Physica C 368 (2002) 32–36
www.elsevier.com/locate/physc

Position determine system for lymph node relatingbreast cancer using a high-Tc SQUID
Saburo Tanaka a,*, Hajime Ota a, Yoichi Kondo a, Yasuhiro Tamaki b,
Shinzaburo Noguchi b, Masakatsu Hasegawa ca

Ecological Engineering, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi, Aichi 441-8580, Japanb
Department of Surgical Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine,2-2-E10 Yamadaoka, Suita, Osaka 565-0871, Japanc
Nagoya Research Laboratory, Meito Sangyo Co., Ltd., 25-5 Kaechi Kishibiwajima Nishikasugai, Aichi 452-0067, JapanAbstract
The performance of a lymph-node detection system used with a high-Tc superconducting quantum interference
device was investigated. Ultra-small iron oxide particles containing 360 pg in weight of iron could be detected at a
distance of 1 mm using Helmholtz coils. When a pair of angled ﬁeld coils, which were of a more practical design, wereused this value was increased to 2.8 ng. This value is still large enough to apply the technique for sentinel-node biopsy
and lymphatic mapping. Ó 2001 Elsevier Science B.V. All rights reserved.
Keywords: SQUID; Biopsy; Detection; Lymph node

1. Introduction
We have recently proposed the application ofa high-Tc superconducting quantum interference
device (SQUID) to the newly developed surgical
technique of sentinel lymph-node biopsy. Axillary
lymph-node dissection is an important procedurein the surgical treatment of breast cancer. However, in the early diagnosis stage, the number ofdissections in which axillary nodes are free of
disease is apt to be increased. These treatments
lead to some problems such as a lymph edema anda sensory neuropathy in the patient. The sentinelnode biopsy is a kind of test to investigate whether*Corresponding author. Fax: +81-532-44-6929.
E-mail address: tanakas@eco.tut.ac.jp (S. Tanaka).

the sentinel node, which initially receives malignant cells from a breast carcinoma is disease-freeor not. If the sentinel node is free of disease, you
can leave the rest of the lymph nodes because of noconcern for progression. This biopsy is based on
the hypothesis that if the ﬁrst lymph node (sentinelnode) is free of disease, the second and the rest of
the nodes must be negative. Two methods which
detect the sentinel node have been developed andreported to date [1–3]. One is a kind of radio guide,
which uses a gamma detector and a radio isotope
such as technetium labeled sulfur colloid. Afterinjecting the isotope into a breast lesion, the sentinel lymph node will be identiﬁed by the gamma
detector. Then the sentinel node is excised andexamined. In this method the sentinel lymph nodeis successfully identiﬁed with 94.4% accuracy[1]. Though the predictability of this method is0921-4534/01/$ - see front matter Ó 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 9 2 1 - 4 5 3 4 ( 0 1 ) 0 1 1 3 5 - 2

S. Tanaka et al. / Physica C 368 (2002) 32–3633Fig. 1. The system diagram of the sentinel-node biopsy using high-Tc SQUID, which we are proposing. The particles would be injected
into the breast; and the high-Tc SQUID is used as a sensing detector for the particles. This method has an advantage of no radiation
exposure.

extremely high, radiation exposure is inevitable for
medical staﬀ. The other method uses a blue dye; asurgeon identiﬁes the sentinel lymph node with hisnaked eye. With this method the predictability isstill 70% accurate [2].
Therefore we propose a localization system
combined with a high sensitivity SQUID magnetometer and ultra-small iron oxide particles. Thesystem we are proposing is shown in Fig. 1. The
particles would be injected into the breast; andthe high-Tc SQUID is used as a sensing detector
for the particles. This method has some advantages: no radiation exposure and an accurate identiﬁcation because of the visible color of theparticles themselves. For this application, theSQUID magnetic sensor should identify the location of the small quantity of particles under thesensor. Although a SQUID biosusceptometry
system has been reported [4], it is very diﬃcult
to detect the location because of the small quantity. Detection methods of small magnetic particles
with a SQUID immunoassay, which can be also
applied to our detection system, have been proposed in several groups [5–7]. Even if the particles
are made of iron oxide, if their size becomes toosmall, they show superparamagnetic properties.
Therefore, some magnetic ﬁeld should be applied
to the particles for detection because they havealmost no permanent magnetic dipole at room
temperature. Koetitz et al. applied a pulse ﬁeld tothe particles and then measured the ﬁeld decay
from the particles in the range of ms. Empuku
et al. measured the ﬁeld from the particles undera DC magnetic ﬁeld. For the work described here,
we measured the ﬁeld from the particles under an
AC magnetic ﬁeld.
We have already reported the results of preliminary study using particles dispersed liquid in atube [8].
In this paper, we describe the results of the morepractical system design and the performances.

