ARTICLE IN PRESS

Journal of Magnetism and Magnetic Materials 270 (2004) 345357

Maghemite nanoparticles with very high AC-losses for

application in RF-magnetic hyperthermia
R. Hergta,*, R. Hiergeista, I. Hilgerb, W.A. Kaiserb, Y. Lapatnikovc,
S. Margelc, U. Richterd
b

a
Institut fur
. Physikalische Hochtechnologie e.V., P.O. Box 100239, Jena D-07702, Germany
Institut fur
. Diagnostische und Interventionelle Radiologie der Friedrich-Schiller-Universitat,
. Forschungszentrum Lobeda
P.O. Box D-07740, Jena, Germany
c
Department of Chemistry, Bar-Ilan University, Ramat Gan 52900, Israel
d
Labor fur
. Elektronenmikroskopie, Weinbergweg 23, Halle/Saale D-06120, Germany

Received 8 May 2003; received in revised form 8 May 2003

Abstract
Maghemite nanoparticles covalently coated with polyethylene glycol are investigated with respect to different loss
processes in magnetic AC-elds. Transmission electron microscopy reveals a narrow size distribution which may be well
approximated by a normal distribution (mean diameter 15.3 nm and distribution width 4.9 nm). Aqueous ferrouids
were characterised by DC-magnetometry, by measuring susceptibility spectra for a frequency range 20 Hz to 1 MHz
and by calorimetric measurements of specic loss power (SLP) at 330 and 410 kHz for eld amplitudes up to 11.7 kA/m.
Extremely high values of SLP in the order of 600 W/g result for 400 kHz and 11 kA/m. In addition to liquid ferrouids
measurements were performed with suspensions in gel in order to elucidate the role of Brownian relaxation. The
measured susceptibility spectra may be well reproduced by a model using a superposition of N!eel and Brown loss
processes under consideration of the observed narrow normal size distribution. In this way the observed very high
specic heating power may be well understood. Results are discussed with respect to further optimisation of SLP for
medical as well as technical RF-heating applications.
r 2003 Elsevier B.V. All rights reserved.
PACS: 75.50.Tt; 75.50.Mm; 75.40.Gb; 75.60.Jk; 75.60.Lr; 87.54.Br
Keywords: Magnetic nanoparticle; Ferrouids; Brown relaxation; N!eel relaxation; AC Losses; Magnetic hyperthermia

1. Introduction
RF-magnetic losses in small magnetic particles
were suggested as heat source for hyperthermia of
*Corresponding author. Magnetics IPHT Jena, Winzerlaer
Str. 10, Jena 07745, Germany. Tel.: +49-364-120-6133; fax:
+49-364-120-6199.
E-mail address: rudolf.hergt@ipht-jena.de (R. Hergt).

cancerous tissue already in the 1950s of the last

century [1]. Meanwhile the method was further
developed by many investigators (for a review see
Refs. [2,3]). However, clinical applications are not
known up to now. As one of the main obstacles
the restricted specic loss power (SLP) of commonly used particle systems may be the reason. In
particular, the heating efciency of available
particles cannot be risen simply by increasing the

0304-8853/$ - see front matter r 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jmmm.2003.09.001

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RF-magnetic eld amplitude H and eld frequency f since in this way inductive heating (i.e.
due to eddy currents) of the healthy tissue would
grow prohibitively high. Upper limits of the
product (fH) for hyperthermia were discussed
already by Brezovich [4]. Besides medical applications, magnetic nanoparticles are also of interest
for technical heating processes, e.g. hardening of
adhesives. Here, demand for high SLP is given by
economical reasons. A summary of experimental
data of SLP reported in literature was given
recently by Andr.a [3]. However, it is difcult to
compare different materials the data of which were
measured for different values of eld amplitude
and frequency, since the dependence on that
parameters may vary considerably for different
loss processes. Losses occurring in magnetic
particles may be roughly differentiated in three
types: hysteresis losses, relaxational losses and
resonance losses (e.g. Ref. [2]). Relaxational losses
being of particular interest for medical applications are divided in two kinds: Ne! el losses [5] due
to reorientation of the magnetic moment in a
particle and Brown losses due to reorientation of
the magnetic particle itself in the uid. In the rst
case the anisotropy barrier, in the second case
viscous friction determines the characteristic relaxation time (for a review see Refs. [6,7]). For
describing the spectrum of the complex susceptibility the Debye model [8] proved useful. Especially, for viscous losses it was shown by magnetooptic investigations which are sensitive to this
relaxation path only, that experimental data may
be well described by Debye proles (e.g. Refs.
[9,10]). Especially for particle systems with high
anisotropy (e.g. CoFe2O4 [9]) Brown relaxation
was well investigated while Ne! el relaxation is
restricted to comparably small particle size in that
case. Contrary, by AC-susceptometry of magnetite
or maghemite involving all relaxation processes
only shallow peaks are commonly found in
susceptibility spectra. Often the imaginary part is
reported to be frequency independent over many
decades. For instance, for magnetite in kerosene a
completely at frequency dependence of the
imaginary part of the susceptibility was reported
which is interpreted by a very broad size distribution [11]. The main reason is that Ne! el relaxation

