Superparamagnetism : Theory and Applications

-
Discussion of Two Papers on Magnetic Nanoparticles

Manuel Benz

December 14, 2012

Contents
1 Introduction 3

2 Basic Concepts 3
2.1 An Introduction to Superparamagnetism . . . . . . . . . . . . 3
2.2 Bulk to Nano . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.3 The Energy Barrier ∆E . . . . . . . . . . . . . . . . . . . . . . . 7
2.4 M-H Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.5 Forces on Magnetic Nanoparticles . . . . . . . . . . . . . . . . . 11

3 Application of Magnetic Nanoparticles in Biomedicine 12

3.1 Magnetic Separation . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.1.1 Cell Labelling & Magnetic Separation . . . . . . . . . . 12
3.1.2 Separator Design . . . . . . . . . . . . . . . . . . . . . . 13
3.1.3 Applications of Magnetic Separation . . . . . . . . . . . 14
3.2 Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2.1 Basic Understanding & Motivation . . . . . . . . . . . . 15
3.2.2 Magnetic Carriers . . . . . . . . . . . . . . . . . . . . . . 15
3.2.3 Applications of Drug Delivery . . . . . . . . . . . . . . . 15
3.2.4 Radionuclide and Gene Delivery . . . . . . . . . . . . . 16
3.3 Hyperthermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.3.1 Basic Understanding & Motivation . . . . . . . . . . . . 16
3.3.2 Heating Mechanism . . . . . . . . . . . . . . . . . . . . . 17
3.4 MRI Contrast Enhancement . . . . . . . . . . . . . . . . . . . . 19
3.4.1 Basic Understanding . . . . . . . . . . . . . . . . . . . . 19
3.4.2 Contrast Enhancement trough SPM Particles . . . . . 21
3.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

4 Nanoparticle Magnetism 22
4.1 Intrinsic Spin Structure and Dynamic Spin Relaxation . . . . 22
4.2 Applications: Current Trends and Future Directions . . . . . . 26

References 27
1 Introduction
This script’s intention is to give a brief overview of two papers studying the
behaviour of magnetic nanoparticles and its possible applications. Nanopar-
ticles, from a certain size on and smaller, can show a special magnetic prop-
erty called superparamagnetism.

The first paper “Applications of magnetic nanoparticles in biomedicine”

introduces the basic concepts of superparamagnetism and then presents the
following applications in biomedicine [1]:
• Magnetic separation of labelled cells and other biological entities;
• Drug, gene and radionuclide delivery;
• Artificial hyperthermia treatments of tumours;
• Contrast enhancement agents for magnetic resonance imaging appli-
cations (MRI).
The second paper “Nanoparticle magnetism” presents a discussion on
the following topics [2]:
• In how far do bulk particles behave differently from nanoparticles;
• How can spin reversal in uniaxial magnetic nanoparticles be explained;
• How is the intrinsic spin structure of nanoparticles to be explained;
• And last but not least: Current trends and future directions of appli-
cations through these findings.
But before starting the discussion on the papers, a phenomenological intro-
duction to the theory of superparamagnetism is given.

2 Basic Concepts
2.1 An Introduction to Superparamagnetism
Superparamagnetism (SPM) is a type of magnetism that occurs in small
ferromagnetic or ferrimagnetic nanoparticles. This implies sizes around a
few nanometers to a couple of tenth of nanometers, depending on the ma-
terial. Additionally, these nanoparticles are single-domain particles. In a
simple approximation, the total magnetic moment of the nanoparticle can
be regarded as one giant magnetic moment, composed of all the individual
magnetic moments of the atoms which form the nanoparticle.

Since these nanoparticles may be used in different applications, the sizes

of a few relevant entities are given[1]:

3
 • Size of a cell: 10 to 100 µm.

• Size of a virus: 20 to 450 nm.

• Size of a protein: 5 to 50 nm.

• Size of a gene: 2 nm wide and 10 to 100 nm long.

Very often, nanoparticles show a certain preference for the direction, along
which their magnetization aligns to. These nanoparticles are said to have
an anisotropy in these directions. If it is mainly one preferred direction, we
speak of uniaxial anisotropy 1 .

Nanoparticles with an uniaxial anisotropy randomly flip the direction of

their magnetization. This effect is induced by thermal energy. The average
time to perform such a flip is given by the relaxation time:
∆E
τ = τ0 exp ( ) (1)
kB T
with

• τ0 : The length of time characteristic of the probed material. Often it

is of a magnitude of around 10−9 to 10−12 s [2].

• ∆E: The energy barrier the magnetization flip has to overcome by

thermal energy. See figure 3 for more details.

• kB : The Boltzmann constant.

• T : The temperature.

The observation of nanoparticles in a superparamagnetic state however does

not only depend on the temperature T and the energy barrier ∆E: Each ex-
perimental technique comes with its own measurement time τm . Depending
on the measurement time, the following two scenarios can occur:
1
Magnetic anisotropies imply a directional dependence of the material’s magnetic be-
haviour. The following anisotropies can be distinguished [4]:
• Magnetocrystalline anisotropy: A preference in direction from the atomic
structure of the crystal.
• Shape anisotropy: Arising from the fact that particles may not be perfectly
spherical.
• Magnetoelasticanisotropy: Arising from tensions within the nanoparticle.
• Exchange anisotropy: Arising from interactions between antiferromagnetic and
ferromagnetic materials.

4
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M–H curves
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and antiferromagnets, is given by M = !χH, where !χ = χm − χw mis th
it isthat
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(a) (a) (b) (b) approximate
approximate the overall
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of the particles
system
system by B = byµ0B 0 H, equation
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(4) becomes:
Vm !χ Vm !χ
Fm = Fm = (B · ∇)B.
(B · ∇)B.
µ0 µ0
Furthermore,
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there arethere are no time-var
no time-varying ele
or currents
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in the medium, we canthe
we can apply apply the
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∇×B∇ = 0×toB the
= 0following
to the following mathematical
mathematical identity:i
∇ (B · B) 2B
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= × ( ∇ × B) + 2(B · 2(B
)B ·=∇
to obtaintoaobtain a more intuitive
more intuitive form of form of equation
equation (5): (
! 2 "! 2 "
B B
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!χ∇ or
2µ0 2µ 0
# #$ $
Figure 2.Figure 2. Illustration
Illustration of(a) of the of
the concept concept of superparamagnetism,
superparamagnetism,
(b) where where Fm = VF mm!χ∇ B · H 21,B · H ,
= Vm21!χ∇
thedepict
the circles circlesthree
depict three magnetic
magnetic nanoparticles,
nanoparticles, and the arrows
and the arrows
representrepresent the net magnetization
the net magnetization directiondirection in those particles.
in those particles. in whichinthewhich the magnetic
magnetic force is force is to
related related to the
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Figure 1:In case
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(a), case (a),The measurement
at temperatures
at temperatures well belowwellthebelow time
the τm is much smaller magnetostatic
than field
magnetostatic field density,
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2
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measurement-technique-dependent
measurement-technique-dependent
relaxation time. A well defined state canblocking
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or for relaxation times
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for
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reversals)reversals)
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longer
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Due to the the net moments
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at temperature
magnetization, awell well
time-averaged net mo- they are attracted towards that
above TBabove
, or forTBτ, much
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the moment reversalsreversals
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ment of zero willin zero
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thatexternal
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time-averaged net moment
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net moment
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Source:
basis [1]the biomedical
the forbasis for the biomedical applications
applications of ma
of magnetic
particlesparticles
is zero. is zero. and drugand drug delivery,
delivery, as will beas discussed
will be discussed in se3
in sections

• τm ≪ τ : The average time between flips is much larger than the mea-
surement time. This puts the particles in a well defined state and is
usually referred to as the blocked state of the system (see figure 1(a)).

• τm ≫ τ : Alternatively, the average time between flips can be much

smaller than the measurement time. This implies that the measure-
ment actually observes a fluctuating state with different unresolved
magnetization spin directions. As long as there is no external field ap-
plied, a time-averaged net moment of zero is measured. This situation
is called the superparamagnetic state of a system (see figure 1(b)).

Equation 1 gives us a connection between the time τ and the temper-

ature T . A blocking temperature TB can be defined as the temperature
between the blocked and the superparamagnetic state (this implies that at
the blocking temperature TB : τm = τ .)

∆E
TB = . (2)
kB ln ( ττm0 )

Consequentially, the two states can be distinguished as follows:

• The blocked state: τm ≪ τ or T < TB .

• The superparamagnetic state: τm ≫ τ or T > TB .

5
 Since measurement times influence the observed state heavily, it would
be nice to know some typical measurement times [1]:

• DC magnetization: 100 s.

• AC susceptibility: 10−1 to 10−5 s.

• Mössbauer spectroscopy: 10−7 to 10−9 s.

What are the implications of such superparamagnetic states? Without

external magnetic field, the net moment is zero. As soon as an external
field is applied, the nanoparticles react similar to a paramagnet (hence the
“paramagnetism” in the name) with the one exception that their magnetic
susceptibility is much larger (hence the “super” in the name).

A word of clarification: Normally, any ferromagnetic or ferrimagnetic ma-

terial can behave paramagnetically. This is from a certain temperature on
and upwards, the so called Curie temperature TC . However, superparamag-
netic behaviour is observed below the Cure temperature and thus has to be
explained differently.

2.2 Bulk to Nano

Spins can retain their collinearity only over a certain length. This depends
on the material, but is usually around 100 nm and smaller. For spherical
particles, this size limit R can be approximated by [2]:
√
6 AK
R= . (3)
µ0 Ms2
with

• A: Called exchange stiffness and is a measure for the critical temper-

ature for magnetic ordering of this specific material.

• K: Is the magnetic anisotropy of the particle.

• µ0 : Is the permeability of free space.

• Ms : Is the saturation magnetization. This quantity is relevant since

single domain particles are necessarily magnetically saturated, since all
magnetizations are aligned anyway (without or with external magnetic
field).

This determines the size of a domain, within which all spins are aligned
along the same direction (single-domain).

Bulk particles: If the material is bigger than these 100 nm, we speak of a

6
 Eani (˛) = −KV cos2 ˛ (4)
where ˛ is the angle between the direction of magnetiza-
tion M" and the easy axis, V is the volume of the particle
and K is the uniaxial magnetic anisotropy constant. Fig. 2(b)
gives a graphical representation of the magnetic anisotropy
energy as a function of the angle, ˛. The potential energy
landscape has two minima of equal depth, for ˛ = 0 and !,
separated by an energy barrier U = KV. In the absence of an
external field the particle moment has equal probability to
lie along either direction of the easy axis. Moment rever-
monodispersed magnetic nanoparticles point to an intrin
sic spin structure of greater complexity compared to th
simple collinear model of Stoner—Wohlfarth [26]. The com
plexity arises from the abrupt interruption of the crysta
and spin-lattice structure at the particle’s surface. It is gen
erally recognized that novel properties at the nanosca
arise from the large number of atoms that lie on the su
face, along grain boundaries or particle/support interface
Lattice distortions at the surface trap atoms in thermod
namically non-equilibrium states, which are not general
encountered in the bulk, as depicted in Fig. 3 [39]. Thus, th

FigureFigure
2: A 2 prolate
(a) Schematic of a prolate
spheroid spheroid depicting
representing a nanoparticle with
a nanoparticle withuniaxial magnetic anisotropy in the presence
uniaxial
an external magnetic field H
anisotropy in an external magnetic field ⃗ θ is the angle between the
" at an angle # relative to the direction of the anisotropy axis. Angles ˛, ϕ give the orientation th
H.
magnetization of the particle, M, " relative to the anisotropy axis and the magnetic field, respectively. (b) Magnetic orientation
direction of the
potential external
energy field
as a function and ˛the
of angle easy
in the axis.
absence of anαapplied
and field,
ϕ give
solid the mag-
line (—), and in the presence of an applied fie
along the
netization anisotropyrelative
direction axis, brokentoline
the(— — —). The
easy minima
axes, occur at ˛ = 0 and
respectively relative
!. to the
external field. Source: [2].

bulk and have to expect that several domains with domains-walls in between
are formed (multi-domain). These domains have a collinear spin within one
domain, but not necessarily compared to other domains.