2. Instrumentation
The schematic diagram of the system is shownin Fig. 2. The SQUID is made of YBa2 Cu3 O7 ythin ﬁlm. The junctions utilized in the SQUID areof the step-edge type. The washer size of theSQUID is about 2:5  2:5 mm2 and the eﬀective
area is 0.11 mm2 . The SQUID was operated in aﬂux-locked loop. The magnetic ﬂux noise in thewhite noise region was about 30 l/0 =Hz1=2 .
The cryostat was specially designed for aSQUID microscope. The SQUID was located inside a vacuum and separated by a 50 lm thickquartz window. A more detailed description can befound elsewhere [9]. Two coils (Helmholtz type)were mounted just above the SQUID microscope[10,11]. A ﬁne polytetraﬂuoroethylene tube with34S. Tanaka et al. / Physica C 368 (2002) 32–36

3. Magnetic particles

Fig. 2. Schematic diagram of the system for the feasibility test.
A pair of coils were mounted just above the SQUID cryostat.
External AC magnetic ﬁeld was applied by the coils. A motor
driven syringe pump was employed to push the magnetic particle sample inside a thin tube. The modulated signal associatedwith the particle motion was demodulated by the lock-in ampliﬁer.

an inner dimension of 0.85–0.95 mm diameter,
which conveys small particles, was threaded
into the coils. A motor driven syringe pump wasemployed to convey the particles by pushing air
inside the tube. A sinusoidal AC current with afrequency of 5–100 Hz was directed to the coils;
the magnetic ﬁeld generated from the coil wasmodulated by the frequency. The modulated signal associated with the particle motion was thendemodulated by the lock-in ampliﬁer. The lock-in
ampliﬁer consists of a phase sensitive detector, aphase shifter and a low-pass ﬁlter [12,13]. The rolloﬀ frequency of the ﬁlter, which sets the bandwidth was 3 Hz. Since the roll oﬀ gives you sensitivity to noise only within 3 Hz of the desired
signal, the signal/noise ratio is improved. However, you cannot sweep the particles faster than 3Hz. The phase shifter was adjusted to give themaximum output signal.
The use of the lock-in ampliﬁer is a crucial
point to obtain a good resolution in the system. In
this scheme, as with signal averaging, the eﬀect ofthe modulation is to center the signal at themodulation frequency, rather than at DC, in orderto get away from 1=f noise, which occurs usuallyin the range from DC to 1 Hz. The SQUID position was carefully adjusted before measurement, sothat the SQUID output signal without particles
became zero.

After adjusting the SQUID, the system wasready to measure magnetic ﬁeld from the particles.
We used ultra-small particles from Meito Sangyo
Co., Ltd. Similar particles are used as a magnetic
resonance imaging contrast agent. The core of theparticle is iron oxide Fe3 O4 (magnetite) which iscoated with an alkali-treated dextran. The averagecore diameter was 11 nm, which was measured
from the X-ray diﬀraction pattern using Scherrer’s
equation [14]. The averaged diameter of the coatedparticles was 100 nm. The particles had superparamagnetic properties. The particles were supplied in the form of an aqueous magnetic ﬂuid.
The original ﬂuid contained 5.9 mg/ml of iron. If
we suppose 5.2 g/cm3 as the speciﬁc gravity of thecore, we can estimate the weight of the monoparticle as 3:6  10 18 g and the total number ofparticles in the original solution as 1:5  1016 ml 1 .
The original ﬂuid was diluted with distilled water
to have the desired concentrations. Then the ﬂuid
was swept in the ﬁne tube with the scan speed of
0.33–1.1 mm/s under an AC magnetic ﬁeld of
9  10 5 to 7  10 4 T (peak-to-peak value).

4. Results and discussion
We performed all of the measurements in amagnetically shielded room with a shielding factorof 50 dB at 0.1 Hz. Fig. 3 shows the typicalFig. 3. Typical output signal from the lock-in ampliﬁer. Eachpositive and negative peak was observed when each edge of theﬂuid specimen passed over the center of the SQUID.