shows an extremely strong size dependence. As a

consequence, for rather broad lognormal size
distributions being observed for common ferrouids the spectral peaks are very broad. In few
cases clear susceptibility peaks were reported for
iron oxides. Hanson [12] concludes from a relatively
sharp susceptibility peak at about 10 MHz to be
ascribed to Ne! el relaxation that he deals with a
narrow size distribution which, however, was not
investigated by independent methods in that paper.
There was not found any peak due to Brown
relaxation which should be expected at least for a
particle fraction of larger size. In contrast, two
broad peaks in susceptibility spectra were observed
by Fannin et al. [13] which are interpreted by
superposition of Brown and Ne! el relaxation.
Confusingly, in the book of Berkovski [7] these
results are discussed in terms of a bimodal particle
size distribution. In fact, Fannin et al. report a
relatively broad monomode distribution and by
freezing the ferrouid they show that the low
frequency peak has to be ascribed to Brown
relaxation. Later on, investigations were extended
to the GHz range [14] where magnetic resonance is
prevailing. But data were not analysed with respect
to particle size distribution. Understanding of SLP
in nanoparticles was rarely subject of literature till
now (cf. e.g. Ref. [3]). Highest values of SLP till
now are reported by Chan et al. [15]. The data are
discussed qualitatively with respect to some
features of preparation technique. Characterisation is restricted to quasi-static magnetisation
curves; size distributions are not investigated.
From immobilisation experiments using a gel
matrix the authors conclude that Ne! el relaxation
determines the specic loss power. However, they
discuss optimum hydrodynamic diameters of 15
30 nm to be responsible for good heating properties. Recently, the parameter dependence of several
loss processes was discussed with respect to
principal limitations of hyperthermia using ne
magnetic particles [16]. However, the effect of size
distributions on the heating output of ferrouids
was not taken into account till now. In summary,
the dependence of susceptibility spectra on structural parameters (e.g. mean size and size distribution) till now was insufciently investigated and
lack of understanding of SLP data remains.

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In the present paper, experimental results of

SLP measurements for magnetic nanoparticles
with well-dened size distribution will be presented. The data are analysed in the frame of
several loss processes taking into account the
observed narrow size distribution of this ferrouid.
Brown and Ne! el losses are identied. It is shown
that loss spectra may be explained without tting
parameters and that the very high specic heating
power found for this ferrouid may be well
understood. Results are discussed with respect to
further optimisation of SLP for medical as well as
technical RF-heating applications. It is shown that
the estimation given by Charles [7, p. 79] From
the point of view of applications of magnetic
uids, the relaxation mechanism, whether it be
Ne! el or Brownian, is of little consequences
certainly is not valid for heating applications
pursued in the present paper.

2. Preparation and structural properties of

nanoparticles
Aqueous ferrouids with high specic heating
power the properties of which are reported in the
present paper were prepared in the following way
according to [17]. Briey, maghemite (g-Fe2O3)
nanoparticles of narrow size distribution were
prepared by nucleation followed by controlled
growth of maghemite layers onto gelatine nuclei.
These particles were prepared by adding FeCl2
solution (10 mmol/5 ml 0.01 N HCl) to 80 ml aqueous solution containing 200 mg gelatine, followed
by NaNO2 solution (7 mmol/5 ml H2O). After a
reaction time of 10 min NaOH aqueous solution
(1 N) was added up to pH 9.5. This procedure was
repeated four times. The formed magnetic nanoparticles were then washed from excess reagents
using magnetic columns. Dextran coating was
performed by shaking the aqueous suspension of
the magnetic nanoparticles containing 1% dextran
(m.w. 48,000) at 85
C for few hours. The dextran
coated nanoparticles were then washed by means
of magnetic columns. Crosslinking and functionalisation of the nanoparticles was performed by
interacting the dextran coating with divinyl
sulfone. The residual activated double bonds were

