: http://dx.doi.org/10.5772/intechopen.89199*

GFs while controlling their spatial distribution [13].

• To generate therapeutic heat and perform local *hyperthermia* (HT) against

The mechanical stimulation of injured tissues using magneto-responsive scaffolds found application in bone tissue engineering, where static magnetic field (SMF) or low-frequency magnetic field is used to elicit osteoprogenitor cells [1–4]. The rationale of employing magnetic scaffolds as part of a MDD system is the need to have an "attraction platform" to target and control the attraction of magnetic liposomes or MNPs bio-conjugated with growth factors (GFs) [6, 11]. Indeed, recently several magnetic carriers of biomolecules capable of acting on cell function were developed. However, using an external SMF their delivery to deep tissue and to the site of damage is complicated, and the MNPs tend to distribute where the magnetic force is maximum, i.e., at the body surface, where the field is applied [12]. Having a MagS implanted in the injured tissue allows to attract the MNPs and the

Finally, if the external magnetic stimulus is a radio-frequency (RF) magnetic field, the population of MNPs embedded in the biomaterial dissipates a huge amount of heat. The deposited power can be exploited as therapeutic heat, enabling to use the magnetic scaffold as a thermo-seed able to perform HT treatment against

To date, magnetic scaffolds have been synthesized and characterized in terms of chemical and physical properties while proving experimentally their powerful and promising potential in regenerative medicine and oncology [1–4]. However, to translate the use of these nanostructured biomaterials in the clinical practice, several limitations have to be overcome, and further investigations are required to predict their behavior [4]. The potential use of magnetic scaffolds as tissue substitutes needs the combined work of material scientists, biomedical engineers, and biologists. In particular, since in the literature there is a clear lack of mathematical and numerical models, which relate the physical properties of these nanocomposite

response

**Figure 1.**

cancer cells

cancer cells [14].

**3**

**Table 1.**

*Magnetic scaffolds divided by composition, production, and MNPs embedded. Redrafted from [5].*

incorporating magnetic nanoparticles (MNPs) in the biocompatible matrix [4, 5]. **Table 1** reports examples of several magnetic biomaterials synthesized in the literature [6]. An approach to create a magnetic biomaterial is the impregnation of a polymer or ceramic (e.g., ϵ-poly caprolactone or hydroxyapatite) with MNPs dispersed in a ferrofluid (FF) [5, 6]. Subject to the action of capillarity, the nanoparticles fill the superficial defects and pores of the biomaterials. In this way a nanocomposite is created, i.e., the final material is a two-phase system strengthened by the magnetic iron phase [7]. Moreover, a multifunctional and composite material of such type can be obtained by the polymerization of a polymer in the presence of magnetic nanoparticles of magnetite (Fe3O4) or maghemite (*γ*-Fe2O3). This allows to produce a solid object using rapid prototyping and additive manufacturing techniques, such as electrospinning or 3D bioplotting [7].

In alternative, a stable, repeatable, and controllable manufacturing technique of magnetic-responsive biomaterial is the chemical doping of or substitution with F<sup>2</sup><sup>þ</sup> or F<sup>3</sup><sup>þ</sup> ions in a ceramic material (e.g., hydroxyapatite, *β*-tricalcium phosphate, and hardystonite). This process gives rise to an intrinsic magnetic and biocompatible material, which can be used in the form of microparticles or directly as a bulk object with tunable and ad hoc properties for therapeutic or regenerative medicine applications [8, 9].

Given these methods, the magnetic biomaterial can be processed to develop a tissue-guiding structure or a tissue scaffold, i.e., a device intended to be implanted in an injured site for supporting and withstanding the cell adhesion, proliferation, and differentiation, in order to restore tissue continuity and functioning [10]. Magnetic scaffolds (MagS) have been proposed for the following three main applications, as presented in **Figure 1** [1–9]:

*Biomedical Applications of Biomaterials Functionalized with Magnetic Nanoparticles DOI: http://dx.doi.org/10.5772/intechopen.89199*

**Figure 1.**

incorporating magnetic nanoparticles (MNPs) in the biocompatible matrix [4, 5]. **Table 1** reports examples of several magnetic biomaterials synthesized in the literature [6]. An approach to create a magnetic biomaterial is the impregnation of a polymer or ceramic (e.g., ϵ-poly caprolactone or hydroxyapatite) with MNPs dis-

*Magnetic scaffolds divided by composition, production, and MNPs embedded. Redrafted from [5].*