Nanoparticles: Magnetic nanoparticles are small than these 100 nm and

are necessarily single-domain particles.

Bulk particles and nanoparticles show different behaviour in an external

magnetic field. Uniaxial nanoparticles show spin rotation, while bulk parti-
cles react to an external field by movement of their domain-walls.

2.3 The Energy Barrier ∆E

So far, it was not discussed how the energy barrier ∆E affects the spin re-
versals and the corresponding relaxation time. The energy barrier occurs in
particles with anisotropies. Since those particles’s spin shows a preference
for certain directions, their energy landscapes contain minima in the pre-
ferred directions and maxima in the least preferred directions (see figure 3).

A particle with uniaxial anisotropy can be graphically represented as a pro-

late spheroid as shown in figure 2. Its preferred axis is commonly referred to
easy axis and there are two minima: One for each direction along the easy
axis.

Without external magnetic field, the energy barrier takes the form:
∆E = KV (4)
with K an anisotropy constant and V the particle’s volume. But as soon as
an external field is applied, one of the minima gets preferred. The situation

7

shown in Fig. 2(a). The magnetic anisotropy energy:
Eani (˛) = −KV cos2 ˛ (4)
where ˛ is the angle between the direction of magnetiza-
tion M" and the easy axis, V is the volume of the particle
and K is the uniaxial magnetic anisotropy constant. Fig. 2(b)
gives a graphical representation of the magnetic anisotropy
energy as a function of the angle, ˛. The potential energy
landscape has two minima of equal depth, for ˛ = 0 and !,
separated by an energy barrier U = KV. In the absence of an
external field the particle moment has equal probability to
lie along either direction of the easy axis. Moment rever-
tive to the internal spin structure of the particles. Mounting
experimental evidence in studies of well characterized,
monodispersed magnetic nanoparticles point to an intrin-
sic spin structure of greater complexity compared to the
simple collinear model of Stoner—Wohlfarth [26]. The com-
plexity arises from the abrupt interruption of the crystal-
and spin-lattice structure at the particle’s surface. It is gen-
erally recognized that novel properties at the nanoscale
arise from the large number of atoms that lie on the sur-
face, along grain boundaries or particle/support interfaces.
Lattice distortions at the surface trap atoms in thermody-
namically non-equilibrium states, which are not generally
encountered in the bulk, as depicted in Fig. 3 [39]. Thus, the

Figure 2 (a) Schematic of a prolate spheroid depicting a nanoparticle with uniaxial magnetic anisotropy in the presence of
an external magnetic field H Figure 3: The situation of the minima in an uniaxial anisotropic particle
" at an angle # relative to the direction of the anisotropy axis. Angles ˛, ϕ give the orientation the
" relative to the anisotropy axis and the magnetic field, respectively. (b) Magnetic orientational
magnetization of the particle, M,
without (solid line) and with (dashed line) external magnetic field. Source:
potential energy as a function of angle ˛ in the absence of an applied field, solid line (—), and in the presence of an applied field
[2]
along the anisotropy axis, broken line (— — —). The minima occur at ˛ = 0 and !.

is shown in figure 3.

Remembering equation 1 for the relaxation time, one can see that the
volume V of the particle is in the exponential. This explains easily why
as soon as the nanoparticles become too large, the behaviour of moment
reversal ceases to be an interesting aspect and becomes negligible.

2.4 M-H Curves

As a brief repetition: Considering particles of all kinds and sizes, a catego-
rization with respect to their volumetric susceptibility χ makes sense:

• Large χ: Ferromagnetic, ferrimagnetic or antiferromagnetic materials

(FM). These materials can have, even without the influence of an
external magnetic field, a strong order with respect to the alignment
of the magnetic moments (see figure 4).

• Small χ:

– χ > 0: Paramagnetic materials (PM). The magnetic moments

are only aligned under the influence of an external field in the
direction of the magnetic field.
– χ < 0: Diamagnetic materials (DM). The magnetic moments are
only aligned under the influence of an external field in the opposite
direction of the magnetic field.

Many materials show paramagnetic as well as diamagnetic properties. It

is the intrinsic structure of the material, which decides which component
causes the stronger effects.

These different types of magnetisms show different behaviour of the magne-

tization M⃗ when varying the external magnetic field H. ⃗ A comparison of
the differently magnetic materials is shown in figure 5.

8
 (a) (b)

Figure 4: This figure shows the difference between the ordering in ferrimag-
netic materials (figure 4(a)) compared to antiferromagntic materials (figure
4(b)). Source: [5] & [6].

To go a bit more into detail: What happens, if an external magnetic

field H is applied to the superparamagnetic nanoparticles? As with param-
agnetic materials, their magnetic moments start to align along the applied
field. This results in a net magnetization which is in contrast to the zero net
magnetization in a superparamagnetic state without external field. Depend-
ing on the temperature and with all particles alike, the net magnetization of
a sample of nanoparticles is given by the following two equations, depending
on the situation [3]:
• For TB < T < KV /(10kB ): All easy axes should be oriented parallel
to the external field.
µ0 Hm
M (H) = nm tanh ( ) , (5)
kB T

• For KV /(kB ) < T : The orientation of the easy axes does not play a
role anymore.
µ0 Hm
M (H) = nmL ( ) (6)
kB T
with
• n: Density of nanoparticles in the sample.
• m: Magnetic moment of the nanoparticle.
• µ0 : Magnetic permeability in vacuum.
• L(x): The Langevin function in dependence of x.
The forms of the two functions are shown in figure 6 and the correspondent
susceptibilities are given by [3]:
• For TB < T < KV /(10kB ):
nµ0 m2
χ= , (7)
kB T

9
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while of the particle
in smaller [3
H H ground state ground
whichstate leadswhich to a bro lea
!
H H #
smaller sizes smaller
(of the sizes =τ(of
τ order τ=0 expτthe
of exp
0 tens or
can see superparamag k
can see superparamagnetism, w
of thewhere
where #E of#E
particle is theasisparticle
the athe whole
energy energyasbarrier
isafree wh
barr
thermal k Ttheisthermal
the while energy,
thermal whileFot
theenergy.
Figure 1. MagneticFigure 1.responses
Magnetic
(c) responses associated
associated
(d) different classes ofk
with
with different classes of B T isB energy, thermal energy.individu
magnetic material, illustrated for a hypothetical situation in whichthe the their ordered
pre-exponential
theirpre-exponential factor state
factor τrela i
0 is
ordered state relative τto 0 o
ea
magnetic material, illustrated for a hypothetical situation in which
Figure 5:
ferromagnetic Thisferromagnetic
figure
particles shows particles
the of a range ofbehaviour
schematic sizes from nanometre
of up to param-
diamagnetic,
to M are and
and only
only weakly
anhysteretic, anhysteretic,
weakly dependent
dependent
but still but
sigmoidal, still
on te si
on
agnetic, micron
ferromagnetic scaleof
M are injectedor
areasuperparamagnetic
M range ofinto
injected sizes fromvessel.
a blood nanometreM–Hup
materials curves
in an external barrier hasThe
mag- several
underlyingorigins,ph
M
micron scale into a blood vessel. Mcurves are
barrierThe has several
underlying origins, the
physics incm
such asoflaw sup
shownFM M–H
for diamagnetic (DM) and paramagnetic (PM) biomaterials
shown for diamagnetic (DM) and SPM extrinsicon effects
an activation
netic FM field. Figure
in the blood5(a)vessel, andparamagnetic
(diamagnetic (PM) biomaterials
material):
SPM
for the ferromagnetic The
(FM) higher the external
injected extrinsic effects such
on ananisotropies,
activation law as forthe thema re
in the blood
magnetic ⃗ the
vessel,
particles,
field H, and for the
where
lower thethe ferromagnetic
response (FM) M
can be either
magnetization ⃗ . Figure (-
injected
multi-domain - - -(paramag-
5(b) in magnetizationrespectively; of butthebut pa
anisotropies,
magnetization
has respectively;
of the particle [3, in 4
particles,
netic where
material):FM the response
diagram),
The can
thebeexternal
single-domain
higher either
(—— multi-domain
in FM diagram)
magnetic ⃗- inthe higher
(- -or-H,
field the a uniaxial form and is gi
FM diagram), ⃗ . Figure
single-domain
superparamagnetic (——
(SPM), inHFM diagram)
depending on theor size of the particle. has aHK uniaxial
is the form
anisotropy and is
energy give ! d
magnetization M H 5(c) (ferromagnetic material): A Hhysteresis loop
superparamagnetic (SPM), depending on the size of the particle. K is the anisotropy energy denτ
can be seen. For multi-domain particles, the loop is narrower (dashed line),
R168 τ = τ0 exp
while for a single-domain particle, the loop is quite broad (fully drawn line).
R168
Figure 5(d) (superparamagnetic material): Similar to ferromagnetic mate- where #E is the ene
rial is the form of sigmoidal shape, but without any loop. The difference
where #Ek isT the energy barrie
is the thermal e
Figure 1. Magnetic responses associated with different classes of B
Figure 1. the
Magnetic responses associated with kB T is thethethermal energy. fa
pre-exponential F
between ferromagnetic
magnetic behaviour
material, illustratedand adifferent
forthe classes
superparamagnetic
hypothetical of
situation inbehaviour
which
magnetic material,
is primarily illustrated
determined
ferromagnetic for
theasize
byparticles hypothetical
ofofa range situation
the particle.
of in soon
As
sizes from which the pre-exponential factor τ0 is
up tosmall and only weakly depe
as it gets
nanometre
ferromagnetic particles
micron
enough, the latter of aare
scale
effect range
takes of sizes
injected
over. intofrom nanometre
a blood
Source: up to curves are only weakly
[1].vessel. M–H and barrier dependent
has severalon te
o
micron scale are injected
shown into a blood(DM)
for diamagnetic vessel.
andM–H curves are
paramagnetic barrier hasextrinsic
(PM) biomaterials several effects
origins,such
in
shown for diamagnetic (DM)
in the blood andand
vessel, paramagnetic (PM) biomaterials
for the ferromagnetic (FM) injectedextrinsic effects such as the ma
in the blood vessel, andwhere
particles, for thetheferromagnetic
response can(FM) injected
be either multi-domain (- anisotropies,
- - - in anisotropies, respectiv
particles, where
FMthe responsesingle-domain
diagram), can be either (—— multi-domain (- - - - in
in FM diagram) or hasrespectively;
a uniaxial formbut ai
FM diagram),superparamagnetic
single-domain (—— in FM
(SPM), diagram)on
depending has
or the size of the particle. a uniaxial form and is
K is the anisotropy givee
superparamagnetic (SPM), depending on the size of the particle. K is the anisotropy energy den
R168
R168
10
Figure 6: A comparison between the functions tanh(x) (blue) and L(x)
(red), which describe the behaviour of the magnetization M in dependence
of H in different situations. Source: [3].