347

then used for covalent binding, via Michael

addition reaction, of amino terminated polyethyleneglycol (m.w. 5000) to the nanoparticles. The
aqueous ferrouids are non-toxic, the particles are
biodegradable and have a comparatively large
circulation time after iv-injection. It is a special
advantage of the present preparation procedure
that the particle size may be well controlled by
proper preparation conditions. Modelling the frequency dependence of susceptibility as described
below allowed to tailor a size distribution which is
the precondition for a maximum output of specic
heating power of the present nanoparticles.
X-ray diffraction (XRD) investigations show
that the crystalline cores of the ferrouids consist
nearly completely of maghemite. From X-ray line
broadening one deduces a mean diameter of the
magnetic cores of 15 nm. Imaging of the particles
was performed with a high-voltage transmission
electron microscope (Jeol HVEM 1 MeV). Using a
conventional TEM with lower electron energy
(200 keV) rapid degradation of contrast was
observed due to particle interaction with the
electron beam. An example of images taken with
the HVEM is shown in Fig. 1a. Analysis of particle
diameters reveals that the particle size distribution is very narrow (Fig. 1b). The absence of a
tail of large particles in the size distribution is in
contrast to the generally observed lognormal
distributions of common ferrouids. The size
distribution may be well approximated by a
normal distribution (full line in Fig. 1b). The
mean diameter is 15.3 nm with a distribution width
of 4.9 nm.
Closer inspection of the TEM images shows that
some of the particles are not homogeneous spheres
but appear as being composed of a few closely
packed subgrains. Since XRD data gave the same
mean grain diameter as TEM imaging one has to
conclude that the subgrains are crystallographically coherent with each other. Accordingly the
magnetisation of the particles may be assumed to
be nearly homogeneous (single domain particles) and a small deviation from the spherical
shape may result in a shape anisotropy contribution additional to the crystal magnetic anisotropy.
Particle diameters were determined from analysis of magnetisation curves based on Langevin

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R. Hergt et al. / Journal of Magnetism and Magnetic Materials 270 (2004) 345357

determined from photon correlation spectrometry

(PCS). Since light scattering used in PCS measurements increases with the sixth power of particle
diameter one may argue that larger particles in the
hydrodynamic size distribution may be overestimated by that method while the contrary is valid
for susceptibility measurements.
For the identication of the contribution of
viscous losses to the specic loss power of the
ferrouid a method using the solgel transition
was applied. As described previously [18], the
ferrouid was dispersed in an aqueous solution of
gelatine (sol). By temperature decrease the solgel
transition may be induced which is accompanied
by an increase of the viscosity by many orders of
magnitude. At the same time viscous losses are
eliminated by freezing the Brownian motion of the
particles. The method was already applied by
several authors (e.g. Refs. [13,15,19]). For instance, Bacri et al. [19] measured magneto-optical
relaxation in order to determine elastic moduli of
gel near the solgel transition.

3. Experimental results
3.1. Quasi-static magnetic properties

Fig. 1. (a). Transmission electron micrograph of maghemite

ferrouid. (b) Particle size distribution of maghemite ferrrouid
obtained from TEM data with approximation by a normal
distribution.

modelling, too. The results are in fair agreement

with the data from HVEM as well as XRD as will
be discussed below. A hydrodynamic particle
diameter of 61 nm was estimated for the particles
used in the present experiments from AC-susceptometry (see below). In comparison, 70 nm was

Quasi-static magnetic measurements were performed by a vibrating sample magnetometer.

Magnetisation curves of the ferrouid measured
at room temperature can be well tted with the
Langevin function. From the measured saturation
magnetisation of MSFluid 7:53 kA/m the maghemite concentration of the ferrouid sample which
is important for the heating efciency in alternating magnetic elds was determined to be
1.81 vol.%=0.089 g/cm3 using the saturation magnetisation of bulk maghemite MSBulk 417 kA/m
from literature. Magnetisation curves were analysed with respect to magnetic core diameter in the
frame of the Langevin theory (e.g. Ref. [20]).
0
B
M MSFluid @1 

1
kB T
1C
p 3 H A:
m0 MSBulk dCore
6

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From tting the experimental results close to

