# A Proposed Method for Thermal Specific Bioimaging and Therapy Technique for Diagnosis and Treatment of Malignant Tumors by Using Magnetic Nanoparticles

Authors: Iddo M. Gescheit; Moshe Ben-David; Israel Gannot
Journal: Advances in Optical Technologies
 (2008)

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## Abstract

The objective of this research program is to develop a novel, noninvasive,
low-cost infrared
(8–12μm spectral range) imaging technique that would improve upon current methods using nanostructured core/shell magnetic/noble
metal-based imaging and therapies. The biocompatible magnetic nanoparticles are able to produce heat under AC magnetic field. This thermal radiation propagates along the tissue by thermal conduction reaching the medium's (tissue's) surface. The surface temperature distribution is acquired by a thermal camera and can be analyzed to retrieve and reconstruct nanoparticles' temperature and location within the tissue. The technique may function as a diagnostic tool thanks to the ability of specific bioconjugation of these nanoparticles to tumor's outer surface markers. Hence, by applying a magnetic field, we could cause a selective elevation of temperature of the targeted nanoparticles up to 5∘C, which detects the tumor. Furthermore, elevating the temperature over 65∘C and up to 100∘C stimulates a thermo ablating interaction which causes a
localized irreversible damage to the cancerous site with no harm  to the surrounding tissue. While functioning as a diagnostic tool, this procedure may serve as a targeted therapeutic tool under thermal feedback control as well.


---

## Body

## 1. Introduction

Cancer is a very prevalent disease with no satisfying cure and/or treatment.  American Cancer Society statistics shows that about 1 399 790 new
cancer cases were diagnosed in 2006.
This number does not include carcinoma in situ (noninvasive cancer) or
any site except urinary bladder, and does not include basal and squamous cell
skin cancer.  More than 1 million cases
of basal and squamous cell skin cancers were diagnosed in 2006.  In the same year, about 564 830 Americans died
of cancer, more than 1 500 people a day. Cancer is the second most common cause of death in
the US,
exceeded only by heart disease. In the US, cancer accounts for 1 out of every 4 deaths.
The National Institute of Health (NIH) estimates overall costs for cancer in
2005 with $209.9
billion [1–3].Conventional
(anatomical, structural) imaging is insensitive to the presence of cancer,
often failing to yield the very information needed for accurate diagnosis and
staging, for proper treatment selection and monitoring or for effective
followup after treatment.  For example, small
primary tumors go undetected. For many cancers, an internal, aggressive,
noncalcified tumor under containing fewer than 500 000 cells (i.e., under 2 mm
wide) is likely to pass undetected through most body-region scans, including
CT, MRI, ultrasound, radionuclide, and metabolic PET.  At this size, a tumor has effectively
undergone 19 cell doublings about halfway through doubling toward a predicted
lethal load of1010−1012 cells and is likely to be sufficiently repleted with gene defects so that it
will undergo continued and uninterrupted growth if not treated [4].While cancer may be
suspected for a variety of reasons, the definitive diagnosis of most
malignancies must be confirmed by histological
examination of the cancerous cells by a pathologist. After obtaining tissue sample
by a biopsy
or surgery,
the tissue diagnosis
indicates the type of cell that is proliferating, its histological grade and other features of the
tumor. Together, this information is useful to evaluate the prognosis
of this patient and choose the best treatment. However, current therapy
techniques (e.g., surgery, chemotherapy, radiation) still show poor results and
therefore, unfortunately, the standard of care is to blindly treat with
chemotherapy selected by convention using prior retrospective studies. A
treatment is considered a success or failure only in retrospect (i.e., success
is when a patient survives 5 years, and failure is when a relapse occurs).Hence,
the majority of diagnosis and therapy modalities is not capable of
distinguishing between malignant cells and healthy tissue (especially in early
stages) and does not provide the physician with adequate precision and
specificity.  Moreover, there is no
real-time control referring to
the physiological margins distinguishing the malignant and benign tissue.  The implications of the latter are, for
example, in surgery: if the surgeon does not remove all the malignant cells,
the progression or recurrence of the disease is almost without doubt.  On the other hand, if the surgeon removes more
than necessary, the “extra” tissue being removed is a healthy tissue
and may be vital for the organ-life
cycle or patient's life.


## 2. Materials and Methods

### 2.1. The System

The
suggested system and method are schematically depicted in Figure1. After the insertion
of magnetic nanoparticles into a patient's body (either locally to a suspected
tissue or systematically to the blood stream by IV injection), the
nanoparticles arrive in short proximity to the tumor and a process of
bioconjugation occurs in compliance with a pharmacokinetic profile. Thus, the
tumor's outer surface is bound with nanoparticles by virtue of strong chemical
bonds configured as antigen-antibody complex. Since the biocompatible magnetic
nanoparticles are able to produce heat under AC magnetic field, the region of
interest (ROI) is placed under a suitable field. This emitted thermal radiation
propagates along the tissue by thermal conduction reaching medium's (tissue's)
surface. The surface temperature distribution is acquired by a thermal camera
and could be analyzed to retrieve and reconstruct nanoparticles' temperature
and location within the tissue. In future minimal invasive applications, the IR
radiation can be “guided” from internal compartments of the
body to
the outside by waveguides and dedicated optical fibers, for example, thermal
imaging bundles shown by Gannot et al. [5–8].Figure 1
Schematic description of the system employing a targeted imaging technique and a
closed-loop system for therapy under real-time feedback.By
elevating the temperature of the conjugated nanoparticles up to ~5∘C, diagnosis
is enabled while elevation of local temperature over 65∘C allows “clean
treatment,” that is, localized irreversible damage to the cancerous site
almost without harming the surrounding tissue.