S. Tanaka et al. / Physica C 368 (2002) 32–36

35

output signal of the lock-in ampliﬁer [8]. In a ﬂuid
length of about 8 mm in the tube, the weight of iron
was found to be about 65 lg. In this measurement
the distance from the SQUID to the specimen was
10 mm. Each positive and negative peak was observed when each edge of the ﬂuid specimen passed
over the center of the SQUID. We deﬁne eachdiﬀerence of the negative and positive peaks as theSQUID signal hereafter.
We investigated the detectable weights of theiron. The SQUID signal was proportional to theweight of the iron in the ﬂuid. At a distance of40 mm, the minimum detectable weight was 1.6 lg.
When the distance was decreased to 1 mm, thisdecreased to 360 pg [8].
Then we measured the frequency dependence ofthe output signal. The sample consisted of ironparticles of 2.4 lg and distilled water of 4.4 ll. The
modulation frequency of the Helmholtz coil waschanged from 5 to 100 Hz. The results are shownin Fig. 4 (solid circles). The signal from the lock-in
ampliﬁer decreased with the increase of frequency
in the region of more than 10 Hz. The results
suggested that the alignment of the dipole moments or the rotation of the particles is not synchronized with the frequency. Therefore weimmersed a piece of cotton with the liquid sample.
The content of the iron and the volume of theliquid were as same as the former experiment. In

this sample, the rotation of the particles should be
restricted by existence of the cotton though it was
not perfect. The frequency dependence was measured using this sample. The results were shown inFig. 4 (open circles). The signal was one ordersmaller than that of the liquid sample in all thefrequency; this is because of the restriction of theparticle’s rotation. Although further experiments
are needed to clarify this phenomenon [7], not only
the alignment of the dipole moments but also thephysical rotation of the particles is contributed tothe polarization. Therefore the lower frequency
should be chosen in the system.
We prepared a special pair of external ﬁeld coils
to investigate the practical sensitivity of the system. In an actual system, it is diﬃcult to use thestraight wound Helmholtz conﬁguration shown inFig. 2. Therefore a pair of 1000 turn wound coils
were set with angle of 90° as shown in Fig. 5. Thetube with a liquid sample was located under thecoil and the signal from the sample was measured
by the SQUID under the coils. An AC magnetic
ﬁeld of 2:6  10 4 T was applied to the sample.
The position of the SQUID was carefully adjusted
so that the SQUID output signal without samples
become zero. As shown in Fig. 6, magnetic ﬂux
signal was proportional to the weight of the iron in
the ﬂuid. Particles of 2.8 ng in weight of ironwould be detected with a spacing of 1 mm. This

Fig. 4. Frequency dependence of the output signal. The modulation frequency of the Helmholtz coil was changed from 5 to
100 Hz. Closed circles show the results from liquid sample.
Open circles show the results from liquid with a piece of cotton.

Fig. 5. Schematic drawing of the practical coil design. A pair of1000 turn wound coils was set with angle of 90°. Tube with aﬂuid sample was located under the coil and the signal from thesample was measured by the SQUID under the tube.

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S. Tanaka et al. / Physica C 368 (2002) 32–36

Acknowledgements
This work was partially supported by a Grantin Aid for Science Research (B) from the Ministryof Education, Culture, Sports, Science and Technology.
References

Fig. 6. Magnetic ﬂux vs. mass of iron contained in the sample.
Magnetic ﬂux signal was proportional to the weight of the ironin the ﬂuid. Particles of 2.8 ng in weight of iron would be detected with a spacing of 1 mm.

minimum value is about factor of 8 larger thanthat of weight measured in straight Helmholtz coilconﬁguration.
If 10 mg of Fe is injected into a human body,about 5% of the amount will be concentrated in thelymph node; i.e. Fe of 500 lg will exist at the lymph
node. Therefore the detectable value is large enough to be used in mapping of a sentinel lymphnode.
5. Conclusion
We have demonstrated the possibility of realization of a nanoparticle detection system usedwith a high-Tc SQUID, which is useful for sentinel
lymph-node biopsies. The ultra-small iron oxide
particles of 360 pg in weight of iron could bedetected with a spacing of 1 mm. When a pairof angled ﬁeld coils was used, the value wasincreased and was 2.8 ng. This value is large
enough to apply the technology for sentinel-nodebiopsy and lymphatic mapping. The signal fromthe particles was dependent on the frequency ofthe magnetic ﬁeld. This result suggested that thepolarization is due to not only the alignment of thedipole moments but also the physical rotation ofthe particles.

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