• For KV /(kB ) < T :

nµ0 m2
χ= . (8)
3kB T

2.5 Forces on Magnetic Nanoparticles

Since many applications in biomedicine require to manipulate the path of
the nanoparticles, it is vital to understand the force required to do so. While
a static magnetic field may give rise to a torque, it cannot be used for a trans-
lational movement. In order to do the latter, we require a magnetic field
gradient.

⃗ is given by
The magnetic force on a point-like magnetic dipole moment m
[1]
F⃗m = (m ⃗ .
⃗ ⋅ ∇)B (9)
Since many applications using nanoparticles take place in some fluid (e.g.
body fluid), it is reasonable to use this setting for the following calculations.
With some manipulations and simplifications, such as
⃗,
⃗ =VM
• m
⃗ = ∆χH
• M ⃗ with ∆χ = χ−χw (effective susceptibility relative to water),
⃗ = µ0 H,
• dilute suspension of nanoparticles allows approximation: B ⃗
⃗ = 0,
• vector-identities & ∇ ∧ B
one finally arrives at the following forms of the previous equation:
2
B
F⃗m = V ∆χ∇ ( ) (10)
2µ0

11
 1⃗ ⃗
F⃗m = V ∆χ∇ ( B ⋅ H) . (11)
2
⃗ ⋅H
The factor 12 B ⃗ can be understood as the magnetostatic field energy den-
sity. As a result, for a positive ∆χ (cf. paramagnetic materials in section
2.4), there will be a force acting into the direction of the steepest ascent of
the energy density scalar field.

3 Application of Magnetic Nanoparticles in Biomedicine

This section discusses the paper “Applications of magnetic nanoparticles in
biomedicine”. According to the authors, nanoparticles bring along several
qualities, which make them a good candidate for techniques in biomedicine:
• Their size is comparable to the targeted entities (see section 2.1).

• Nanoparticles can be magnetic. An external magnetic field gradient

can be applied to influence their movement. This way, they can either
deliver certain drugs or tag certain entities.

• Nanoparticles may also be resonantly excited. This allows heat trans-

fer to the surrounding tissue.
In the following, a few applications are presented, which make use of the
mentioned qualities of the nanoparticles.

3.1 Magnetic Separation

3.1.1 Cell Labelling & Magnetic Separation
Magnetic separation is in essence separating specific biological entities from
their native environment and studying or manipulating them in a better
controlled environment. This process is usually done in two steps:
1. First, the entities to separate have to be labelled or tagged with the
magnetic particles.

2. In a second step, the entities now attached to the magnetic particles

can be extracted or moved by exerting a force on the latter.
How is the tagging achieved? In brief, the hull of the nanoparticles can be
prepared, i.e. coated with some material that interacts only with the entities
in question.

How is the magnetic separation achieved? The magnetically tagged ma-

terial should be in a fluid. The fluid can then be brought into a region with
a steep magnetic field gradient. The magnetic force needs to overcome two
competing forces:

12
 separation smaller magnetic particle sizes can also be advantageous, for
example, in reducing the likelihood that the magnetic material
ling and magnetic separation will interfere with further tests on the separated cells [20].
ne it is often advantageous to separate out
gical entities from their native •environment 3.2. Separator
The hydrodynamic force of the fluid: Fd = 6πηRm ∆v with
drag design
concentrated samples may be prepared for
alysis or other use. Magnetic separation– usingη: TheMagnetic
viscosity separator
of the design
fluid. can be as simple as the application
and removal of a permanent magnet to the wall of a test tube
nanoparticles is one way to achieve this. – RmIt: The radius of the magnetic particle.
to cause aggregation, followed by removal of the supernatant
process, involving (i) the tagging or labelling
(figure 3(a)). However, this method can be limited by slow
biological entity with magnetic material, – ∆vand = vm − vw : The difference in velocities of the entity and the
accumulation rates [21]. It is often preferable to increase the
ing out of these tagged entities via a fluid-based
water.
separator efficiency by producing regions of high magnetic
ration device.
fieldforce:
gradient to capture thea magnetic nanoparticles as they
s made possible through chemical •modification
The buoyancy While this is competing force, it can generally
float or flow by in their carrier medium. A typical way
of the magnetic nanoparticles, usually be by coating
neglected, due to its small effects in this situation.
to achieve this is to loosely pack a flow column with a
atible molecules such as dextran, polyvinyl
As a side magnetizable matrix of wire (e.g. steel wool) or beads [22]
and phosopholipids—all of which have note:
been It can be observed that the radius of the magnetic particle
xide nanoparticles [8–10]. As R well a role inand
as providing
m plays thetoequation.
pump the magnetically tagged fluid through the column
Even though a larger radius implies a larger
while a field is applied (figure 3(b)). This method is faster
n the particle and the target dragsite onforce,
a cellitorcan be more reasonable to resort to larger particles, so called
than in the first case, although problems can arise due to the
ing has the advantage of increasing the colloidal The reason being is that the microspheres can show more
microspheres. settling and adsorption of magnetically tagged material on the
e magnetic fluid. Specific binding sites on
response to the
manipulations
matrix. An of their velocity
alternative, compared
rapid throughput to nanoparticles.
method which does
s are targeted by antibodies or other biological
es such as hormones or folic acid [11–13]. As not involve any obstructions being placed in the column is the
3.1.2 Separator
ecifically bind to their matching antigen this use of specifically
Design designed field gradient systems, such as
hly accurate way to label cells. For example, the quadrupolar arrangement shown in figure 4 which creates
cles coated with immunospecific agents have a magnetic gradient radially outwards from the centre of the
There are several designs, from quite simple to rather complex ones, to
ully bound to red blood cells [8,separate flow columntagged
the magnetically
14], lung cancer [23]. material from its surrounding [1]:
eria [16], urological cancer cells [17] and Golgi As well as separating out the magnetically tagged material,
• A rather
For larger entities such as the cells, both the
simple spatially
method varying
lets themagnitude
magnetically of thetagged
field gradient
particles canpass by
oparticles and larger particles can beaused: for bemagnet.
permanent used to achieve
All the ‘fluid
taggedflow fractionation’
particles get stuck,[24].while
Thisthe rest
of
e applications use magnetic ‘microspheres’— the fluid is a process
passes. In in
a which
second the
step, fluid
the is split
magnet at the
can outlet
be into and
removed
agglomerations of sub-micron sized magnetic
the tagged fractions
particles containing
can be tagged
flushed cells
out: or proteins with differing
porated in a polymeric binder [19].
etically labelled material is separated from its (a)
by passing the fluid mixture through a region in
a magnetic field gradient which can immobilize
erial via the magnetic force of equation (7). This
overcome the hydrodynamic drag force acting
ic particle in the flowing solution,

Fd = 6πηRm #v, (8)

Disadvantage: This method takes quite some time before collecting a
viscosity of the medium surrounding the cell (b)
seizable amount of tagged particles.
Rm is the radius of the magnetic particle, and
is the difference in velocities of the
• cell and theadvanced technique lets the fluid pass through some material
A more
re is also buoyancy force that affects the motion,
like steel wool, while applying a magnetic field gradient. The mag-
endent on the difference between the density of
e water, and for most cases of interest netically
in biology tagged particles get stuck in the steel wool and then, as in
the
can be neglected. Equating the hydrodynamic method before, can be flushed out as soon as the magnetic field is
4 3 turned off:
netic forces, and writing Vm = 3 πRm , gives the
particle relative to the carrier fluid as:

#χ ξ
∇(B 2 ) or #v = ∇(B 2 ),
η µ0
‘magnetophoretic mobility’ of the particle—a
describes how manipulable a magnetic particle
ple, the magnetophoretic mobility of magnetic
can be much greater than that of nanoparticles,
ger size. This can be an advantage, for example,
ons, where the experimental timeframe for the
correspondingly shorter. On the other hand,
(9)
Figure 3. The standard methods of magnetic separation: in (a) a
magnet is attached to the container wall of a solution of magnetically
tagged (•) and unwanted (◦) biomaterials. The tagged particles are
gathered by the magnet, and the unwanted supernatant solution is
removed. In (b) a solution13containing tagged and unwanted
biomaterials flows continuously through a region of strong magnetic
field gradient, often provided by packing the column with steel wool,
which captures the tagged particles. Thereafter the tagged particles
are recovered by removing the field and flushing through with water.
 nanoparticles and larger particles can be used: for be used to achieve ‘fluid flow fractionation’ [24]. This
some applications use magnetic ‘microspheres’— is a process in which the fluid is split at the outlet into
ized agglomerations of sub-micron sized magnetic fractions containing tagged cells or proteins with differing
incorporated in a polymeric binder [19].
magnetically labelled material is separated from its (a)
ution by passing the fluid mixture through a region in
ere is a magnetic field gradient which can immobilize
d material via the magnetic force of equation (7). This
ds to overcome the hydrodynamic drag force acting
agnetic particle in the flowing solution,

Fd = 6π ηRm #v, (8)

is the viscosity of the medium surrounding the cell (b)