### 2.2. Bioconjugation

A
fundamental issue lying on the basis of this system is the fact that the
magnetic nanoparticles are localized specifically and functions as mediators situated
on the periphery of the tumor. In order to target the tumor and deliver the
nanoparticles reliably and specifically, the suggested transportation leans on
human's immune system. The malignant tumor tends to present specific antigens
on its outer surface. These antigens are able to communicate with corresponding
agents of the immune system (e.g., antibodies) to establish antigen-antibody
complexes which are characterized in strong chemical bonds. For instance, we
can bind the magnetic nanoparticles' surface to the antibodies via adhering
polymers (e.g., PEG) so that antibodies transfer them towards the tumor being
delivered by immune agents (T-cell),
and conjugate them to the tumor, retaining them along the tumor's outer surface
(Figures2 and 3).Figure 2
Bioconjugation of magnetic nanopatricles by using the natural immune system.Figure 3
Magnetic nanoparticles schematic siting along the tumor surface.This
bioconjugation is analogous to that made with fluorophores in research conducted
by Fibich et al. [9] and Gannot et al. [10].


### 2.3. Heat Generation

There
exist at least three different mechanisms by which magnetic materials can
generate heat in an alternating field [11]:(i)
generation of eddy currents in bulk magnetic materials;(ii)
hysteresis losses in bulk and multidomain magnetic materials(iii)
relaxation losses in “superparamagnetic” single-domain magnetic materials.
In
this technique, we use single-domain particles in which mechanism (i) and (ii)
contribute very little to the heating of these particles (if at all) [12], while the significant
mechanism in contribution with heating is the relaxation mechanism (iii) [13, 14].Relaxation
losses in single-domain magnetic nanoparticles fall into two modes: (a) rotational
(Brownian) mode and (b) Néel mode [13, 15]. The principle of heat generation
due to each individual mode is shown in Figure 4.Relaxational losses leading to heating in an alternating magnetic field(H).
(a)(b)In
the Néel mode (Figure4(a)), the magnetic moment (dotted arrow) originally
locked along the crystal easy axis (solid arrow) rotates away from the crystal
axis towards the external field (H). The Néel mechanism is analogous to
the hysteresis loss in multidomain magnetic particles whereby there is an
“internal friction” due to the movement of the magnetic moment in an external
field that results in heat generation.In
the Brownian mode (Figure4(b)), the whole particle oscillates towards the
field with the moment locked along the crystal axis under the effect of a
thermal force against a viscous drag in a suspending medium. This mechanism
essentially represents the mechanical friction component in a given suspending
medium [16].Each
of the relaxation modes that lead to heat generation is characterized by a time
constant.τN is the Néel time constant given by(1)τN=τ0exp(EBkBT), where EB=KuV is analogous to an activation energy that has
to be overcomed by the thermal energy kBT to overcome the inherent magnetic anisotropy
energy.The
energy barrierEB is represented by the constant Ku,
which is a material property and is the anisotropy constant, multiplied by V, which is the volume of the magnetic nanoparticle. The thermal energy is
represented by the constant kB, named by Stephan Boltzmann, and multiplied by
the absolute temperature T. The constant τ0 is of the order of 10−9 seconds [13].The
Brownian time constant represented byτB is given by(2)τB=3ηVHkBT, where VH is the hydrodynamic volume of  the magnetic nanoparticle which is the
effective volume (including that of the nanoparticle and coating or surfactant
attached to the nanoparticle), η is the viscosity of the liquid carrier, and kBT is the thermal energy.The
resultant
power generation is a strong function of the effective time constant,
and the field parameters and is given by(3)PSPM=πμ0χ0H02f2πfτ1+(2πfτ)2, where H0 and f are the amplitude and frequency of the applied
alternating magnetic field, respectively, χ0 is the magnetic susceptibility, μ0 is the permeability of free space, and τ is the effective time constant given by 1/τ=(1/τN)+(1/τB)    [11, 13].


### 2.4. Affecting Parameters

There are numerous parameters affecting the
heat generation, which is produced by magnetic nanoparticles excited by a
magnetic field. A few examples for some crucial parameters are given below which one
should take into consideration when heating with magnetic nanoparticles.


#### 2.4.1. Field Parameters

According to (3), it is obvious that field
strength and frequency are controllable parameters that directly affect the
power produced by the nanoparticles when alternative magnetic field is applied.
It should be understood that the of field parameter is not simply proportional to
the generated power but more complex, and depends on additional parameters such
as the nanoparticles' material properties [17].