**Type of scaffold Synthesis technique <sup>M</sup>***s***, emu**�**g**�**<sup>1</sup> Type of MNPs r***mnp* HA/collagen Impregnation 0.35–15 Fe3O4 200 HA/collagen Impregnation 0.50 *γ*-Fe2O3, Fe3O4 10–50 HA/PLA Electrospinning 0.05 *γ*-Fe2O3 5 *β*-TCP Impregnation 0.6–1.2 Fe3O4 250 Chitosan/PVA membrane Electrospinning 0.7–3.2 Fe3O4 n.s. Calcium silicate/chitosan Mixture 6–10 SrFe12O19 500 PMMA Mixture n.s. Fe3O4 10 Silicate Mixture n.s. *γ*-Fe2O3 n.s. Fe-doped HA Chemical substitution 4 HA-Fe3O4 10–14 Fe-hardystonite Chemical doping 0.1–1.2 Fe3O4 20–60 Bredigite Milling 7–25 Ca7MgSi4O16-Fe3O4 120 HA Impregnation 12–20 Fe3O4 200 HA Impregnation 1–2.5 *γ*-Fe2O3 8 HA Impregnation n.s. *γ*-Fe2O3 5 Chitosan In situ precipitation 4 *γ*-Fe2O3, Fe3O4 n.s ϵ-PCL 3D Bioplotting 0.2–0.3 Fe3O4 25–30 PLGA Electrospinning 2–10 Fe3O4 8.47

*Smart Nanosystems for Biomedicine, Optoelectronics and Catalysis*

nanoparticles fill the superficial defects and pores of the biomaterials. In this way a nanocomposite is created, i.e., the final material is a two-phase system strengthened by the magnetic iron phase [7]. Moreover, a multifunctional and composite material of such type can be obtained by the polymerization of a polymer in the presence of magnetic nanoparticles of magnetite (Fe3O4) or maghemite (*γ*-Fe2O3).

In alternative, a stable, repeatable, and controllable manufacturing technique of magnetic-responsive biomaterial is the chemical doping of or substitution with F<sup>2</sup><sup>þ</sup> or F<sup>3</sup><sup>þ</sup> ions in a ceramic material (e.g., hydroxyapatite, *β*-tricalcium phosphate, and hardystonite). This process gives rise to an intrinsic magnetic and biocompatible material, which can be used in the form of microparticles or directly as a bulk object with tunable and ad hoc properties for therapeutic or regenerative medicine

Given these methods, the magnetic biomaterial can be processed to develop a tissue-guiding structure or a tissue scaffold, i.e., a device intended to be implanted in an injured site for supporting and withstanding the cell adhesion, proliferation, and differentiation, in order to restore tissue continuity and functioning [10]. Magnetic scaffolds (MagS) have been proposed for the following three main

persed in a ferrofluid (FF) [5, 6]. Subject to the action of capillarity, the

This allows to produce a solid object using rapid prototyping and additive manufacturing techniques, such as electrospinning or 3D bioplotting [7].

applications [8, 9].

**2**

**Table 1.**

applications, as presented in **Figure 1** [1–9]:

*Magnetic scaffolds are obtained by the combination of biomaterials and MNPs. They are multifunctional and theranostic nanocomposites. The potential biomedical applications of MagS are shown.*


The mechanical stimulation of injured tissues using magneto-responsive scaffolds found application in bone tissue engineering, where static magnetic field (SMF) or low-frequency magnetic field is used to elicit osteoprogenitor cells [1–4].

The rationale of employing magnetic scaffolds as part of a MDD system is the need to have an "attraction platform" to target and control the attraction of magnetic liposomes or MNPs bio-conjugated with growth factors (GFs) [6, 11]. Indeed, recently several magnetic carriers of biomolecules capable of acting on cell function were developed. However, using an external SMF their delivery to deep tissue and to the site of damage is complicated, and the MNPs tend to distribute where the magnetic force is maximum, i.e., at the body surface, where the field is applied [12]. Having a MagS implanted in the injured tissue allows to attract the MNPs and the GFs while controlling their spatial distribution [13].

Finally, if the external magnetic stimulus is a radio-frequency (RF) magnetic field, the population of MNPs embedded in the biomaterial dissipates a huge amount of heat. The deposited power can be exploited as therapeutic heat, enabling to use the magnetic scaffold as a thermo-seed able to perform HT treatment against cancer cells [14].