saturation according to
p 3
MSFluid kB T
1
dCore
1a
6
MSBulk m0 dM=d1=H
one get a mean core diameter of 10 nm. This value
may be ascribed to small diameter fractions of the
particle distribution considering that the saturation behaviour of the particle system is determined
mainly by its smaller members.
From dc initial susceptibility wdc 1:23 (SI
units) and Langevin theory one has
s
3
3kB T
3
dCore 2
2
w
4p m0 MSBulk MSFluid DC
which results in a mean core diameter of 19 nm.
Ascribing this value to a larger diameter fraction
and averaging with the result from saturation
behaviour we get a mean diameter of 14.5 nm in
fair accordance with the results of the structural
characterisation methods TEM and XRD.
Magnetisation loops measured with a vibrating
sample magnetometer at room temperature show a
rather low coercivity of 0.061 kA/m for the asprepared ferrouids. The observed hysteresis is
caused by a small fraction of particles with large
diameter as far as their relaxation time is larger
than the characteristic time of measurement.
Immobilisation of the particles in a gel, as
described above, results in an increase of the
coercivity up to 0.088 kA/m compared to
0.061 kA/m of the original ferrouid. Since for
immobilised particles the relaxation path via
Brownian rotation is not available the reversal of
magnetisation may occur only by Ne! el relaxation
which is for large particles much slower than
Brown relaxation which results in an increase of
coercivity.
3.2. AC-susceptibility spectra
In order to investigate the response of the
magnetic particle system in a magnetic AC-eld
over a wide frequency range susceptibility spectra
were measured for frequencies of 20 Hz up to
1 MHz by a method using two pick-up coils with
identical geometric data and identical number of
windings. The two pick-up coils were xed into an

349

external solenoid that was driven by the oscillating

current of a RF-generator so that identical
voltages were induced in both pick-up coils. For
frequency-dependent susceptibility measurements
the sample container was inserted into one of the
two pick-up coils and the voltage difference
between both pick-up coils was measured by use
of a lock-in amplier. The real and the imaginary
part of the complex susceptibility was calculated
from the in-phase component and the 90
phase
shifted component, respectively, of the differential
voltage signal with respect to the phase of the
current owing through the external solenoid by
additional considering the geometric data of the
sample vessel, the number of windings of the pickup coils and the amplitude of the oscillating
magnetic eld. Typical spectra of both the real
and the imaginary part of the susceptibility of the
maghemite particles are shown in Fig. 2.
Since the susceptibility spectrum contains contributions due to different relaxation phenomena
we have eliminated Brown relaxation by immobilisation of the particles in gel as described above. A
comparison of the susceptibility data in liquid
state and dispersed in gel (Fig. 2) reveals that the
maximum of the imaginary part (w) of the
original ferrouid situated at about 2 kHz to be
ascribed to Brownian relaxation of the particles in
the liquid is absent in the case of suspension in gel.
The Brownian relaxation time of ferrouids is
related to the hydrodynamic particle volume Vh
according to (e.g. Ref. [8])
tBrown D

3ZVh
:
kB T

Using the viscosity of water (Z 1:01

103 kgm1 s1) one gets from the maximum
position at f 1=2ptBrown 1820 Hz a mean
hydrodynamic particle diameter dh of 61 nm. This
value is in fair accordance with the mean hydrodynamic diameter of 70 nm derived from PCS
measurements.
For presentation of experimental susceptibility
data often ColeCole (CC) plots are used in
literature (e.g. Refs. [6,7,13]). There, the imaginary
part of the susceptibility is plotted versus the real
part with frequency as parameter. It was shown by
several authors (e.g. Refs. [9,10]) in studies of

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350

/ Volume concentration Fe2 O3

100

80

(a)
60

(c)
40

20

(b)
(d)

0
100

1k

10k

100k

1M

f (Hz)
Fig. 2. Spectra of the specic susceptibility, real- (a) and
imaginary part (b) for the original ferrouid and real- (c) and
imaginary part (d) of the suspension in gel.

Brown relaxation by means of magneto-optical

birefringence that in this case the CC data plot
may be well approximated by a half circle which
corresponds to a susceptibility spectrum of the
Debye model. Since magneto-optical effects in
ferrouids are mainly related to the Brownian
motion of particles, other relaxation processes (e.g.
Neel relaxation) are not detected by this method.
In the case of pure Brown relaxation the inuence
of the size distribution on the relatively broad
Debye line prole is rather weak. Accordingly, the
spectra are not very sensitive to changes of size
distribution and various authors using samples of
presumably different size distributions found half
circles as CC plot.
In our case, the CC plot shown in Fig. 3 for the
experimental data of Fig. 2 deviates strongly from
the simple half circle appearance. The occurrence
of both, Ne! el and Brown relaxation for the
original ferrouid has the consequence that only
the low frequency data in Fig. 3 being related to
Brownian relaxation may be approximated by a