#### 2.4.2. Material Properties

An interesting class of magnetic materials that
are common for this purpose is iron oxides such asFe3O4, γ-Fe2O3 and MO⋅Fe2O3 (where
M is Mn, Co, Ni, Cu) [18], because they display
ferrimagnetism.  Magnetite (Fe3O4),
meghemite (γ-Fe2O3), and hematite (α-Fe2O3)
are the most common iron oxides and they are discussed below.Another alternative is the magnetic
nanoshells which were designed and characterized by Nanosonic Inc.
(Figure5(a)).
The nanoshells are comprised of an iron core with diameter of 8 nm coated with
a layer of gold. The gold coatings are made in order to prevent oxidation,
hence demagnetization; ultrathin noble metal coatings of Au (~2 nm) were
prepared to provide long-term stability and biocompatibility for the Fe core.
The Fe core was coated with a series of block copolymer stabilizers that are
compatible with analgesics to prevent flocculation in the arterial system in
vivo (see Figure 5(b)).  In addition, the
block copolymers assist in preventing agglomeration.Fe Nanoparticles produced by Nanosonics Inc. (a)
Magnetic nanoparticles in different
particle size configured as powder. (b)
Schematic illustration of a single Fe-Au nanoparticle.
(a)(b)Other materials are also being investigated
including platinium compounds, vanadium oxides, cobalt, nikel, lanthanum, and
manganase [19, 20].


#### 2.4.3. Size Dependence

The size of the nanoparticles is a
fundamental characteristic in this field. Ma et al. [21] investigated the specific
absorption rate (SAR) values of aqueous suspensions of magnetite particles with
different diameters varying from 7.5 to 416 nm by measuring the
time-independent temperature curves in an external altering magnetic field(80 kHz, 32.5 kA/m). Results indicate that
the SAR values of magnetite particles are strongly size dependent. For
magnetite larger than 46 nm, the SAR values increase as the particle size
decreases where hysteresis loss is the main contribution mechanism. For
magnetite particles of 7.5 and 13 nm which are superparamagnetic, hysteresis
loss decreases to zero and, instead relaxation losses (Néel loss and Brownian rotation loss)
dominate.The dividing line between the two cases
depicted above is given by the ferromagnetic exchange lengthdex≅A/K using the material parameters of magnetite (K=1.35×104J/m3,A=10−11J/m), the exchange length is estimated as dex≅27nm.Therefore, when the particle size is larger
thandex,
the hysteresis loss increases as the particle size decreases. However, once the
particle size is less than dex,
hysteresis loss will vanish and the main contribution will be of relaxation
losses, as shown, for example, by Ma et al. [21].  In addition, Hergt et al. show that in the
critical particles size region where hysteresis losses vanish, Néel losses grow
as a new loss mechanism which, roughly speaking, extends the loss region toward
even smaller particle sizes [12].


#### 2.4.4. Other Parameters

The
parameters discussed above are merely a few examples for a larger collection of
affecting parameters. Some of them have been investigated and some are probably
yet unknown. Amongst them is the concentration of the nanoparticle inserted
into the body [11]. The concentration should be
large enough to effectively produce heat, but yet in an amount that will not be
toxic for the human body. One also needs to be aware of the evacuation of those
particles once their job is done. (We are not dealing with toxicity and
pharmacokinetics issues in this paper.) The coating of nanoparticles (e.g.,
derivatives of dextran, polyethylene glycol (PEG), polyethylene oxide (PEO),
and poloxamers and polyoxamines) and suspending medium also affect the heat
generation [11, 16, 22]. The period of time of
excitation filed application and profile (e.g., continuous, pulsatile) deeply
affects the SAR which is proportional to the power dissipated [23]. Another affecting parameter
under investigation is the presence of nanoparticles' agglomeration in
comparison with the heat generated in single or dispersed nanoparticles [24].


### 2.5. Thermal Analysis

Upon the heating of the bioconjugated
nanoparticles, we generate a heat source within the body. The heat source,
namely the tumor, and in particular the tumor's surface, is actively heated by
external and controlled magnetic fields. Based on a two dimensional thermal image
acquired from the tissue surface, we seek to derive two fundamental
characteristics: thedepth of the tumor and the temperature of
the tumor and its surroundings. Knowing the temperature in real-time is crucial
in order to avoid any damage to all tissues in the diagnostic mode on one hand,
and on the other hand, operating in therapeutic mode, we expect to damage only
the malignant tissue leaving the healthy surrounding tissue with minimal
damage.  There are various techniques for
analyzing the thermal data such as, for example, automatic segmentation
approaches, and feature extraction and classification as shown by Qi and
Diakides [25].