er), Rm is the radius of the magnetic particle, and
− vw is the difference in velocities of the cell and the
There is also buoyancy force that affects the motion,
s dependent on the difference between the density of
nd the water, and for most cases of interest in biology
cine can be neglected. Equating the hydrodynamic
magnetic forces, and writing Vm = 43 πRm 3
, gives the
of the particle relative to the carrier fluid as:
2
Rm #χ ξ
∇(B 2 ) or #v = ∇(B 2 ), (9)
9µ0 η µ0
Figure 3. The standard methods of magnetic separation: in (a) a
is the ‘magnetophoretic mobility’ of the particle—amethod
• Another magnet isuses
attached to the container
a magnet in awall of a solution ofsetup.
quadrature magnetically
View from top
r that describes how manipulable a magnetic particle tagged (•) and unwanted (◦) biomaterials. The tagged particles are
(first figure) and from the side (second figure):
xample, the magnetophoretic mobility of magnetic gathered by the magnet, and the unwanted supernatant solution is Topical Review
removed. In (b) a solution containing(a)tagged and unwanted (b) separation is used to
eres can be much greater
(a) than that of nanoparticles, separation is used to increase the concentration
(b)biomaterials flows continuously through a region of strong magnetic of the material. The mobility of the
eir larger size. This can be an advantage, for example, field gradient, often provided The mobility of the magnetic nanoparticles allows a shorter reaction time and a g
by packing the column with steel wool,
reaction time
parations, where the experimental timeframe for the which captures the tagged particles. and a greater
Thereafter volume
the tagged of reagent to be used than
particles in standard immuno
ns is correspondingly shorter. On the other hand, are recovered by removing the field and flushing through with water.antibody is bound to a
in standard immunoassays where the plate. In a variation
plate. In a variation of this procedure, magnetic separation has been used to lo
has been used to localize labelled cells at known locations for cell detection and
for cell detection and counting via optical scanning [14]. The cells are labelled both
cells are labelled both magnetically and fluorescently and move through a magnetic fi
through a magnetic field gradient towards a plate on which lines of ferromagnetic ma
of ferromagnetic material have been lithographically etched. The cells align along
The cells align along these lines and the fluorescent tag is used for optical detection
Figure
for optical 4. A rapid
detection of the cells. method of magnetic separation, in
throughput
Figure 4. A rapid throughput
Themethod of magnetic
particles areseparation,
pulledin towards the whichwall,
an annular
fromcolumn containing
where a flowing
they cansolution
be of
which an annular column containing a flowing solution of magnetically tagged (•) and unwanted (◦) biomaterials is placed 4. Drug delivery
magnetically tagged (•) and
flushed
unwanted (◦) as
out soon as
biomaterials 4. Drugwithin
the magnets
is placed delivery
are turned off. arranged in quadrature: (a) longitudinal
a set of magnets
within a set of magnets arranged in quadrature: (a) longitudinal cross-section of the annular column; (b) transverse cross-section of 4.1. Motivation and
the four magnets with theprinciples
resulting magnetic field lines. Under the
• Alternatively,
cross-section of the annular column; (b) transverse particlesof can4.1.
thecross-section beMotivation
static and physical
and the magnets itself moves.
action of the magnetic field gradient the tagged particles move to the The major disadva
the four magnets with the resulting magnetic field lines. Under the
The
action of the magnetic field particles
gradient move to the inThe
are collected
the tagged particles major
column
a container disadvantage
walls,
atwhere ofend
thethey most ofchemotherapies
are held until
thethepipe
field isbyis thatand
removed they are relatively
column walls, where they are held until the field is removed and they
they areThis are recovered
relatively by flushing through
non-specific. The with water. Thedrugs
therapeutic central core are administered in
the means of a permanent
they are recovered by flushing through with water. The central core
magnet. allows an easy removal of the
of the column is made of non-magnetic material to avoid
are administered intravenously leading to general systemic distribution, resultin
of the column is made of container
non-magnetic material
with totheavoid
captured particles. complications due to the near-zero field gradients there.
distribution, resulting in deleterious side-effects as the drug attacks normal, heal
complications due to the near-zero field gradients there.
attacks normal, healthy cells in addition to the target tumour cells. For example
magnetophoretic
cells. For example, themobilities.
side effects In aofvariant of this, the fluid is
anti-inflammatory drugs on patients w
magnetophoretic 3.1.3 Applications
mobilities. In a variant of this,ofthe
Magnetic
fluid is drugs Separation
static while an applied magnetic field
on patients who have chronic arthritis can lead is moved up to
thethe
container discontinuation of th
static while an applied magnetic field is moved up the container discontinuation [25]. The particles
of their move up ifthe
use. However, suchcontainer
treatmentsin the
could resulting be localized, e.g. to t
Magnetic
[25]. The particles move up separation
the containercan be resulting
in the used in several applications,
field gradient at a especially
velocity dependent exceeding
on their
be localized, e.g. to the site of a joint, then the continued use of magnetophoretic these very potent and
field gradient atwhen
a velocity
thedependent
targeted on their magnetophoretic
entities only appear mobility. At the top of the container they enter a removable Recognition of
these on
very small
potent and numbers:
effective agents could be made possible.
mobility. At the top of the container they enter a removable section and are held here by a permanent magnet. The bottom to propose the use
Recognition of this led researchers in the late 1970s
section and are held•hereAsbyaa highly
permanentsensitive
magnet. The bottom toto
technique sectionand
select
propose
of the container rare
the use remove
movestumour
of magnetic carriers
to the next cells.
section, a magnetic
to target specific sites (generally canc
field with different strength to the
section of the container moves to the next section, a magnetic sites (generally cancerous tumours) within the body [34–36]. first is applied and the process The objectives are
• Enhanced
field with different strength to the first isdetection
applied and the
andprocess
separation repeats.
of The result
malarial is a fractionation
parasites in of the sample
blood sam- into aliquots systemic distributio
The objectives are two-fold: (i) to reduce the amount of
of differing magnetophoretic mobility.
repeats. The result is a fractionation of the sample into aliquots systemic distribution of the cytotoxic drug, thus reducing the associated side-
ples (using the parasites magnetic properties). required by more
of differing magnetophoretic mobility. the associated side-effects; and (ii) to reduce the dosage
required3.3.byApplications
more efficient, localized targeting of the drug. In magnetica
• Cell counting techniques. attached to a bioco
3.3. Applications drug. InMagnetic
magnetically targeted
separation has therapy, a cytotoxic
been successfully drug is
applied to many
attachedaspects
to a biocompatible magnetic nanoparticle carrier. These drug/carrier
Magnetic separation• has Combined with applied
been successfully opticalto sensing
many These to perform of
drug/carrier
biomedical
tests and
regarding
complexes—usually
biological
the research.
presence It has proven biocompatible ferro
aspects of biomedical or and concentration
biological research.ofIt certain
has provensubstances. to be a highly sensitive techniqueinforthe theform of aof rare
selection the circulatory syste
biocompatible The magnetic separation
tumour ferrofluid—are
cells from blood,injected into thetech-
and is especially patient via to the
well suited
to be a highly sensitive technique for the selection of rare the circulatory system. When the particles have entered the bloodstream, externa
nique guarantees an efficient taggingseparation and a high enough concentration
of low numbers of target cells [26]. This has, for to concentrate the co
tumour cells from blood, and is especially well suited to the bloodstream, external, high-gradient magnetic fields are used
of the substance, example, led to the enhanced
use adetection of malarial parasites body (figure 5). On
separation of low numbers of target cells [26]. while the
This has, for optical sensing
to concentrate
can then fluorescent
in bloodthe complex
samples at abyspecific
either utilizing target site within
the magnetic the
properties of target, the drug can b
example, led to the enhanced
tag todetection
detectofthe malarial parasites body (figure 5). Once the drug/carrier is concentrated at the
substance. the parasite [27] or through labelling the red blood cells with changes in physiolo
in blood samples either by utilizing the magnetic properties of target, the drug can be released either via enzymatic activity or
an immunospecific magnetic fluid [28]. It has been used as or temperature [37]
the parasite [27] or through labelling the red blood cells with changes in physiological conditions such as pH, osmolality,
a pre-processing technology for polymerase chain reactions, This system, in theo
an immunospecific magnetic fluid [28]. It has been used as or14 temperature [37], and be taken up by isthe tumourand cells.
through which the DNA of a sample amplified identified non-targeted method
a pre-processing technology for polymerase chain reactions, This system, [29]. in theory,
Cell has major
counting advantages
techniques have also over thedeveloped.
been normal, One The physical p
through which the DNA of a sample is amplified and identified non-targeted method methods of cytotoxic
estimates the location drugandtherapy.
number of cells tagged by therapy are similar
[29]. Cell counting techniques have also been developed. One Themeasuring
physical the principles
magneticunderlying
moment ofmagnetic
the microspheretargetingtags [30], and are derived from
method estimates the location and number of cells tagged by therapy while are similar to those used in magnetic separation,
another uses a giant magnetoresistive sensor to measure nanoparticle by a m
measuring the magnetic moment of the microsphere tags [30], and are the derived
locationfrom the magnetic attached
of microspheres force exerted on a layered
to a surface SPM with The effectiveness o
while another uses a giant magnetoresistive sensor to measure nanoparticle a boundby aanalyte
magnetic[31].field gradient, as in equation (7). physical parameters
the location of microspheres attached to a surface layered with The effectiveness of application,
In another the therapy magnetic
is dependent separationon several
has been used and volumetric and
a bound analyte [31]. physicalinparameters,
combinationincluding
with opticalthe field
sensing strength, gradient
to perform ‘magnetic As the carriers (f
In another application, magnetic separation has been used and volumetric and magnetic properties of the particles.
3.2 Drug Delivery
3.2.1 Basic Understanding & Motivation
Drug delivery through magnetic nanoparticles works in a similar fashion to
magnetic separation: The drug can be attached to the magnetic particle and
then a magnetic force can change the path of the tagged particles. Once at
the correct place, the drug can be released from its carrier either via enzy-
matic activity or physiological changes (pH, osmolality, temperature).

As before, not only nanoparticles, but also microspheres should be con-

sidered due to their high likeliness to be influenced in their path. They are
more successful at withstanding the general flow in the body’s circulatory
system.

In general, drug delivery seems to be more successful in regions with a slow

flow and when the magnet can come into close proximity.

3.2.2 Magnetic Carriers

How should these magnetic particles be built to fulfil their tasks most effi-
ciently? As for the tagging process, coating is required. These coatings can
be of organic or inorganic origin. During their journey the coating protects
the magnetic nanoparticles or microspheres and once at their target, it can
serve as an attachment point to the targeted entity. In general, there are
two types of structural configurations [1]:

• Magnetic core with a biocompatible polymer as coating.

• Porous biocompatible polymer, in which the magnetic nanoparticles

can diffuse through the pores.

3.2.3 Applications of Drug Delivery

The advantages of targeted drug delivery seem numerous: Most drugs are
non-specific, i.e. they get distributed over the whole body as soon as they
get administered intravenously. Targeted delivery can ensure that

• only specific areas get influenced by the (otherwise harmful) drugs and

• as little as possible of the drug needs to be administered.

This method seems especially applicable, when the drug is very damaging
to healthy tissue. Fields of application:

• Chemotherapy,

• radionuclide therapy,

15
 • arthritis or

• gene therapy.

As a side note: While having proven to be very successful in animal tests,

to the date of the publication of this paper (2003) there were not many
studies with humans as test subjects. And while being very promising for
the future, a couple of problems should not be neglected:

• Embolization of blood vessels due to too high concentration of the

magnetic carriers.

• Larger distances to cover in humans compared with animals.

• As soon as the drug is released, it cannot be influenced any longer by

magnetic field gradients.

• The magnetic carriers itself may have unwanted side effects.

3.2.4 Radionuclide and Gene Delivery

These two fields of study have only recently become popular among scientific
researchers.

• Radionuclide Delivery: An advantage of radionuclide therapy is

that the radionuclides do not have to decouple from the magnetic car-
riers. The magnetic carriers can transport the radionuclides to the
target area where they can destroy the cancerous tissue. After the de-
sired result has been achieved, both the carriers and the radionuclides
can be directed out of the circulatory system.

• Gene Therapy: In gene therapies, the magnetic carriers are coated

with the therapeutical gene and transported to the target area. Thanks
to the possibilitiy of holding the gene and carrier at the target for an
extended time, the chances rise that the gene can get transfected. Ap-
plications in this field of study are only in their beginning.

3.3 Hyperthermia
3.3.1 Basic Understanding & Motivation
The idea of the treatment is to artificially introduce hyperthermia2 in order
to heat malignant tissue at specific areas while sparing benignant tissue.

2
Hyperthermia is usually an unwanted overheating of the body not to be confused with
common fever. In a hyperthermic state, the body absorbes or produces more heat than
it can dissipate. However, hyperthermia can also be a wanted effect in order to destroy
tumorous cells and hence is sometimes created artificially.