circle segment. Deviations from that circle segment

at higher frequencies are due to the superposition
of Ne! el relaxation. This contribution due to Ne! el
relaxation is reected in the CC plot for immobilised particles shown in Fig. 3 too. The measurement points cover only part of the expected circle
segment since the dispersion region due to Ne! el
processes extents to larger frequencies beyond the
present range of measurements. Besides, the
extremely strong size dependence of Ne! el relaxation causes considerable broadening of Debye lines
which is reected in CC plots as considerable
attening of circular segments. Experimental data
in literature, e.g. measured with AC-susceptometry
for aqueous suspensions of magnetite are commonly approximated by rather at circular arcs
[6,13] or half-ellipses [13] which may be related to
special types of distribution of relaxation times
(e.g. Ref. [7, p. 290]). Instead of those procedures,
we have reconstructed the Brownian relaxation
part in the CC-plot by separating the Nee! l
contribution measured separately in gel from the
susceptibility spectrum of the original ferrouid.
The calculation has shown that one has to take
into account the following: In liquid suspensions
alignment of the magnetic particle axes may be
assumed as supposed in the Debye model. In
contrast, for the preparation conditions of the
particle dispersion in gel described above, one has
to expect a random distribution of the axes in the
gel sample. This implies that in the case of the gel
the measured susceptibility is smaller than expected for the Debye model by a numerical factor.
The corresponding factor for the gel may be 3 at
most. It may be smaller than 3 due to not
completely random axes orientation in the gel or
due to dipolar interactions or non-uniaxial anisotropy contributions which was not investigated in
further detail. Using a factor 3/2 for the gel
contribution we get reasonable results as shown in
Fig. 3. The Brownian contribution separated in
this way shows nearly a half circle in accordance
with the Debye model. However, because of
uncertainties in separating effects due to different
relaxation paths and due to size distribution we
prefer instead of the CC analysis to calculate the
susceptibility spectra directly from the measured
size distribution as described in Section 4.

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40

/ Volume concentration
Fe O

R. Hergt et al. / Journal of Magnetism and Magnetic Materials 270 (2004) 345357

20

10k
100k

1k

1M

100

0
20

40

60

80

100

/ Volume concentration Fe2 O3

Fig. 3. ColeCole plot of maghemite ferrouid (full symbols) and of particles immobilised in gel multiplied by a factor of 3/2 (open
symbols) as well as the separated Brownian contribution (small dots, for details see text).

The specic loss power of the present ferrouid

in an alternating magnetic eld was measured
calorimetrically by registration of the temperature
increase in the ferrouid after applying the ACeld under dened conditions as described previously [18]. Using the known heat capacity of the
setup the heating power was calculated. Measurements were performed at two frequencies (327 and
410 kHz) in dependence on AC-eld amplitude up
to 11.7 kA/m. The heating efciency of the present
ferrouid exceeds by far what is reported in
literatureto our knowledgeunder comparable
conditions. For instance, for a frequency of
410 kHz and eld amplitude of 11.2 kA/m, which
are typical values of biological experiments performed recently by our group (e.g. Refs. [2,21,22])
the present ferrouid delivers a specic loss power
of 600 W/g.
The eld amplitude dependence follows a square
law as may be deduced from the experimental
results shown in Fig. 4. From this observation one
may conclude that the linear response theory
may be applied and that the loss power density p
in [W/g] may be derived from susceptibility data
according to (see e.g. Ref. [23])
pf

m0 H 2 2pf w* 00
2
r

(r 4:6 g/cm3 is the mass density of maghemite

[24]). However, calculations by means of Eq. (4)
result in lower values of the specic loss power
differing at about a factor 2/3 from the experi-

Specific loss power (W/g)

800

3.3. Specific loss power

600

400

200

10

12

H (kA/m)
Fig. 4. Calorimetrically measured specic loss power vs. eld
amplitude for the case of 327 kHz (open symbols) and 410 kHz
(full symbols) with tting curves (full line: 410 kHz, dashed line:
327 kHz) demonstrating the H 2 dependence of the specic loss
power.

mental results of calorimetrical measurements.

This may be due to that eld amplitude is only
in the order of 0.1 kA/m for AC-susceptometry
and amounts to a few kA/m for calorimetrical
measurements. Further experiments regarding the
amplitude dependence of the susceptibility may

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Specific loss power (W/g)

352

4. Discussion

1k

100

For achieving a quantitative understanding of

the above reported experimental results we consider the effect of the measured particle size
distribution on the magnetic relaxation of the
present particle ensemble. Neglecting particle
interactions we assume in the usual way that there
are two paths of relaxation: reorientation of the
magnetic moment across an effective anisotropy
barrier within each particle (Ne! el relaxation) and
reorientation of a particle itself against the viscous
friction within the uid (Brown relaxation). For
the relaxation times we take for the case of Brown
relaxation Eq. (3) and for the case of Ne! el
relaxation

KV
tN t0 exp
;
5
kB T

(a)

10

0.1

(b)

-0.01

0.001
100

1k

10k

100k

1M

f (Hz)
Fig. 5. Frequency dependence of specic loss power deduced
from the measured imaginary part of susceptibility for original
ferrouid (a) and suspension in gel (b) for a eld amplitude of
11.2 kA/m.