### 2.6. Setup

The main building blocks of the suggested
system are comprised of means for (shown in Figure6):Figure 6
Schematic description of the system.(i)
heat generation;(ii)
thermal image acquisition;(iii)
thermal image analysis;(iv)
heat generation.
Heat generation is conceptually comprised of
two parts:(i)
magnetic nanoparticles (for “heat
emission”);(ii)
magnetic field (for nanoparticles’
excitation).
The magnetic field is generated by a magnetic
system usually comprised of the
following:(i)
antenna
(e.g., coils)(ii)
AC current generator.
The design of the magnetic system is
implemented bottom-to-up, that is, after choosing the desirable field
parameters (e.g., field strength, frequency), we are capable of designing the
system itself (e.g., coils, circuitry). Determination of the desirable
parameters is not trivial since the system is characterized by a large number
of degrees-of-freedom.Previous research works investigated various
fields: Kalambur et al. used a 1 kW generator and 4 turn RF coils to produce field
strength ofH0=14[kA/m] and frequency f=175[kHz];  Giri et al. examined the fields (10–45[kA/m],300[kHz]);Ma et al. used a 15 kW RF generator to produce
the field(32.5[kA/m],80[kHz]);  Hergt et al. (2004) showed losses under the
AC field (11[kA/m],410[kHz]);  Pankhurst et al. investigated nanoparticles
under the extensive field region of (0–15[kA/m],0.0.5–1.2[MHz]) and Kim et al. examined the influence of
fields of (110[kA/m],0.1–15[MHz]).The two principle parameters of the
externally applied magnetic field, that is, the frequency and strength, are
limited by deleterious physiological responses to high-frequency magnetic
fields [26, 27]:  stimulation of peripheral and skeletal
muscles, possible cardiac stimulation and arrhythmia, and nonspecific inductive
heating of tissue.  Generally, the
useable range of frequencies and amplitudes is considered to be f=0.05–1.2MHz and
H=0–15kA/m.Experimental data on exposure to much higher
frequency fields come from groups such as Oleson et al. [28] who developed a hyperthermia
system based on inductive of tissue, and Atkinson et al.  who developed a treatment system based on
eddy current heating of implantable metal thermoseeds.  Atkinson et al. [29] concluded that exposure to
fields where the product H⋅f
does not exceed 4.85×108, kA/(m⋅s)−1 is safe and
tolerable [30].Hence, following the physiological
constraints shown above and based on previous research results such as those
mentioned above, the desirable averaged working point was chosen to beH0≈10[kA/m];f≈100[kHz].Trying to meet with the fundamental
objectives of the suggested system, particularly cost effectiveness and
bed-side capability, we
seek an alternative technology for the commonly used giant and expensive RF
generators of several kilowatts and up, since they cost about 10 k–100 k of dollars
and are not comfortable to be located near the patient’s bed or at the clinic.
Most of research works in this field are using a single RF coil with a few
turns, for example, 3-4 turns. A major drawback of the coil configuration is
that there is no accessibility for any imaging element, such as an IR camera.
If we had desired to use that kind of solenoid coil, it would have been
characterized with a very large diameter, and the camera
would have been exposed to the AC field.
Hence, this configuration is not applicable and does not apply to our
needs.An alternative preferred method relies on a
Helmholtz coil configuration.  The
fundamental premise of this configuration is that it produces a uniform
(homogeneous) magnetic field between the coils with the primary field component
parallel to the axes of the two coils.  The
Helmholtz configuration further enables an open
workspace for sample (tissue) handling and imaging device accessibility, that
is, an easy and safe path for placing the IR camera, and further enables the
change of the distance between the two coils, that is, adjustable workspace.In order to produce a desired high voltage
over the coils, the system design includes power transformer for voltage
elevation, as shown in Figure7.Figure 7
System's block scheme.The power supply of the system is composed of
an oscillator (PMW controller) with a tunable frequency, boost transformer, and
a push-pull full bridge inverter (H-bridge), as shown in
Figure8.  The full bridge is mainly composed of four
FETs to allow the alternate current.Figure 8
The power generator's block scheme.The thermal imaging is carried out by an IR
camera (FLIR A40M), which detect  the infrared emission which is emitted from
the examined object’s surface (e.g., phantom).The IR camera is positioned perpendicularly
above the object, which is situated within the magnetic field induced between
the two coils.  When the magnetic field
is applied, the nanoparticles generate heat which can be detected by the IR
camera.Integrating the main building blocks of the
required system mentioned above comprises the system as shown in
Figure9.  The system should preferably include a
closed-loop feedback to allow the adjustment of the field parameters (generated
by the coils) according to the temperature readings (acquired via the IR
camera).Figure 9
Schematic description of the closed-loop system.Figure 10
Laboratory system.Obviously, interruption by the user (e.g., physicist)
is possible, such as the tuning of magnetic field when changing its mode of
operation (e.g., achieving therapy requires a substantial increase of the
temperature within the treated tissue).


## 2.1. The System

The
suggested system and method are schematically depicted in Figure1. After the insertion
of magnetic nanoparticles into a patient's body (either locally to a suspected
tissue or systematically to the blood stream by IV injection), the
nanoparticles arrive in short proximity to the tumor and a process of
bioconjugation occurs in compliance with a pharmacokinetic profile. Thus, the
tumor's outer surface is bound with nanoparticles by virtue of strong chemical
bonds configured as antigen-antibody complex. Since the biocompatible magnetic
nanoparticles are able to produce heat under AC magnetic field, the region of
interest (ROI) is placed under a suitable field. This emitted thermal radiation
propagates along the tissue by thermal conduction reaching medium's (tissue's)
surface. The surface temperature distribution is acquired by a thermal camera
and could be analyzed to retrieve and reconstruct nanoparticles' temperature
and location within the tissue. In future minimal invasive applications, the IR
radiation can be “guided” from internal compartments of the
body to
the outside by waveguides and dedicated optical fibers, for example, thermal
imaging bundles shown by Gannot et al. [5–8].Figure 1
Schematic description of the system employing a targeted imaging technique and a
closed-loop system for therapy under real-time feedback.By
elevating the temperature of the conjugated nanoparticles up to ~5∘C, diagnosis
is enabled while elevation of local temperature over 65∘C allows “clean
treatment,” that is, localized irreversible damage to the cancerous site
almost without harming the surrounding tissue.