16
e magnetic targeting to improve drug because of unacceptable coincidental heating of healthy tissue,
ss safety issues [68, 72]. magnetic particle hyperthermia is appealing because it offers
a way to ensure only the intended target tissue is heated (see
figure 7).
ene delivery
e limitation caused by the release of the 5.2. Operational constraints
o use a system in which the therapeutic
to the magnetic carrier throughout A number of studies have demonstrated the therapeutic efficacy
eatment. Based on this idea, the of this form of treatment in animal models (see, e.g. the review
radionuclides via magnetic carriers
The advantage these complexes have 46
gnetic carrier complexes is that the
onuclide does not require the tumour 44

Temperature (˚C)
he agent. If the radionuclide is targeted 42
ur site and held there, the radiation will
40
mour tissue while it is still attached to
his type of system was tested in 1995 38
e models. In both cases, targeting of 36
ed to a β-emitter (Y-90) was effective
on to the desired site. In the mouse 34
a significant increase in radioactivity 32
red to using the same complex without
30
2% vs 6 ± 4% [73]. Since this study,
] have demonstrated the effectiveness 0 10 20 30 4
40 50
animal and cell culture studies using Time (minutes)
nium-188.
have begun with a view towards Figure 7. Animal trial data on hyperthermia treatments in rabbits,
using7: This
Figure data
showing has been
preferential taken
heating of a from
tumourtests
using with rabbits (liver tumour)
intra-vascularly
ne therapy. In this case, a viral vector
and showsinfused
the tissue’s temperature
ferromagnetic in a( specific
microspheres; ) tumourregion
edge, (!)over time. Legend:
tumour
c gene is coated onto the magnetic
(∎) tumourcentre,
edge,(")(◆)
normal liver 1–2
tumour cm from
centre, (▲)tumour,
normal(×)liver
alternative
1-2 cmlobe,from tumour,
lding the carrier at the target(×)sitealternate
via and (♦) core body temperature.
lobe, (◇) core body temperature. The targeting of a specific
area (here the liver) is quite successful: The tumour centre and R173 tumour edge
get heated to the required temperature, while the core body temperature
stays stable. Source: [1].

The magnetic particles first have to be brought to the target area, where
they can be caused to heat up by an AC magnetic field of sufficient strength
and frequency. The heat should exceed the threshold of 42○ Celsius and last
for about 30 minutes in order to properly destroy the tumour.

Tests with animals were successful and quite promising (see figure 7), but so
far it could not be applied to humans due to our larger size. A vastly larger
size would require vastly larger alternating magnetic fields, which in turn
would be harmful to the organism. Lowering the field on the other hand,
would not result in enough heat production.

3.3.2 Heating Mechanism

As already mentioned, an alternating magnetic field is required to produce
heat. However, the total heat balance is quite complicated: Additionally to
the magnetic heat production, the cooling of the blood through blood flow
and tissue perfusion have to be considered. As a simplification and rule of
thumb, one can expect that 100 mW cm−3 of heat deposition is necessary
to guarantee an effective treatment.

17
As for the amount of magnetic material needed: The adequate amount varies
with the method of how the magnetic nanoparticles are introduced into the
tumorous region. Direct injection allows to accumulate larger quantities of
nanoparticles at the target area and thus needs less material injected over-
all. Intravascular or antibody targeting needs larger overall quantities of
nanoparticles, since their distribution to the target area is not as successful.
Again as a rule of thumb, around 5-10 mg/cm3 of magnetic material should
be achieved.

As for the best suited material: Particles from around 10 µm and lower
are considered to be small enough. This implies that they may work as
ferro- or ferrimagnetic microspheres or, when even smaller, as superparam-
agnetic nanoparticles. The heat generation mechanism needs in each case a
different explanation.

Heating mechanism for FM particles: Ferromagnetic or ferrimagnetic

particles show hysteresis, which allows magnetically induced heating. The
amount of heating can be found to be [1]:

PF M = µ0 f ∮ HdM (12)

with
• µ0 : The magnetic permeability of free space.
• f : Frequency of the alternating magnetic field.
• The loop integral is over the hysteresis loop.
This formula deliberately ignores other possible mechanism for heating (such
as eddy current heating or ferromagnetic resonance heating), since they are
negligible for these types of particles. However, it is difficult to achieve
configurations in vivo, which can use the full capacity of this heating. In
general, it should be assumed that about 25% of that heat production can
actually contribute the heating of the tissue.

Heating mechanism for SPM particles: Superparamagnetic particles

can be suspended in water or a similar fluid in order to yield a magnetic
fluid or ferrofluid. Consequentially, a change in M slightly lags behind a
change in H. The susceptibility has to be composed of a real and a complex
part: χ = χ′ + χ′′ . The latter, χ′′ , is the out of phase component which yields
the heat generation [1]:
PSP M = µ0 πf χ′′ H 2 . (13)

18
 drodynamic properties of the fluid; is equivalent to only three of Review
Topical every million proton moments
cess is determined by the magnetic m being aligned parallel to B0 , there are so many protons
rbon fluid to relative
PM particles 6. MRI contrast
to the thermalenhancement available—6.6×1019 in every mm3 of water—that the effective
12]. When a
d Néel processes may be present in signal, 2 × 1014 proton moments per mm3 , is observable. As
magnetization
τN is relevant in 6.1. fixedPhysical principles
SPM particles illustrated in figure 8, this signal can be captured by making use
nal ofenergy of
the particle is possible. The
ond to MRIonrelies
eitherdifferently of resonant absorption:
on the counterbalance between theapplying exceedingly a time-varying magnetic field
depend particle size;
s within small magnetic momentin on a plane perpendicular
a proton, and the to B0 , tuned to the Larmor precession
exceedingly
otation arethe generally maximized at 1
s within each large number of protonsfrequency of thewhichprotons. For H protons the
e those due to Néel relaxation
Heat absorption for a from present inωbiological
0 = γ B0 tissue,
the tissue is usually given in the units8of W −1 g−1 . −1
as ‘Brownian leads to a measurable
If compared, techniquesgyromagnetic
effect in theferro-
using ratio
presence
or of = 2.67
γ large
ferrimagnetic × 10 radyield
magnetic
microspheres s aT , so that in a
each particle fields maximum [122, 123]. Thus, even −1 though the effect of a steady
possible 75field
W gof B 0 = 1the
(before T the Larmor
frequency precession
becomes unsafe frequency
for the corresponds
the heating of SPM particles by AC
se processes state field of B0−1 = 1 Ttoona aradio
organism), while techniques collection
using frequency of protons,
superparamagnetic such ωas0 /2π = 42.57 MHz. In
field with
nanoparticles yield up
eviewed
he Brownian by Rosensweig to 209[113].
W g It. is
the hydrogen nuclei in practice
s, which was originally
of the fluid; developed to a water molecule, the radio isfrequency so small transverse
that it field is applied in a
is equivalent to only three of every million proton moments
ersion
the in polar fluids 3.4
magnetic [114],MRI the pulsed
and Contrast sequence, of duration sufficient to derive a coherent
Enhancement
m being aligned parallel to B0 , from
response there the are net so magnetic
many protons moment of the protons in the
oratetheof change of
thermal in a ferrofluid
M 3.4.1 Basic Understanding
available—6.6×10 in every 19
mm 3
of water—that the effective
dbeHpresent
. For small in field amplitudes, and MRI scanner. From the instant that the radio frequency pulse is
× 10a14magnetic
signal,In2short, proton turned
moments per
resonance imaging
off the mm 3
,
scanner,
relaxation is observable.
or MRI scanner,
of the As systemat-
coherent
tions between the constituentalters SPM
PM particles illustrated in figure 8, this signal can be captured by making use
ically the alignment of the magnetization of particles in a body.response
This is measured
e magnetization
ossible. The of a ferrofluid to an magnetic
results in rotating via induced fields duecurrents
to the in pick-up
nuclei. This incoils
turnincanthe
be scanner. These
of resonant absorption: applying aimage
time-varying magnetic field
nparticle
terms of size;its complex susceptibility resonantly tuned detection coils enhance the signal by a quality
detected and put together to an of the body. A more detailed analysis
! !! [1]: perpendicular to B0 , tuned to the Larmor precession
in a plane
χ and χ are
maximized at frequency dependent. factor of ca 50–100. 1As shown in figure 8, for B0 parallel to
frequency B0 of magnetic
ω0 =an γexternal the protons. ⃗0For H protons the
mponent
axation for resultsa in heat generation
1. First, field B
8
is applied:
−1 −1
gyromagnetic ratio γ = 2.67 × 10 rad s T , so that in a
rticles by AC field of B0 = 1 T the Larmor precession (a) frequency corresponds (b)
!! 2 B0 B0
= µ0 πf χIt is
g [113]. H , to a radio frequency (11) field with ω0 /2π = 42.57 MHz. In
developed practice the radio frequency transverse fieldmis applied in a
physicallytoas pulsed meaning that if M
sequence, of duration sufficient to derive a coherent
114], and
e conversion of the magnetic energy
n a ferrofluid response from the net magnetic moment of the protons in the m
simple theory compares favourably
plitudes, and MRI scanner. From the instant that the radio frequency pulse is
for example, inturned predicting
off the a square
relaxation of the coherent response is measured
stituent SPM !!
[91], and the dependence of χ on ⃗0 at a specific Larmor frequency
rrofluid to an via induced currents in pick-up
A net moment then precessescoils
(c) in the
around B scanner. These mxy
–117]. ω0 .
susceptibility resonantly tuned detection coils enhance the signal by a quality
amplitude

ey dependent.
heat generation factorfrom magnetic ⃗0 is applied,
signal

of2.caIn50–100.
a second step,As shown
another in figure field
magnetic 8, for B0 parallel
perpendicular to toB
d
at −1 in terms
generation of the specific absorption
oscillating with above mentioned precession frequency ω0 :
g . Multiplying the SAR by the tim
time
ds PFM and PSPM , so the parameter (a)
B0
(b)
B0
e efficacies (11) of magnetic particles
ng es that
[88, if111, M 118–121]. It is clear
m
(d) mz
at most
netic energy real FM materials require
amplitude

ca 100 kA m−1 or more before they m

es favourably
signal

dting loop, and therefore only minor

a square
zed of
nce given !!
χ on the operational constraint
(c)
se to low SARs. In contrast, Even SPMthough the second m magnetic
xy field may well be much weaker than
⃗0 , it results in a resonant excitation of the magnetic moment preces- time
amplitude

B
nerating
m magnetic impressive levels of heating
signal

sion into the plane perpendicular to the direction of B ⃗0 .

e, the
fic best of the ferrofluids reported Figure 8. Illustration of magnetic resonance for a large ensemble of
absorption
aSAR SARbyofthe 45 W g−1 at 6.5 kA m−1 protons with net magnetic tim moment m in the presence of a external
time
he parameter
olates to 209 W g−1 for 14 kA m−1 , magnetic field 19 B0 . In (a) the net moment precesses around B0 at the
etic m for the best FM magnetite characteristic Larmor frequency, ω0 . In (b) a second external field is
4 kAparticles −1

se. It is clearwould be adequate

samples for applied, perpendicular to B0 , oscillating at ω0 . Despite being much
(d) m
weaker than B0 , this has the effect of resonantly exciting the
z
erials require
rmia, importantly, it seems clear that moment precession
plitude

into the plane perpendicular to B0 . In (c) and (d)