elucidate this problem. The frequency dependence

of the loss power density derived according to
Eq. (4) from the measured susceptibility spectra is
shown in Fig. 5 for the original ferrouid and the
suspension in gel. There, the experimental susceptibility data of gel were multiplied by factor 3/2 in
order to take into account particle orientation
effects as discussed above for the CC plot.
At medium frequencies (say 110 kHz) the
original liquid suspension shows considerably
higher loss power than particles being immobilised
by dispersion in gel. This extra contribution to
losses obviously is related to Brownian relaxation.
This may have practical consequences for planning
hyperthermia therapy runs. One has to take into
account that a considerable decrease of SLP may
occur if nanoparticle immobilisation (e.g. on cell
membranes) may be expected in dependence on
frequency. That difference depends on the orientation distribution of the immobilised particles in
comparison to the liquid as discussed above.

where t0 109 s; kB is the Boltzmann constant, T

is temperature (i.e. 300 K in the present case), V
p dc3 =6 is the volume of the magnetic particle core,
K is the magnetic anisotropy energy density. The
crystalline magnetic anisotropy of maghemite has
a rather low value of 4.6 kJ/m3 [24]. Additionally,
we take into account an anisotropy contribution
due to a possible prolate elliptical particle shape.
Assuming a contribution of shape anisotropy of
3.5 kJ/m3 (which corresponds to an axis ratio of
about 1.1) an effective anisotropy of about 8 kJ/m3
results. Besides Eq. (5) we have considered similar
expressions given in Ref. [25], too, but there are only
minor consequences for the results reported below.
Qualitatively, Ne! el relaxation occurs for smaller
particle size while for larger particle size Brown
relaxation is prevailing. The transition appears for
a characteristic value dt of the particle core size
where tN tB tt : Assuming a relation dH 3dC
between core diameter dC and hydrodynamic
diameter dH one get from Eqs. (3) to (5) for the
present particles dt 23 nm and 2ptt 5  104 s:
Comparing this with the measured particle size
distribution, it may be seen, that at least for a large
particle fraction Ne! el relaxation is essentially and
accordingly both relaxation processes have to
included into analysis of the present ferrouid.
The problem of competing relaxation mechanisms
was treated by Shliomis and Stepanov [25] in the

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x
;
1 x2
m M2 V
w0 0 SBulk :
akB T
w00D d; f w0

f
;
nd
6

In the expression of w0 we have included a factor

a which depends on KV =kB T (cf. Ref. [20]) and is
expected in the range of 13. The results shown
below were calculated with a 2:2:
For analytically describing the experimental size
distribution a normal distribution fN (Eq. (7)) is
used with the mean diameter dm 15:3 nm and the
distribution width s 4:9 nm.


1
d  dm 2
fN d p exp
:
7
2s2
2ps
This size distribution used for tting the experimental data shown in Fig. 1b is a distribution of
number fractions normalised to the sum of
particles count. It has to be converted into a
distribution of volume fractions being normalised
to the sum volume. Accordingly, calculation of the
susceptibility spectrum is done by weighting with
the size distribution function fN according to
Z
1
00
* f f d d*3 dd:
*
w00D d;
w f R
N
* d*3 dd*
fN d
8

assumes alignment of particle axis with the applied

eld direction while in the experiments nearly a
random distribution of anisotropy axes of the
particles may be expected. Using the same
correction factor discussed already for the data
evaluation of the CC-plot (Fig. 3) a good data
approximation is achieved. The calculated spectra
of the imaginary part of the susceptibility for the
original ferrouid and for particles immobilised in
gel are compared with experimental results in
Fig. 6.
Considering that essential tting parameters are
not used, the description of the experimental
spectra is very satisfying. In particular, comparison of the results for uid and gel suspensions
shows that the experimental peak of w00 at a few
kHz is mainly due to Brown relaxation of larger
particles. In the case of particle suspension in gel
Ne! el relaxation causes a broad susceptibility peak
the maximum of which is found theoretically at
about 200 kHz. Besides, at very low frequencies

24

" / Volume concentration Fe2 O3

frame of their Egg model. Here, for simplicity

we assume that the relaxation frequency n 1=2pt
of the particle ensemble is given by n nN nB :
The ferromagnetic resonance region is not taken
into account since the corresponding frequencies
are beyond the frequency range being of interest
for hyperthermia. We assume the susceptibility
spectrum to consist of Debye proles the validity
of which was proved by several authors (e.g.
Refs. [9,10]) at least for Brown relaxation. Since
we are interested in the specic loss power we
consider only the dependence of the imaginary
part of the susceptibility on the external eld
frequency f to be described according to

20

Fluid
16

12

Immobilized
Particles

0
100

For modelling of the spectrum measured for

particles immobilised in gel we use the same
procedure but assuming for the viscosity a value
Z 105 Pa s. In that case of immobilised particles
it was taken into account that the used Ne! el model

353

1k

10k

100k

1M

f (Hz)
Fig. 6. Calculated spectra of the imaginary part of the specic
susceptibility for the original ferrouid (full line) and for
particles immobilised in gel (dashed line) compared with
experimental results (open and full data points).