## 2.2. Bioconjugation

A
fundamental issue lying on the basis of this system is the fact that the
magnetic nanoparticles are localized specifically and functions as mediators situated
on the periphery of the tumor. In order to target the tumor and deliver the
nanoparticles reliably and specifically, the suggested transportation leans on
human's immune system. The malignant tumor tends to present specific antigens
on its outer surface. These antigens are able to communicate with corresponding
agents of the immune system (e.g., antibodies) to establish antigen-antibody
complexes which are characterized in strong chemical bonds. For instance, we
can bind the magnetic nanoparticles' surface to the antibodies via adhering
polymers (e.g., PEG) so that antibodies transfer them towards the tumor being
delivered by immune agents (T-cell),
and conjugate them to the tumor, retaining them along the tumor's outer surface
(Figures2 and 3).Figure 2
Bioconjugation of magnetic nanopatricles by using the natural immune system.Figure 3
Magnetic nanoparticles schematic siting along the tumor surface.This
bioconjugation is analogous to that made with fluorophores in research conducted
by Fibich et al. [9] and Gannot et al. [10].


## 2.3. Heat Generation

There
exist at least three different mechanisms by which magnetic materials can
generate heat in an alternating field [11]:(i)
generation of eddy currents in bulk magnetic materials;(ii)
hysteresis losses in bulk and multidomain magnetic materials(iii)
relaxation losses in “superparamagnetic” single-domain magnetic materials.
In
this technique, we use single-domain particles in which mechanism (i) and (ii)
contribute very little to the heating of these particles (if at all) [12], while the significant
mechanism in contribution with heating is the relaxation mechanism (iii) [13, 14].Relaxation
losses in single-domain magnetic nanoparticles fall into two modes: (a) rotational
(Brownian) mode and (b) Néel mode [13, 15]. The principle of heat generation
due to each individual mode is shown in Figure 4.Relaxational losses leading to heating in an alternating magnetic field(H).
(a)(b)In
the Néel mode (Figure4(a)), the magnetic moment (dotted arrow) originally
locked along the crystal easy axis (solid arrow) rotates away from the crystal
axis towards the external field (H). The Néel mechanism is analogous to
the hysteresis loss in multidomain magnetic particles whereby there is an
“internal friction” due to the movement of the magnetic moment in an external
field that results in heat generation.In
the Brownian mode (Figure4(b)), the whole particle oscillates towards the
field with the moment locked along the crystal axis under the effect of a
thermal force against a viscous drag in a suspending medium. This mechanism
essentially represents the mechanical friction component in a given suspending
medium [16].Each
of the relaxation modes that lead to heat generation is characterized by a time
constant.τN is the Néel time constant given by(1)τN=τ0exp(EBkBT), where EB=KuV is analogous to an activation energy that has
to be overcomed by the thermal energy kBT to overcome the inherent magnetic anisotropy
energy.The
energy barrierEB is represented by the constant Ku,
which is a material property and is the anisotropy constant, multiplied by V, which is the volume of the magnetic nanoparticle. The thermal energy is
represented by the constant kB, named by Stephan Boltzmann, and multiplied by
the absolute temperature T. The constant τ0 is of the order of 10−9 seconds [13].The
Brownian time constant represented byτB is given by(2)τB=3ηVHkBT, where VH is the hydrodynamic volume of  the magnetic nanoparticle which is the
effective volume (including that of the nanoparticle and coating or surfactant
attached to the nanoparticle), η is the viscosity of the liquid carrier, and kBT is the thermal energy.The
resultant
power generation is a strong function of the effective time constant,
and the field parameters and is given by(3)PSPM=πμ0χ0H02f2πfτ1+(2πfτ)2, where H0 and f are the amplitude and frequency of the applied
alternating magnetic field, respectively, χ0 is the magnetic susceptibility, μ0 is the permeability of free space, and τ is the effective time constant given by 1/τ=(1/τN)+(1/τB)    [11, 13].


## 2.4. Affecting Parameters

There are numerous parameters affecting the
heat generation, which is produced by magnetic nanoparticles excited by a
magnetic field. A few examples for some crucial parameters are given below which one
should take into consideration when heating with magnetic nanoparticles.


### 2.4.1. Field Parameters

According to (3), it is obvious that field
strength and frequency are controllable parameters that directly affect the
power produced by the nanoparticles when alternative magnetic field is applied.
It should be understood that the of field parameter is not simply proportional to
the generated power but more complex, and depends on additional parameters such
as the nanoparticles' material properties [17].


### 2.4.2. Material Properties

An interesting class of magnetic materials that
are common for this purpose is iron oxides such asFe3O4, γ-Fe2O3 and MO⋅Fe2O3 (where
M is Mn, Co, Ni, Cu) [18], because they display
ferrimagnetism.  Magnetite (Fe3O4),
meghemite (γ-Fe2O3), and hematite (α-Fe2O3)
are the most common iron oxides and they are discussed below.Another alternative is the magnetic
nanoshells which were designed and characterized by Nanosonic Inc.
(Figure5(a)).
The nanoshells are comprised of an iron core with diameter of 8 nm coated with
a layer of gold. The gold coatings are made in order to prevent oxidation,
hence demagnetization; ultrathin noble metal coatings of Au (~2 nm) were
prepared to provide long-term stability and biocompatibility for the Fe core.
The Fe core was coated with a series of block copolymer stabilizers that are
compatible with analgesics to prevent flocculation in the arterial system in
vivo (see Figure 5(b)).  In addition, the
block copolymers assist in preventing agglomeration.Fe Nanoparticles produced by Nanosonics Inc. (a)
Magnetic nanoparticles in different
particle size configured as powder. (b)
Schematic illustration of a single Fe-Au nanoparticle.
(a)(b)Other materials are also being investigated
including platinium compounds, vanadium oxides, cobalt, nikel, lanthanum, and
manganase [19, 20].