e before
cles they likely to offer useful
are more
signal

the oscillating field is removed at time zero, and the in-plane (c) and
etic onlyfieldminorstrengths. longitudinal (d) moment amplitudes relax back to their initial values.
 available—6.6×10 in every mm of water—that the effective
nian and Néel processes may be present in signal, 2 × 1014 proton moments per mm3 , is observable. As
s only τN is relevant in fixed SPM particles illustrated in figure 8, this signal can be captured byTopical makingReview
use
rotation of the particle is possible. The
ended of resonant absorption:
to 6. MRI contrast enhancement applying a time-varying magnetic field
and τNindepend water differently
or a hydrocarbon
on particle fluidsize;
in a plane perpendicular to B0 , tuned to the Larmor precession
wnian rotation are generally maximized ata
fluid’ or ‘ferrofluid’ [98, 111, 112]. When
ed frequency ω = γ B0 of the protons. For 1 H protons the
hanfrom are athose
magnetic
due tofieldNéelitsrelaxation
magnetization for a 6.1. Physical0 principles
ro due to the ambient thermal energy of gyromagnetic ratio γ = 2.67 × 108 rad s−1 T−1 , so that in a
Thisofrelaxation MRIofrelies
B0 =on 1 Tthethe counterbalance between the corresponds
exceedingly
asis the heatingcan correspond
of SPM particles either
by AC to field Larmor precession frequency
on of reviewed
the particles themselves [113]. withinItthe small magnetic moment on a proton, and the exceedingly
been by Rosensweig is to a radio frequency field with ω0 /2π = 42.57 MHz. In
the atomic magnetic moments within
model, which was originally developed to large number each practice the radioof protons
frequency present in biological
transverse field istissue,
appliedwhich
in a
of the particles is referred to
ric dispersion in polar fluids [114], and the as ‘Brownian leads
pulsed to a measurable
sequence, of effect
duration in the presence
sufficient to of
derivelarge a magnetic
coherent
eation
finiteofrate theofmoment
change within
of M ineach a 3. particle fields
Now, theresponse
ferrofluid [122,
oscillating
from123]. Thus,
fieldnet
the even though
ismagnetic
turned off. The
moment the effect
of following of a quantities
the protons steady
in the can
l relaxation’. Each of these processes
g behind H . For small field amplitudes, and MRI scanner. From
be state
measured field
and of
then B 0 =
used 1 T on a collection of protons,
the instant that the radio frequency pulse is
to compose an image of thesuch as
studied body.
yinteractions
a relaxation time: τthe
between B for the Brownian
constituent SPM turned the hydrogen nuclei in aofwater
off the relaxation molecule,
the coherent is so small
response that it
is measured
nnse theofhydrodynamic properties
the magnetization of a ferrofluid of the fluid;
The is equivalent
via
to anin-plane induced
amplitude to only
currents three
in
relaxes of every
pick-up
accordingcoilsmillion
tothe proton
in scanner. moments
These
éel process
cribed in termsis determined
of its complex by susceptibility
the magnetic resonantly m being aligned to B0enhance
parallel coils
tuned detection , there the are signal
so many by aprotons
quality
of the SPM
e both χ ! andparticles
χ !! are relative
frequency to the thermal available—6.6×1019 in every mm3 of water—that
dependent. factor of ca 50–100. mx, y = Asmshown
sin(ωin + φ)e−t/T
0 t figure 8, for
2
B0the effective
parallel to (14)
nian and Néel processes may be present in 14
χ component results in heat generation signal, 2 × 10 proton moments per mm , is observable. As
!! 3
s only τN is relevant in fixed SPM particles illustrated in figure 8, this signal can be captured by making use
with
rotation of the particle is possible. The (a) (b)
!! 2 of resonant absorption: B0 applying a time-varying B0 magnetic field
and
PSPMτN=depend µ0 πf χdifferently
H , on particle size; (11)
• T2 : inThe transverse relaxation time.
a plane perpendicular to B0 , tuned to the Larmor precession
wnian rotation are generally maximized at
rpreted physically as meaning that if • M φ: Afrequency ω0 = γm
phase constant. B0 of the protons. For 1 H protons the
than are those due to Néel relaxation for a
positive conversion of magnetic energy gyromagnetic ratio γ = 2.67 × 108 rad s−1 T−1 , so that in a
m
. This
asis of simple theory
the heating of compares
SPM particles favourably
This
by ACsituationfield of B = 1 T the
is0 shown inLarmor precession
the following frequency corresponds
figure:
esults, for example,
been reviewed in predicting
by Rosensweig a square
[113]. to a radio frequency field with ω0 /2π = 42.57 MHz. In
!!It is
on H [91],
Mmodel, and the dependence
which was originally developed to of χ on practice the
(c) radio frequency transverse field is applied in a
cy [115–117]. mxy
ric dispersion in polar fluids [114], and the pulsed sequence, of duration sufficient to derive a coherent
amplitude

of the heat generation from magnetic

e finite rate of change of M in a ferrofluid response from the net magnetic moment of the protons in the
signal

y quoted in terms of the specific absorption MRI scanner. From the instant that the radio frequency pulse is
g behind H . For small field amplitudes, and tim
time
s of W g−1 . Multiplying the SAR by the turned off the relaxation of the coherent response is measured
interactions between the constituent SPM
cle of
nse yields PFM and PSPMof
the magnetization , so the parameter
a ferrofluid to an via induced currents in pick-up coils in the scanner. These
of the
cribed efficacies
in terms of its of magnetic
complex particles resonantly tuned detection coils enhance the signal by a quality
susceptibility
ze ranges! [88, 111, 118–121]. It is clear
e both χ and χ !! are frequency dependent. factor of ca(d)50–100. As shown inmfigure z 8, for B0 parallel to
sons that most real FM materials require
χ !! component results −1 in heat generation
The transverse relaxation is driven by the loss of phase coherence due
amplitude

ths of ca 100 kA m or more before they

signal

to the interactions of the moments with each other. This dephasing is

aturated loop, and therefore only minor (a) (b)
!! 2 also B0
helped by local inhomogeneities, which shortensB0 the already short
be
PSPM utilized
= µ0given
πf χ the H operational
, constraint(11)
iving rise to low SARs. In contrast, SPM relaxation time T 2 further. m
rpreted physically as meaning that if M time
e of generating impressive levels of heating
positive the
example, conversion
best of theofferrofluids
magneticreportedenergy
The longitudinal amplitude relaxes resonance
according
y.1] This simple theory compares favourably Figure 8. Illustration of magnetic for to
a large mensemble of
has a SAR of 45 W g at 6.5 kA m−1 protons with net magnetic moment m in the presence of a external
−1
results,
extrapolatesfor example,
to 209 W in gpredicting
−1
for 14 kA a square
m!! −1 , magnetic field B0 . In (a) mzthe= net
m(1 − e−t/T
moment )
precesses
1
around B0 at the (15)
on H [91], and the dependence of
gM−1 at 14 kA m−1 for the best FM magnetite characteristic χ on (c)Larmor frequency, ω0 . In (b) a second external field is
cy mxy
of[115–117].
these samples would be adequate with for applied, perpendicular to B0 , oscillating at ω0 . Despite being much
amplitude

of the heat generation from magnetic weaker than B0 , this has the effect of resonantly exciting the
signal

yperthermia, importantly, it seems clear that moment precession into the plane perpendicular to B . In (c) and (d)
M y quoted
particles in terms
are more of the specific
likely absorption
to offer useful• T1 : the
The longitudinal relaxation 0
oscillating field is removed at timetime.
zero, and thetime in-plane (c) and
tim
of W g−1field
sr magnetic . Multiplying
strengths. the SAR by the longitudinal (d) moment amplitudes relax back to their initial values.
cle yields PFM and PSPM , so the parameter The corresponding situation is shown in the following figure:
of the efficacies of magnetic particles R175
ze ranges [88, 111, 118–121]. It is clear (d) mz
sons that most real FM materials require
amplitude

ths of ca 100 kA m−1 or more before they

signal

aturated loop, and therefore only minor

n be utilized given the operational constraint
iving rise to low SARs. In contrast, SPM time
le of generating impressive levels of heating
example, the best of the ferrofluids reported Figure 8. Illustration of magnetic resonance for a large ensemble of
1] has a SAR of 45 W g−1 at 6.5 kA The m−1longitudinal
protons withrelaxation
net magneticismomenta signmofinenergythe presencelossofofa the
external
system to its
extrapolates to 209 W g for 14 kA m−1 , magnetic field B0 . In (a) the net moment precesses around B0 at the
−1
surrounding.
g−1 at 14 kA m−1 for the best FM magnetite characteristic Larmor frequency, ω0 . In (b) a second external field is
of these samples would be adequate for applied, perpendicular to B0 , oscillating at ω0 . Despite being much
weaker than B0 , this has the effect of resonantly exciting the
yperthermia, importantly, it seems clear that moment precession 20 perpendicular to B0 . In (c) and (d)
into the plane
M particles are more likely to offer useful the oscillating field is removed at time zero, and the in-plane (c) and
r magnetic field strengths. longitudinal (d) moment amplitudes relax back to their initial values.

R175
 usedon
areSPM nanoparticles
PM gadolinium are commercially
ion complexes, althoughavailable,
agents basedsuch have
as also been utilized for the in vivo monitoring o
expressa aprocess
expression, given gene. Thiscells
in which process leads to thet
are engineered
‘Feridex I. V.’, an iron oxide contrast
on SPM nanoparticles are commercially available, such asagent marketed by
increased
express a given numbers
gene. Thisof process
certain cell
leadswall
to receptors,
the produc
Advanced
‘Feridex I. V.’,Magnetics
an iron oxideInc. contrast
for the agent
organ-specific
marketedtargeting
by can be targeted using specially coated
increased numbers of certain cell wall receptors, nanopart
which
of liver lesions. The SPM particles used
Advanced Magnetics Inc. for the organ-specific targeting are magnetically
can beallowing
targetedausing
differentiation between
specially coated the express
nanoparticles,
saturated in the normal range of magnetic field
of liver lesions. The SPM particles used are magnetically strengths used
theirasurroundings
allowing differentiation[137].
betweenAnother aspect of ce
the expressing th
in MRI
saturated scanners,
in the normal thereby
range of establishing
magnetic fielda strengths
substantial
usedlocally
cell receptors has been to selectively study cells
perturbing
in MRI scanners,dipolar fieldestablishing
thereby which leads, (14), totheir
via equationlocally
a substantial a surroundings [137]. Another aspect of the targe
∗ process of
cell receptors hascell
beendeath [138]. study cells that ar
to selectively
marked shortening of
perturbing dipolar field which T 2 (see figure 9) along with a less
leads, via equation (14), to a marked
reduction of T1of[123].
∗ process of cell death [138].
marked shortening T2 (see figure 9) along with a less marked
reduction of T1 [123]. 7. Discussion and future prospects
7. Discussion and future prospects
In this paper we have reviewed some basic conc
(a) (b) In thisthe interactions
paper between some
we have reviewed magnetic
basicnanoparticle
concepts re
(a) (b) or time-varying
the interactions between external
magnetic magnetic field, and
nanoparticles and
these pertainexternal
or time-varying to current biomedical
magnetic field,application
and show
these nanoparticles.
pertain to current Webiomedical
have focused in particular
applications of m
separation,We
nanoparticles. drug
havedelivery,
focused hyperthermia
in particular on andm
separation, drug delivery,
enhancement, althoughhyperthermia
these are and only MRI
four c
enhancement,
biomedical although these of
applications aremagnetic
only four of the
nanopart
biomedical
currentlyapplications of magnetic
being explored. For nanoparticles
example, reset
currently being into
conducted explored.
magneticFor example,
twisting research
cytometry, i
a pro
conducted into magnetic
ferromagnetic twisting cytometry,
microspheres are boundato process
specifii
ferromagnetic microspheres
a cell wall. Changing the aredirection
bound toof specific recep
an applied
a cell twists
wall. Changing the direction
the microsphere of an applied
by a measurable magnew
amount,
twistsbetherelated
microsphere
to the by a measurable
mechanical amount,of
properties which
the cc
timebe related to the mechanical
and cytoskeleton propertiesMagnetic
[139–143]. of the cellnan
me
time and cytoskeleton [139–143]. Magnetic nanopartic
Figure 9.(a)
Effect of magnetic particle internalization (b)in cells on T2∗ also being tested for tissue engineering app
Figure 9. Effect
relaxation of magnetic
times: particle in
(a) the protons internalization in cells
cells tagged by
also example,
on T2particles
magnetic ∗ being tested formechanical
in the tissue engineering
conditioningapplicatio
of cel
relaxation times: (a) the
∗ protons in cells tagged by magnetic particles
have a shorter T2 relaxation time than those in (b) untagged cells. example, in
culture the mechanical
[144–146]. Inconditioning
such systems of cells grow
magnetic
Figure 8: A qualitative
have a shorter T2∗graph
relaxationoftime
thethanchanged
those in (b)relaxation
untagged cells. time. culture
Figure[144–146].
8(a): In such systems magnetic partic
Cells tagged withR176
magnetic nanoparticles and a short relaxation time. Figure
R176
8(b): Cells without any enhancement and thus the original relaxation time.
Source: [1].