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R. Hergt et al. / Journal of Magnetism and Magnetic Materials 270 (2004) 345357

354

the susceptibility of liquid suspension is lower than

that of gel suspension.
The imaginary part of the susceptibility was
used to calculate the specic loss power according
to Eq. (4) for a magnetic eld amplitude of
H 11:2 kA/m which is a value being technically
suitable for hyperthermia. Results of the calculations for liquid and gel suspensions are compared
in Fig. 7.
The main features of the frequency dependence
of the SLP for liquid and solid suspensions are
qualitatively good reected by the theoretical
calculations in comparison to the experimental
data. Notably, the excess of SLP of gel compared
to liquid suspension found experimentally below
about 55 Hz (Fig. 5) is qualitatively conrmed by
the theoretical model. In the liquid suspension SLP
increases with the square of frequency in the
Brown regime below 1 kHz and changes above a
transition region into a linear dependence in the
frequency range of the Ne! el regime. Above the
Ne! el peak a saturation value of 50 kW/g of losses

Specific loss power (W/g)

10k

1k

100

(a)
10

(b)
0.1

0.01

0.001

0.0001
100

1k

10k

100k

1M

10M

f (Hz)
Fig. 7. Calculated frequency dependence of specic loss power
for the original ferrouid (a) and for particles immobilised in
gel (b) for a eld amplitude of 11.2 kA/m.

is found theoretically at about 1 GHz. However,

one has to keep in mind that the applied model
becomes invalid for such frequencies since the
there occurring ferromagnetic resonance is not
taken into account in the present calculations.
Experimental results of Fannin et al. [14] show
that for magnetite a considerable maximum of
losses appear near 1 GHz.
Considering the practical goal of the present
investigations the question arises how useful is an
enhancement of AC-eld frequency in order to
achieve an increase of loss power. In the case of
hyperthermia, we assume for avoidance of inductive heating of the tissue a limit of Hf o3  109 A/
(m s) (suitable for breast tumor treatment). Then,
a eld amplitude of 10 kA/m would allow a
maximum frequency of 300 kHz. Further increase
of the frequency combined with a reduction of the
eld amplitude is not useful since SLP increases
above 300 kHz not stronger than linear with
frequency compared to a square dependence of
SLP on eld amplitude. Contrary, a reduction of
frequency in favour of a higher amplitude would
bring an increase of SLP as long as SLP grows
weaker than square with frequency. However, one
has to keep in mind that the square dependence of
SLP on eld amplitude according to Eq. (4) which
was proved by the data of Fig. 4 at least up to
11 kA/m may be expected to change into weaker
dependence at higher eld. So, a remarkable
increase of SLP for hyperthermia under the
constraint of the eddy current limitation may not
be expected for the present ferrouid. For
technical applications one has to consider that in
generator technique an enhancement of frequency
in general has to be paid with a reduction of eld
amplitude for economical reasons. The AC-eld
parameters have to be chosen according to the
allowable energy consumption considering the
above reported parameter dependencies of
the SLP. It should be pointed out that the size
distribution of the present ferrouid is nearly
optimal for the AC-eld parameters used in our
previous biological experiments [21,22]. Further
reduction of the distribution width which would
result in an increase of SLP seems to be hardly
achievable at present. For changing the AC-eld
parameters a suitable change of particle size

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R. Hergt et al. / Journal of Magnetism and Magnetic Materials 270 (2004) 345357

the particle ensemble. Moreover, using the above

presented model considerations one may argue on
possibilities for further enhancement of specic
loss power the necessity of which is evident for
various heating applications. In particular, in the
case of hyperthermia an enhancement of SLP
allows for reduction of the ferrouid dose in the
case of intratumoral application of massive
tumours. For smaller tumours, it was shown
previously by modelling of the heat conductivity
problem for a ferrouid enriched tumour that the
achievable temperature increase depends strongly
on the tumour diameter [16,28]. Using those
results the amount of ferrouid concentration in
the tissue needed to achieve a temperature increase
of 10 K for a nearly spherical tumor was calculated
in dependence on tumor radius. Fig. 8 shows the
theoretical results for three ferrouids differing in
SLP by three orders of magnitude. Considering
that a tissue concentration of more than 0.1 g/cm3
ferrrouid hardly may be achievable it follows
from the data of Fig. 8 that common ferrouids
with a SLP of 50 W/g are suitable for application
of tumours not smaller than about 4 mm diameter.
In the case of the present ferrouid this critical size
is reduced to about 1 mm tumor diameter. On the
other hand, for the treatment of larger tissue