### 2.4.3. Size Dependence

The size of the nanoparticles is a
fundamental characteristic in this field. Ma et al. [21] investigated the specific
absorption rate (SAR) values of aqueous suspensions of magnetite particles with
different diameters varying from 7.5 to 416 nm by measuring the
time-independent temperature curves in an external altering magnetic field(80 kHz, 32.5 kA/m). Results indicate that
the SAR values of magnetite particles are strongly size dependent. For
magnetite larger than 46 nm, the SAR values increase as the particle size
decreases where hysteresis loss is the main contribution mechanism. For
magnetite particles of 7.5 and 13 nm which are superparamagnetic, hysteresis
loss decreases to zero and, instead relaxation losses (Néel loss and Brownian rotation loss)
dominate.The dividing line between the two cases
depicted above is given by the ferromagnetic exchange lengthdex≅A/K using the material parameters of magnetite (K=1.35×104J/m3,A=10−11J/m), the exchange length is estimated as dex≅27nm.Therefore, when the particle size is larger
thandex,
the hysteresis loss increases as the particle size decreases. However, once the
particle size is less than dex,
hysteresis loss will vanish and the main contribution will be of relaxation
losses, as shown, for example, by Ma et al. [21].  In addition, Hergt et al. show that in the
critical particles size region where hysteresis losses vanish, Néel losses grow
as a new loss mechanism which, roughly speaking, extends the loss region toward
even smaller particle sizes [12].


### 2.4.4. Other Parameters

The
parameters discussed above are merely a few examples for a larger collection of
affecting parameters. Some of them have been investigated and some are probably
yet unknown. Amongst them is the concentration of the nanoparticle inserted
into the body [11]. The concentration should be
large enough to effectively produce heat, but yet in an amount that will not be
toxic for the human body. One also needs to be aware of the evacuation of those
particles once their job is done. (We are not dealing with toxicity and
pharmacokinetics issues in this paper.) The coating of nanoparticles (e.g.,
derivatives of dextran, polyethylene glycol (PEG), polyethylene oxide (PEO),
and poloxamers and polyoxamines) and suspending medium also affect the heat
generation [11, 16, 22]. The period of time of
excitation filed application and profile (e.g., continuous, pulsatile) deeply
affects the SAR which is proportional to the power dissipated [23]. Another affecting parameter
under investigation is the presence of nanoparticles' agglomeration in
comparison with the heat generated in single or dispersed nanoparticles [24].


## 2.4.1. Field Parameters

According to (3), it is obvious that field
strength and frequency are controllable parameters that directly affect the
power produced by the nanoparticles when alternative magnetic field is applied.
It should be understood that the of field parameter is not simply proportional to
the generated power but more complex, and depends on additional parameters such
as the nanoparticles' material properties [17].


## 2.4.2. Material Properties

An interesting class of magnetic materials that
are common for this purpose is iron oxides such asFe3O4, γ-Fe2O3 and MO⋅Fe2O3 (where
M is Mn, Co, Ni, Cu) [18], because they display
ferrimagnetism.  Magnetite (Fe3O4),
meghemite (γ-Fe2O3), and hematite (α-Fe2O3)
are the most common iron oxides and they are discussed below.Another alternative is the magnetic
nanoshells which were designed and characterized by Nanosonic Inc.
(Figure5(a)).
The nanoshells are comprised of an iron core with diameter of 8 nm coated with
a layer of gold. The gold coatings are made in order to prevent oxidation,
hence demagnetization; ultrathin noble metal coatings of Au (~2 nm) were
prepared to provide long-term stability and biocompatibility for the Fe core.
The Fe core was coated with a series of block copolymer stabilizers that are
compatible with analgesics to prevent flocculation in the arterial system in
vivo (see Figure 5(b)).  In addition, the
block copolymers assist in preventing agglomeration.Fe Nanoparticles produced by Nanosonics Inc. (a)
Magnetic nanoparticles in different
particle size configured as powder. (b)
Schematic illustration of a single Fe-Au nanoparticle.
(a)(b)Other materials are also being investigated
including platinium compounds, vanadium oxides, cobalt, nikel, lanthanum, and
manganase [19, 20].