To date, magnetic scaffolds have been synthesized and characterized in terms of chemical and physical properties while proving experimentally their powerful and promising potential in regenerative medicine and oncology [1–4]. However, to translate the use of these nanostructured biomaterials in the clinical practice, several limitations have to be overcome, and further investigations are required to predict their behavior [4]. The potential use of magnetic scaffolds as tissue substitutes needs the combined work of material scientists, biomedical engineers, and biologists. In particular, since in the literature there is a clear lack of mathematical and numerical models, which relate the physical properties of these nanocomposite biomaterials with the magnetic drug delivery or the hyperthermia, in this chapter, two mathematical models for their use as hyperthermia agent and as a tool for magnetic drug delivery are provided.

the complex magnetic susceptibility of the particles. For ferrofluids, the magnetic

*<sup>χ</sup>*ð Þ¼ *<sup>f</sup> <sup>χ</sup>*<sup>0</sup> � *<sup>j</sup>χ*<sup>00</sup> <sup>¼</sup> *<sup>χ</sup>*<sup>0</sup>

The term *χ*<sup>0</sup> is the equilibrium susceptibility that is defined as [17]:

3

*<sup>ζ</sup>*ð Þ¼ *<sup>T</sup> <sup>μ</sup>*0*ϕM*<sup>2</sup>

*<sup>ζ</sup> coth* ð Þ� *<sup>ζ</sup>* <sup>1</sup>

where *ζ* is the ratio between the magnetic energy of the set of magnetic dipoles

where M*<sup>s</sup>* is the saturation magnetization of the single MNPs, in Am�1; V*mnp* is the particle volume in nm3; k*<sup>B</sup>* is the Boltzmann's constant; and T is system temperature. In Eq. (3), *χ*<sup>0</sup> is the initial susceptibility, which is defined as [17]:

*<sup>χ</sup><sup>i</sup> <sup>H</sup>*, *<sup>T</sup>* � � <sup>¼</sup> *<sup>μ</sup>*0*ϕMsVm*∣*H*<sup>∣</sup>

The term *τ* in the Debye model (Eq. 2) is the effective relaxation time, in s, which can be evaluated as the parallel of the Néel and Brownian processes [17]:

The time required to the magnetic dipole moment to align with the direction of

ffiffiffi *π* p <sup>2</sup> *<sup>τ</sup>*<sup>0</sup> *e*Γ

The pre-exponential factor *τ*<sup>0</sup> is a time, and its value can range from 0.1 ps to 1 ns, but this term is a function of system temperature, i.e., *τ*<sup>0</sup> ¼ *τ*0ð Þ *T* [13]. The term Γ is the ratio of the anisotropy energy of the nanoparticle to the thermal

<sup>Γ</sup> <sup>¼</sup> *KaVm*

where K*<sup>a</sup>* is the magnetic anisotropy energy per unit volume in Jm�<sup>3</sup> and V*<sup>m</sup>* is

In a FF, the nanoparticles are allowed to rotate and move according to Brownian motion in the viscous medium where they are dispersed. When subject to a timevarying magnetic field, the particles rotate to orient with the direction of the external energy source, thus contributing to the relaxation process. The Brownian

*<sup>τ</sup>B*ð Þ¼ *<sup>η</sup>*, *<sup>T</sup>* <sup>3</sup>*ηVh*

being *η* the viscosity of the medium, in Pa�s, and V*<sup>h</sup>* the hydrodynamic radius of

1 *<sup>τ</sup>* <sup>¼</sup> <sup>1</sup> *τN* þ 1 *τB*

the external magnetic field is called the Néel relaxation time, *τ<sup>N</sup>* [16, 17]:

*τ<sup>N</sup>* ¼

*ζ*

*sVmnp*∣*H*∣

<sup>1</sup> <sup>þ</sup> *<sup>j</sup>*2*π<sup>f</sup> <sup>τ</sup>* (2)

� � (3)

<sup>3</sup>*kBT* (4)

<sup>3</sup>*kBT* (5)

<sup>Γ</sup> (7)

*kBT* (8)

*kBT* (9)

(6)

susceptibility is known to be described by the Debye model [13, 16]:

*Biomedical Applications of Biomaterials Functionalized with Magnetic Nanoparticles*

*χ*<sup>0</sup> ¼ *χ<sup>i</sup>*

and the thermal energy. Mathematically speaking:

*DOI: http://dx.doi.org/10.5772/intechopen.89199*

energy of the system, i.e.:

the MNP volume in nm3.

the particle in solution.

**5**

relaxation time can be evaluated as [16]:

Section 2 briefly reviews the use of MagS as magneto-responsive biomaterials for the stimulation of tissues, in particular bone tissues. In Section 3 the nonlinear chemico-physical properties of magnetic scaffolds are presented, described, and used to introduce a recent in silico model for the planning of bone tumor hyperthermia [14]. Finally, in Section 4 the use of MagS as tool for active magnetic drug delivery is discussed. Furthermore, a mathematical model able of providing insights into the parameters of influence of the phenomenon is presented and analyzed [13]. The complete description of magnetic scaffolds favors the assessment of their effectiveness and their potential clinical impact.