1
3

Concentration (g/cm )

parameters according to the presently reported

theoretical guidelines would be advisable to gain
maximum output power.
The present results show, that remarkable excess
power density for liquid suspensions compared to
solid ones occurs due to viscous losses in the
frequency range 0.220 kHz. In this frequency
range particle immobilisation (e.g. by sticking at
membranes) would lead to a reduction of the
amount of loss power being available for therapeutical means. In previous biological experiments with various ferrouids it was shown by
TEM investigations that a particle sticking on cell
membranes may occur [26]. In literature, particle
immobilisation for binding processes on immunoassays was detected by relaxation measurements
[27]. The present results show that the role of
Brown relaxation has to be carefully checked for
biological applications.
For technical heating applications knowledge of
the viscosity inuence on the SLP of the particular
ferrouid under consideration is essentially, too.
For instance, for polymeric adhesives a decline of
heating power with hardening due to elimination
of the Brown contribution to the SLP would be
highly desirable in order to avoid overheating by a
suitable limitation automatism.
Comparing the calorimetrically determined specic loss power of the present ferrouid with data
from literature shows the very high performance of
the present material. Literature data were compiled recently by Andr.a [3]. There, a certain
normalisation using the above cited criteria of
Brezovich [4] was applied in order to compare the
data measured by different authors with different
AC-eld parameters. Data for common ferrouids
are in the order of 100 W per g iron oxide. Highest
values are due to Chan et al. [15] who report for
dextran coated maghemite values up to 500 W/g
for a eld amplitude of 8 kA/m and a frequency of
1 MHz.For explanation of their high SLP data
Chan et al. state merely a peculiar spatial
organisation of magnetic grains without giving
data of the size distribution [15]. The above
reported investigations have shown that the
present high values of SLP may be well understood
in terms of the known relaxation mechanism by
taking into account the actual size distribution of

355

-1

(a)

10

(b)
-2

10

(c)

-3

10

-4

10

10-5

10

Tumor radius (mm)

Fig. 8. Ferrouid concentration needed for temperature
enhancement of 10 K in dependence on tumour radius for
specic loss power of 50 (a), 500 (b) and 5000 W/g (c).

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356

R. Hergt et al. / Journal of Magnetism and Magnetic Materials 270 (2004) 345357

regions, say 20 mm diameter, the ferrouid concentration of the tissue may be reduced below
103 g/cm3 with the present ferrouid. A lower
concentration offers the possibility to use methods
of ferrouid application being more subtle than
intratumoral injection, e.g. using targeted blood
transport. Further increase of SLP by optimised
particle systems could open the route to antigen
mediated targeting.
However, the above considerations also make
clear that a signicant heating effect for isolated
particle lled tumor cells situated within normal
tissue is negligibly small. Accordingly, as already
stated by Rabin [29] it is completely illusional to
expect any benecial effect of the type of intracellular hyperthermia claimed by Jordan et al. [30].

5. Conclusions
The present investigations have shown that
special aqueous suspensions of polyethylene glycol
coated maghemite exhibit excellent magnetic
properties under the inuence of AC-elds. The
special geometric-structural properties of the
nanoparticles, i.e. size distributions of magnetic
core and hydrodynamic diameter lead to susceptibility spectra which guarantee the specic loss
power of the ferrouid essentially exceeding
comparable data of ferrouids published so far
in literature. The loss spectra may be well understood on the base of a superposition of Ne! el and
Brown relaxational processes taking into account
the actual particle size distribution. The special
frequency dependence of the imaginary part of the
susceptibility allows for an optimum choice of the
AC-eld frequency and amplitude under consideration of hyperthermia typical constraints. The
presented analysis of AC-eld properties of
nanoparticle systems represents a basis for tailoring of ferrouids with respect to enhanced heat
output for bio-medical as well as technical heating
applications. So, essential reduction of the effective ferrouid dosage and accordingly more subtle
targeting methods may be achievable. In summary, superior ferrouids for hyperthermia or
thermoablation as well as technical heating problems may be anticipated.

Acknowledgements
The present work was funded by the Deutsche
Forschungsgemeinschaft under contract number
HE 2878/9-2 and HI 698/3-2.

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