## 2.4.3. Size Dependence

The size of the nanoparticles is a
fundamental characteristic in this field. Ma et al. [21] investigated the specific
absorption rate (SAR) values of aqueous suspensions of magnetite particles with
different diameters varying from 7.5 to 416 nm by measuring the
time-independent temperature curves in an external altering magnetic field(80 kHz, 32.5 kA/m). Results indicate that
the SAR values of magnetite particles are strongly size dependent. For
magnetite larger than 46 nm, the SAR values increase as the particle size
decreases where hysteresis loss is the main contribution mechanism. For
magnetite particles of 7.5 and 13 nm which are superparamagnetic, hysteresis
loss decreases to zero and, instead relaxation losses (Néel loss and Brownian rotation loss)
dominate.The dividing line between the two cases
depicted above is given by the ferromagnetic exchange lengthdex≅A/K using the material parameters of magnetite (K=1.35×104J/m3,A=10−11J/m), the exchange length is estimated as dex≅27nm.Therefore, when the particle size is larger
thandex,
the hysteresis loss increases as the particle size decreases. However, once the
particle size is less than dex,
hysteresis loss will vanish and the main contribution will be of relaxation
losses, as shown, for example, by Ma et al. [21].  In addition, Hergt et al. show that in the
critical particles size region where hysteresis losses vanish, Néel losses grow
as a new loss mechanism which, roughly speaking, extends the loss region toward
even smaller particle sizes [12].


## 2.4.4. Other Parameters

The
parameters discussed above are merely a few examples for a larger collection of
affecting parameters. Some of them have been investigated and some are probably
yet unknown. Amongst them is the concentration of the nanoparticle inserted
into the body [11]. The concentration should be
large enough to effectively produce heat, but yet in an amount that will not be
toxic for the human body. One also needs to be aware of the evacuation of those
particles once their job is done. (We are not dealing with toxicity and
pharmacokinetics issues in this paper.) The coating of nanoparticles (e.g.,
derivatives of dextran, polyethylene glycol (PEG), polyethylene oxide (PEO),
and poloxamers and polyoxamines) and suspending medium also affect the heat
generation [11, 16, 22]. The period of time of
excitation filed application and profile (e.g., continuous, pulsatile) deeply
affects the SAR which is proportional to the power dissipated [23]. Another affecting parameter
under investigation is the presence of nanoparticles' agglomeration in
comparison with the heat generated in single or dispersed nanoparticles [24].


## 2.5. Thermal Analysis

Upon the heating of the bioconjugated
nanoparticles, we generate a heat source within the body. The heat source,
namely the tumor, and in particular the tumor's surface, is actively heated by
external and controlled magnetic fields. Based on a two dimensional thermal image
acquired from the tissue surface, we seek to derive two fundamental
characteristics: thedepth of the tumor and the temperature of
the tumor and its surroundings. Knowing the temperature in real-time is crucial
in order to avoid any damage to all tissues in the diagnostic mode on one hand,
and on the other hand, operating in therapeutic mode, we expect to damage only
the malignant tissue leaving the healthy surrounding tissue with minimal
damage.  There are various techniques for
analyzing the thermal data such as, for example, automatic segmentation
approaches, and feature extraction and classification as shown by Qi and
Diakides [25].


## 2.6. Setup

The main building blocks of the suggested
system are comprised of means for (shown in Figure6):Figure 6
Schematic description of the system.(i)
heat generation;(ii)
thermal image acquisition;(iii)
thermal image analysis;(iv)
heat generation.
Heat generation is conceptually comprised of
two parts:(i)
magnetic nanoparticles (for “heat
emission”);(ii)
magnetic field (for nanoparticles’
excitation).
The magnetic field is generated by a magnetic
system usually comprised of the
following:(i)
antenna
(e.g., coils)(ii)
AC current generator.
The design of the magnetic system is
implemented bottom-to-up, that is, after choosing the desirable field
parameters (e.g., field strength, frequency), we are capable of designing the
system itself (e.g., coils, circuitry). Determination of the desirable
parameters is not trivial since the system is characterized by a large number
of degrees-of-freedom.Previous research works investigated various
fields: Kalambur et al. used a 1 kW generator and 4 turn RF coils to produce field
strength ofH0=14[kA/m] and frequency f=175[kHz];  Giri et al. examined the fields (10–45[kA/m],300[kHz]);Ma et al. used a 15 kW RF generator to produce
the field(32.5[kA/m],80[kHz]);  Hergt et al. (2004) showed losses under the
AC field (11[kA/m],410[kHz]);  Pankhurst et al. investigated nanoparticles
under the extensive field region of (0–15[kA/m],0.0.5–1.2[MHz]) and Kim et al. examined the influence of
fields of (110[kA/m],0.1–15[MHz]).The two principle parameters of the
externally applied magnetic field, that is, the frequency and strength, are
limited by deleterious physiological responses to high-frequency magnetic
fields [26, 27]:  stimulation of peripheral and skeletal
muscles, possible cardiac stimulation and arrhythmia, and nonspecific inductive
heating of tissue.  Generally, the
useable range of frequencies and amplitudes is considered to be f=0.05–1.2MHz and
H=0–15kA/m.Experimental data on exposure to much higher
frequency fields come from groups such as Oleson et al. [28] who developed a hyperthermia
system based on inductive of tissue, and Atkinson et al.  who developed a treatment system based on
eddy current heating of implantable metal thermoseeds.  Atkinson et al. [29] concluded that exposure to
fields where the product H⋅f
does not exceed 4.85×108, kA/(m⋅s)−1 is safe and
tolerable [30].Hence, following the physiological
constraints shown above and based on previous research results such as those
mentioned above, the desirable averaged working point was chosen to beH0≈10[kA/m];f≈100[kHz].Trying to meet with the fundamental
objectives of the suggested system, particularly cost effectiveness and
bed-side capability, we
seek an alternative technology for the commonly used giant and expensive RF
generators of several kilowatts and up, since they cost about 10 k–100 k of dollars
and are not comfortable to be located near the patient’s bed or at the clinic.
Most of research works in this field are using a single RF coil with a few
turns, for example, 3-4 turns. A major drawback of the coil configuration is
that there is no accessibility for any imaging element, such as an IR camera.
If we had desired to use that kind of solenoid coil, it would have been
characterized with a very large diameter, and the camera
would have been exposed to the AC field.
Hence, this configuration is not applicable and does not apply to our
needs.An alternative preferred method relies on a
Helmholtz coil configuration.  The
fundamental premise of this configuration is that it produces a uniform
(homogeneous) magnetic field between the coils with the primary field component
parallel to the axes of the two coils.  The
Helmholtz configuration further enables an open
workspace for sample (tissue) handling and imaging device accessibility, that
is, an easy and safe path for placing the IR camera, and further enables the
change of the distance between the two coils, that is, adjustable workspace.In order to produce a desired high voltage
over the coils, the system design includes power transformer for voltage
elevation, as shown in Figure7.Figure 7
System's block scheme.The power supply of the system is composed of
an oscillator (PMW controller) with a tunable frequency, boost transformer, and
a push-pull full bridge inverter (H-bridge), as shown in
Figure8.  The full bridge is mainly composed of four
FETs to allow the alternate current.Figure 8
The power generator's block scheme.The thermal imaging is carried out by an IR
camera (FLIR A40M), which detect  the infrared emission which is emitted from
the examined object’s surface (e.g., phantom).The IR camera is positioned perpendicularly
above the object, which is situated within the magnetic field induced between
the two coils.  When the magnetic field
is applied, the nanoparticles generate heat which can be detected by the IR
camera.Integrating the main building blocks of the
required system mentioned above comprises the system as shown in
Figure9.  The system should preferably include a
closed-loop feedback to allow the adjustment of the field parameters (generated
by the coils) according to the temperature readings (acquired via the IR
camera).Figure 9
Schematic description of the closed-loop system.Figure 10
Laboratory system.Obviously, interruption by the user (e.g., physicist)
is possible, such as the tuning of magnetic field when changing its mode of
operation (e.g., achieving therapy requires a substantial increase of the
temperature within the treated tissue).