3.4.2 Contrast Enhancement trough SPM Particles

How do magnetic nanoparticles come into play? In short, nanoparticles at-
tached to a cell or cell compound can shorten both the transverse relaxation
time T1 and the longitudinal relaxation time T2 . Figures 8(a) & 8(b) show
the qualitative effect of superparamagnetic nanoparticles on the relaxation
time T2 .

Due to the fact that different tissues take up the nanoparticles differently,
an enhancement between the different tissues is achieved and the contrast
between them is higher. Also, it has been shown that some tumour cells do
not have their relaxation time altered and hence can be identified through
this characteristics.

3.5 Summary
As of 2003, the status of the discussed techniques is as follows:

• Magnetic separation via protein and cell tagging is available.

• MRI contrast enhancement techniques are available as well.

• Drug delivery was successfully tested with animals, but so far not with
humans.

• Hyperthermia treatments are not yet available for humans.

21
These fields of study are prove that there is a long way between successful
in vitro results and successful in vivo results.

4 Nanoparticle Magnetism
This section presents the paper “Nanoparticle magnetism”. The author ar-
gues that with the high interest in nanoparticle technology and applications,
it seems reasonable to be able to understand the underlying mechanics and
theories as well as possible. With magnetism of nanoparticles as a prominent
direction in nanotechnology, they present their findings in that field. Pub-
lished around six years later than the previous paper, this paper presents
new material on the following topics [2]:
• Dynamic spin fluctuations and spin reversal of uniaxial nanoparticles.
• The intrinsic spin structure of nanoparticles as influenced by surface
and finite-size effects.
• Core versus surface contributions to the total magnetic behaviour of
the nanoparticles.
Quite a substantial part of the paper’s results have already been presented in
the previous sections in order to explain the mechanisms of superparamag-
netism. The rest of the results shall be presented in the upcoming sections.

4.1 Intrinsic Spin Structure and Dynamic Spin Relaxation

Experimental evidence suggests that the simple model used so far does
not cover the true extent of complexity of the spin structure in magnetic
nanoparticles. The unexplained properties are partly believed to arise from
the comparatively large fraction of atoms on the nanoparticle’s surface. At
the surface, the crystal structure gets abruptly interrupted. Consequentially,
this effect weights much more for particles with a large surface to volume
ratio.

One property that is very sensitive to the surface structure is the particle’s
magnetic anisotropy. The anisotropy constant influences the energy barrier
∆E = KV , which in turn changes the relaxation time. While in bulk ma-
terial, magnetocrystalline anisotropy is the deciding factor, in nanoparticles
surface effects come into play and change the overall anisotropy constant K
by up to two orders of magnitude. K shall thus be adapted to incorporate
the diameter D of a particle:
6Ks
K = Kc + (16)
D
with

22
me and coercivity values. In the bulk, is shown in Fig. 6(a) for the biomineral core of ferritin, the
induced magnetocrystalline anisotropy is shown in Fig. protein
6(a) for the biomineral core of ferritin, the
nduced magnetocrystalline anisotropy iron storage where antiferromagnetic ferrihydrite
ce of anisotropy. In small particles, iron storage sequesters
protein where antiferromagnetic ferrihydrite
e ofdueanisotropy. naturally within the interior cavity of a protein
ons to surfaceIneffects
small and
particles,
surface naturally sequesters
ns dueIntomagnetic
surface effects and surface nanotemplate of 7within the interior
nm interior and 12 cavity of a protein
nm exterior diameters
nant. nanoparticles values nanotemplate
ant. In magnetic nanoparticles values [51,52]. Theofthick
7 nm interior
protein and
coat12insures
nm exterior diameters
magnetic isolation
py have been observed up to two orders [51,52].
y compared
have been observed up to two orders of the The thick protein
particles. At 4.2 Kcoat
twoinsures magnetic
magnetic isolation
sites are resolved
to the magnetocrystalline of associated
the particles.
compared to the magnetocrystalline withAtcore
4.2 K two
and magnetic
surface sitesrespectively,
atoms, are resolvedwith
ulk [40,41]. For spherical particles of associated
k [40,41]. Forofspherical particles of differentwith core magnetic
internal and surface atoms, respectively,
hyperfine fields of Hc ∼with
495 kOe
rical formula Eq. (6) [40,42—45] has different of Hc ∼ 495
and Hs internal
∼ 450 kOe,magnetic hyperfine
as measured byfields
the overall kOe of
splitting
eted many experimental results: has
cal formula of Eq. (6) [40,42—45]
and H
ted many experimental results: the sexternal lines of each magnetic subspectrum (Fig. of
∼ 450 kOe, as measured by the overall splitting 6(a)).
the external lines of each magnetic subspectrum (Fig. 6(a)).
(6)
(6)
netocrystalline anisotropy of the core
etocrystalline anisotropy of the core
aracteristic of the material, and Ks
acteristic of the material, and Ks
otropy characteristic of the particle,
ropy characteristic of the particle,
eated as uniaxial. The above equation
ated as uniaxial. The above equation
ditive effectofofthe
tive effect thesurface
surface ignoring
ignoring anyany
nd predicts effective total anisotropies
d predicts effective total anisotropies
reportedininFig.
eported Fig.4 4[43]
[43]forfor small
small metal
metal
rangeofof2—7
ange 2—7nm nmdiameter.
diameter.
sare,
are,thus,
thus,modeled
modeledasastwo-phase
two-phase sys-
sys-
highly
ighly crystalline core surrounded by a a
crystalline core surrounded by (a) (b)
ayer. Vacancies,broken
yer. Vacancies, brokenbondsbonds and and lat-
lat-
faceproduce
ace producenot notonly
onlyatomic
atomic disorder Figure
disorder Figure5 5 (a)(a) Schematic
Schematic representation
representation of aof a spherical
spherical particle
particle
ation whichdestabilizes
destabilizesthe Figure
thecollinear
collinear 9: Figure
with 9(a) shows
uniform a particle
magnetization with uniform
according to the magnetization,
Stoner Wohl- a model
ion which with uniform magnetization according to the Stoner and and
Wohl-
theStoner—Wohlfarth
he Stoner—Wohlfarth model
model which
atat
the the served us
sur- farth
sur- farth up to
model:
model: now
all all
spins quite
spins
arearewell. Figure
collinear
collinear andand 9(b)
rotate
rotate shows (b) particle
a
in unison.
in unison. (b) with
ous cantedspin
us canted spinstructures
structures (Fig.
(Fig. 5).5).
different Thiscore
This Schematic
and surface
Schematic representation of two-phased
magnetization.
representation of two-phased Source particle
withwith
[2].
particle different
different
nstructure
structureisissupported
supportedbybyboth both theo- core
theo- coreandand surface
surface magnetization.
magnetization. Surface
Surface spins
spins are are canted
canted rela-rela-
ntalstudies
ntal studiesininsmall
smallparticle
particle systems, tive
systems, tive
to to
thethe core’s
core’s magnetization
magnetization andand
are are subject
subject to low
to low energy
energy
Consequences
onsequences are reducedMsM
arereduced , lack
, slack of of excitations
excitations (see
(see text).
text).
• Kc : The magnetocrystalline anisotropy constant of the core.

• Ks : The surface anisotropy constant.

The larger a particle, the less important the second factor Ks . Although
this ignores interferences between the anisotropies, it yields quite acceptable
results.

Consequentially, it makes sense to regard the magnetic particles as hav-

ing a crystalline core surrounded by a disordered surface (see figure 9). The
consequences of this model are (among others) [2]:

• Reduced magnetization saturation Ms .

• Lack of magnetic saturation even in large magnetic fields.

• Hysteresis loop shifts in antiferromagnetic nanoparticles.

Mössbauer spectroscopy was successful at proving this newly introduced

model. It uses the Zeeman splitting caused by the internal magnetic field.
Figure 10 shows the results for a measurement of “iron ferrihydrite nanopar-
ticles grown within horse spleen apo-ferritin nanotemplates measured at 4.2
K” [2]. Strong indications for two phase magnetic particles can be seen.

As a side note: This temperature is well below the blocking temperature

TB . In other words, this particle is not in a superparamagnetic state at the
moment, but rather in a blocked state.

Figure 11 shows the temperature dependence of the spectral lines. The

higher the temperature, the more important become the spin reversals,

23
 442

H/H0 , is shown in Fig. 8. Here,

assumed to be the saturation
the interior iron sites of the cor
ature dependence of the reduc
is consistent with the CME mod
described by Eq. (7):
H kT
=1−
H0 2KV