## 3. Conclusions

This
system is dedicated to the detection of malignant tumors and for the treatment
of those tumors based on the physical principle of heat generation for both
diagnosis and therapy.  The heat
generation and its amplification above the body’s normal temperature level are
achieved by biocompatible magnetic nanoparticles which are bioconjugated to the
tumor and their stimulation by a suitable external magnetic field.This
procedure is specifically targeted to the tumor since it relies on the
capability of the immune system and its detectability, that is, the body knows
best how to locate
the malignant cells. Hence, the bioconjugation of the nanoparticles to the
antigen-antibody complex is probably the most accurate method to reach the real
malignancies.The
preferable configuration for the generation of the AC magnetic field in our
view is the Helmholtz configuration, however the characteristics of the current
generator and coils should still be evaluated.In
conclusion, this research work may serve as a novel fundamental concept for
having both diagnosis and therapy in a single device, where the transfer
between the two modes is merely a simple alteration of field parameters.  The minimally invasive method is selective
and has the potential of being very accurate, reliable, and friendly both to
the operator (e.g., physician) and to the patient.  It incorporates various field of research and
we believe and hope that it can be developed into a bedside, cost effective,
and applicable device that may assist in a better and improved detection and
treatment of one of the prevalence diseases that the medical industry currently
has to deal with.


## 4. Future Work

This
research shows a fundamental design of the system which is meant to pursue
thermal diagnosis and therapy in one single device which is still not bulky and
can operate near the patient’s bed, be accurate, reliable, and cost
effective.  The concept and modularly
design that were described in this research work are the basis for such a system.  The system comprises several main modules:
heat generation (including nanoparticles and the external field generation),
thermal imaging, analysis and feedback. This multidisciplinary system
incorporates various scientific and technological fields.  Furthermore, each module may be investigated
and improved independently with no direct relation to the other modules.Producing
the required external magnetic field should be designed to generate a higher
magnetic field, preferably with adjusted parameters, for example, magnitude,
frequency, distance between the coils.
One of the goals in our view is to increase the efficiency of this
module and to enable the use of standard voltage and current one of a domestic
electrical infrastructure.The
analysis module is based on the acquired raw thermal image and includes the
processing for improving the data quality and derivation of desired
parameters.  This module may be
approached by various methods implementing different mathematical models,
computational algorithms, and so forth.  It is
desirable to try and derive additional parameters (other than tumor’s depth and
tumor’s temperature) such as 3D geometrical boundaries of the tumor.The
current model is a basic model that relies on ideal assumptions (e.g.,
homogeneous tissue, steady state). Furthermore, the inverse model assumes a
point source which is merely an ideal approximation for much more complicated
scenarios that involve undefined tumor boundaries, noise signals,
physiological, anatomical abnormalities, and so forth.The
closed-loop feedback that allows control on the external magnetic field’s
parameters (e.g., magnitude and frequency) can be automatically adjusted based
on the thermal imaging to maintain appropriate contrast and to achieve control
on the heat expansion within the tissue in real time in order not to harm
surrounding healthy tissue.  This can be
carried out by a LabView dedicated program.



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*Source: 275080-2008-06-22.xml*