442 A maximum
G.C. of 15% diminution
Papaefthymiou
through this process, before
paramagnetic doublet due to su
H/H0 , is shown in Fig. 8. Here, H = Hhf (T) and H0 = Hhf (4.2 K),
cipitous collapse of the reduc
assumed to be the saturation hyperfine field as T → 0. For
sites observed in Fig. 8 indicat
the interior iron sites of the core of the particle,
surfacethe
spintemper-
excitation modes
ature dependence of the reduced hyperfine magnetic
multi-spin fields
nano-magnet system
is consistent with the CME model of Mørup and Topsøe
introduce spin[55],
canting and a
described by Eq. (7): potential energy landscape at
The temperature at whic
H kT
=1− primarily magnetic(7)(six-line ab
H0 2KV netic (two-line absorption spec
temperature,
A maximum of 15% diminution in hyperfine TB , of the ensem
field is expected
ple. For the sample of Fig. 7,
through this process, before the spectrum collapses to a
40 K, where the absorption a
paramagnetic doublet due to superparamagnetism. The pre-
cipitous collapse of the reduced hyperfine field at surface
sites observed in Fig. 8 indicates the presence of additional
surface spin excitation modes, consistent with theories of
(a) Figure 6 (a) Mössbauer spectra of iron ferrihydrite nanopar-
(b) nano-magnet
multi-spin systems, where surface anisotropies
ticles grown within horse spleen apo-ferritin nanotemplates
introduce spin canting and a greater complexity in the
measured at 4.2 K. Two magnetic subsites are resolved associ-
potential energy(b)
ated with core andspectra
Figure 10: Figure 10(a): “The Mossbauer surface ironof ironlandscape
atoms.
The oftemperature
at the
Core/surface
ferrihydrite
at which
surface [56].
model
the spectra change from
of the iron biomineral core ferritin [Reprinted by permis-
nanoparticles grown within horse spleen apo-ferritin
sion from R.A. Brooks,primarilynanotemplates
magnetic
J. Vymazal, (six-line
R.B. Goldfarb, mea-
absorption
J.W. Bulte, P. spectra) to paramag-
Aisen, Magn.
sured at 4.2 K” [2]. The highly crystalline Res. Med.
core netic
with a(two-line
40 (1998) absorption
227, Ref.
larger [53]]. spectra)
magnetic field determines the blocking
temperature, TB , of the ensemble of particles in the sam-
shows sharper and deeper absorption lines. The ple. amorphous
For the sample surface
of Fig.shows
7, TB is estimated to be about
The iron site with larger magnetic field exhibits sharper
40 K, where
broadened and less deep absorption lines. Figure 10(b): A model accordingthe absorption area of the spectrum is com-
absorption lines indicating a highly crystalline core, while
to the spectra: A large protein shelltheto smaller hyperfine
protect thefield site exhibits
magnetic broadened absorp-
interior. The
tion lines indicating a more disordered or amorphous state
magnetic part consists not only of anatordered the surface.core, but also
A two-phase modelof anferritin
of the amorphous
biomineral
Figure 6 Source:
surface. (a) Mössbauer core depicted
[2] spectra of iron ferrihydrite nanopar-in Fig. 6(b) was originally proposed by Brooks
ticles grown within horse spleen apo-ferritin et al. [53] on the basis of relaxometry measurements.
nanotemplates
measured at 4.2 K. Two magnetic subsites are resolved Fig. 7associ-
shows the full spectral profile of reconstituted
horse spleen
ated with core and surface iron atoms. (b) Core/surface model ferritin in the temperature range from 4.2
of the iron biomineral core of ferritin [Reprinted to 80byK permis-
[54]. As temperature increases above 4.2 K, the
which areR.A.soBrooks,
characteristic spectra broaden due to theAn
forGoldfarb,
superparamagnetism. onsetadditional
of dynamic spin relax-
effect
sion from J. Vymazal, R.B. J.W. Bulte, P.
ation processes prior to full magnetization reversals at
Aisen, reduces
which Magn. Res. Med.
the 40strength
(1998) 227,of
Ref.the
[53]].hyperfine magnetic field, happens well
thermal energies above the superparamagnetic energy bar-
before the field collapses due to superparamagentic rier KV (Fig. 2). Simultaneously,
behaviour. the magnitudes
It is theofef-the
The iron site with larger magnetic field exhibits observed hyperfine fields decrease, prior to their collapse
sharper
fect that the magnetization vector due starts to precess around
to superparamagnetism the easy and
at high temperatures axisthe
absorption lines indicating a highly crystalline core, while
due to rising thermal energy. The appearance
change
the smaller hyperfine field site exhibits broadened absorp- of
from a quadrupole
primarily doublet. The
magnetic reduction
spectrain the
magnitude of the magnetic hyperfine field is due to the
tion lines indicating a more disordered
(six absorption lines) to superparamagnetic or amorphous state
precession ofspectra (twomagnetization
the particle’s absorption lines)
vector about
at the surface. A two-phase model of the ferritin biomineral
is characterized by the already its anisotropy
introduced axis, at temperature
blocking temperatures insufficient
T to
(for induce
the
core depicted in Fig. 6(b) was originally proposed by Brooks B
spin reversals, as proposed by Mørup and Topsøe in their Figure 7 Mössbauer spectra o
et al. [53]
sample in on the basis
figure 11 ofit relaxometry
is aroundmeasurements.
40 k).
collective magnetic excitation (CME) model [55], which tuted horse spleen ferritin at va
Fig. 7 shows the full spectral profile of successfully
reconstituted describes spin dynamics below the blocking (black) through the experiment
horse spleen ferritin in the temperature range from 4.2where the magnetization vector is trapped
temperature, to a superposition of iron subsit
Different
to 80 K [54]. measurement
As temperature techniques orcan
increases above 4.2be
blocked used atosingle
K, the
within determine the The
potential well. blocking
tempera- green, surface sites; red, super
spectra broaden due to the onset of dynamic
ture spin relax-
dependence
temperature T of a specific material. This in turn leads to the material’s of the reduced hyperfine magnetic fields, [54]].
B
ation processes prior to full magnetization reversals at
anisotropy constant
thermal energies K.superparamagnetic
above the A general approach
energy bar- is described in the next few
rier KV (Fig. 2). Simultaneously, the magnitudes of the
steps:
observed hyperfine fields decrease, prior to their collapse
due
1. to
A superparamagnetism
sample is cooled at high temperatures
without and the
any magnetic field. Since the two min-
appearance of a quadrupole doublet. The reduction in the
ima (with
magnitude of the orientations
magnetic hyperfinein opposite
field is due directions)
to the are equally likely to be
precession of the particle’s
populated, the overallmagnetization vector about
magnetization should be zero.
its anisotropy axis, at temperatures insufficient to induce
spin
2. A reversals,
small asmagnetic
proposed byfield
Mørupisand Topsøe insotheir
applied, Figure
that it 7 Mössbauer
is not spectra
sufficient lyophilized, in vitro reconsti-
forofthe
collective magnetic excitation (CME) model [55], which tuted horse spleen ferritin at various temperatures. Solid lines
magnetic
successfully moments
describes to fully
spin dynamics align
below thewith the field.
blocking (black) through the experimental points are least square fits,
temperature, where the magnetization vector is trapped to a superposition of iron subsites: purple, interior core sites;
3. blocked
or Increasing
within the temperature
a single allows
potential well. the magnetic
The tempera- green,moments tored,
surface sites; have more
superparamagnetic sites [from Ref.
ture thermal
dependence of the reduced hyperfine magnetic fields, [54]].
energy and hence get aligned along the external magnetic field.

24
 0 hf 0 hf
assumed to be the saturation hyperfine field as T → 0. For
the interior iron sites of the core of the particle, the temper-
ature dependence of the reduced hyperfine magnetic fields
is consistent with the CME model of Mørup and Topsøe [55],
described by Eq. (7):
H kT
=1− (7)
H0 2KV
A maximum of 15% diminution in hyperfine field is expected
through this process, before the spectrum collapses to a
paramagnetic doublet due to superparamagnetism. The pre-
cipitous collapse of the reduced hyperfine field at surface
sites observed in Fig. 8 indicates the presence of additional
surface spin excitation modes, consistent with theories of
multi-spin nano-magnet systems, where surface anisotropies
introduce spin canting and a greater complexity in the
potential energy landscape at the surface [56].
The temperature at which the spectra change from
primarily magnetic (six-line absorption spectra) to paramag-
netic (two-line absorption spectra) determines the blocking
temperature, TB , of the ensemble of particles in the sam-
ple. For the sample of Fig. 7, TB is estimated to be about
40 K, where the absorption area of the spectrum is com-

(a) Mössbauer spectra of iron ferrihydrite nanopar-

own within horse spleen apo-ferritin nanotemplates
d at 4.2 K. Two magnetic subsites are resolved associ-
h core and surface iron atoms. (b) Core/surface model
ron biomineral core of ferritin [Reprinted by permis-
m R.A. Brooks, J. Vymazal, R.B. Goldfarb, J.W. Bulte, P.
agn. Res. Med. 40 (1998) 227, Ref. [53]].

n site with larger magnetic field exhibits sharper

on lines indicating a highly crystalline core, while
ller hyperfine field site exhibits broadened absorp-
es indicating a more disordered or amorphous state
urface. A two-phase model of the ferritin biomineral
picted in Fig. 6(b) was originally proposed by Brooks
3] on the basis of relaxometry measurements.
7 shows the full spectral profile of reconstituted
pleen ferritin in the temperature range from 4.2
[54]. As temperature increases above 4.2 K, the
broaden due to the onset of dynamic spin relax-
rocesses prior to full magnetization reversals at
energies above the superparamagnetic energy bar-
(Fig. 2). Simultaneously, the magnitudes of the
d hyperfine fields decrease, prior to their collapse
superparamagnetism at high temperatures and the
nce of a quadrupole doublet. The reduction in the
de of the magnetic hyperfine field is due to the
on of the particle’s magnetization vector about
otropy axis, at temperatures insufficient to induce
ersals, as proposed by Mørup and Topsøe in their Figure 7 Mössbauer spectra of lyophilized, in vitro reconsti-
ve magnetic excitation (CME) model [55],11:
Figure which
This tuted
figurehorse spleen the
shows ferritin at various temperatures.
Mössbauer spectra of Solid lines
“lyophilized, in vitro
ully describes spin dynamics below the blocking (black) through the experimental points are least square fits,
reconstituted
ature, where the magnetization vector is trapped horse spleen ferritin at various temperatures”
to a superposition of iron subsites: purple, interior core sites; [2]. Green lines
ked within a single potential well. The tempera-
refer to surface spectral lines, purple to core spectral lines and red to super-
green, surface sites; red, superparamagnetic sites [from Ref.
pendence of the reduced hyperfine magnetic fields, [54]].
paramagnetic site spectral lines. The black line is a superposition of all the
sites. Source: [2].

25
 4. There is a maximal magnetization before the heat introduces random
orientation. This maximum determines the blocking temperature TB .

5. Since this technique was performed within a certain measurement time

τm , another technique with a different τm has to be used in order to
determine the anisotropy constant K and the parameter τ0 .
A quick side note on results obtained from Monte Carlo simulations: Monte
Carlo simulations for γ-Fe2 O3 particles have suggested that surface contri-
butions to the magnetization of particles with 8.3 nm diameter lie around
43%, while the ones for particles with 2.5 nm diameter lie around almost
95%. They also found that different hysteresis loops have to be expected for
the surface compared to the core of the nanoparticle. The differences can be
partly explained through the presence of spin disorder and spin frustrations
at the surface, which makes it easier to reverse a surface spin.

4.2 Applications: Current Trends and Future Directions

On the contrary to the first paper, this paper also includes applications
outside of biomedicine and delves into possible future fields of study:
• Advanced magnetic recording media: They need a well ordered two
dimensional nanoparticle array. One of the difficulties of such media
is to keep them well ordered. As soon as the thermal energy gets too
high, spin reversal becomes an (unwanted) factor, which diminishes
the storage capabilities of the media.

• Magneto-resistive sensors & spin electronics: Spin up-up particles

show a different resistance compared to (for example) spin up-down
particles. Sending currents through these resistances can be used to
detect the spin direction of particles. If the spins can be controlled
well enough, they could be incorporated into existing semiconductor
technology. This would enhance and create new functionalities, not
achievable by today’s electronics.

• Biomedical applications: This field is equally mentioned, but already

well discussed in the previous section dealing with the first paper.

• Very dense spin systems under special conditions may form spin-glass
like phases with very complex energy landscapes. This effect arises
due to ferromagnetic and antiferromagnetic interactions, also known
as spin frustrations. There is a so called spin-glass-freezing tempera-
ture, below which the particles show mentioned characteristics. Addi-
tionally, they change their behaviour, the longer they stay below the
freezing temperature (so called aging). This field promises interesting
findings, but needs further study.

26
References
[1] Q. A. Pankhurst, J. Connolly, S. K. Jones and J- Dobson, Applications
of magnetic nanoparticles in biomedicine, J. Phys. D: Appl. Phys. 36
(2003) R167-R181 (18th of June 2003).

[2] Georgia C. Papaefthymiou, Nanoparticle magnetism, Nano Today

(2009) 4, 438-447 (11th of September 2009).

[3] Wikipedia.org, English Magnetic Anisotropy [Online], 8th of December

2012,

http://en.wikipedia.org/wiki/Superparamagnetism

[4] Wikipedia.org, English Magnetic Anisotropy [Online], 8th of December

2012,

http://en.wikipedia.org/wiki/Magnetic_anisotropy

[5] Wikipedia.org, English Ferrimagnetism [Online], 8th of December

2012,

http://en.wikipedia.org/wiki/Ferrimagnetism

[6] Wikipedia.org, English Antiferromagnetism [Online], 8th of December

2012,

http://en.wikipedia.org/wiki/Antiferromagnetism

27