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2016 IEEE International Conference on Robotics and Automation (ICRA)

Stockholm, Sweden, May 16-21, 2016

Development of a 3D-Magnetic Tweezer System Having Magnetic


Pole Positioning Mechanism
Daisuke Matsuura, Hitoshi Aoki and Yukio Takeda

Since the magnetomotive force is always only attractive,


Abstract— This paper discusses the design and


implementation of a three dimensional magnetic tweezer system driving currents for multiple poles should be carefully
to achieve measurement of mechanical properties of living cells controlled in those systems so that the summation of the
by touching a magnetically levitated micro probe to specimen magnetic field diverged from each pole generates the desired
cells. The system consists of a three dimensional magnetic field gradient. However, there are many problems to satisfy
tweezer, an inverted optical microscope for 3D probe position this requirements in practical apparatus such as non-linearly of
measurement, and control/interface software. For reducing the magnetic field, hysteresis of magnetization etc. Although
assembly error in the magnetic tweezer and accurate decreasing the gap distance between a probe particle and each
adjustment of the gap distance between sextuple magnetic poles magnetic pole tip is necessary to achieve strong
that are sharpen-tipped permalloy rods having a driving coil on magnetomotive force exertion, it is difficult because the effect
each, a pole positioning mechanism was implemented in the
of the above error factors becomes especially significant in
magnetic tweezer. Finally, two experiments were performed on
the fabricated prototype: trajectory tracking in which a
such case. Precise development of prototype apparatus and
magnetic particle of 4.5μm diameter floating in medium was mathematical modeling is therefore required to solve this
steered to follow target trajectories, and homogeneity evaluation problem and to achieve enough strength force of several
that compared force generation from each magnetic pole. hundred pico-newton for practical use. Our research team has
developed a prototype 3D-MT based on a sextuple pole
I. INTRODUCTION system, and has successfully achieved 3D-position control of
For research and development in the fields of medical and spherical probes of 4.5μm diameter[12] in pure water. However,
bioengineering, evaluation of live cell specimens’ mechanical accurate force control has not yet succeeded due to the
and rheological properties is very important. To establish difficulty of force estimation.
effective measurement of these properties, precision probing In order to investigate the effect of error factors to
system capable of exerting desired force at a precise location establish a precise model construction and successfully
on/in a target cell becomes a key technology. For such probing implement accurate force control while achieving high force
system, there are two measure requirements in addition to the strength, nonlinearity of the magnetic field can be taken into
capability of precise manipulation; (1) exertion of arbitrary account. From the point of view of implementation,
directional force of several tenth or hundreds pico-Newton positioning accuracy of the magnetic poles is important to
amplitude, and (2) capability for continuing experiments experimentally reveal the effect of misalignment and change
during a few days or weeks. For such a purpose, there are three of the magnetic field with respect to the change of the gap
different kinds of methods available[1]; photonic force distance between the poles. In this paper, the authors therefore
microscopy (PFM), atomic force microscopy (AFM) and developed a new 3D-MT system having a pole positioning
magnetic tweezers (MT). The advantages and disadvantages mechanism and other essential components. In the following
of the above three methods are summarized as shown in table sections, design and implementation of the important
1. In short, it can be said that MT is especially suitable for
intracellular experiments and lengthy experiments due to the
TABLE 1 COMPARISONS OF THREE METHODS FOR BIO CELLULAR MANIPULATION
transparency and harmlessness of magnetomotive force
against living organisms. Although utilization of the AFM PFM MT
magnetomotive force has a long history[2] because of the
1pN – 100pN
above advantages, application of MTs has been limited mainly Force strength 100pN - 1nN 1pN – 100pN
(Obj.).
to static magnetic fields with a single magnetic pole[3]-[7].
Several 10nm Down to sub μm Down to sub μm
Spatial
To achieve multiple degrees-of-freedom probe steering, resolution
(cantilever tip (probe particle (probe particle
multiple degrees-of-freedom magnetic manipulation systems radius) diameter) diameter)

with three- or four magnetic poles has also been proposed[8]-[11]. force exertion
Downward only Arbitrary Arbitrary
direction

D. Matsuura is with Department of Mechanical Sciences and Engineering, Hazard for Heating by
Tip contamination None
Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo bio-specimen trapping laser
152-8552 Japan (corresponding author to provide phone and Fax:
Capability of
+81-3-5734-2177; e-mail: matsuura@mech.titech.ac.jp). N.A. N.A. Available
intra-cellular
H. Aoki is with Department of Mechanical Sciences and Engineering, probe steering
Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo
152-8552 Japan (e-mail: aoki.h.ai@m.titech.ac.jp). Fine spatial Transparency &
Ease of particle
Y. Takeda is with Department of Mechanical Sciences and Engineering, Advantage resolution and non-harmfulness of
trapping
Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo high force strength magnetic force
152-8552 Japan (e-mail: takeda@mech.titech.ac.jp).

978-1-4673-8026-3/16/$31.00 ©2016 IEEE 1745


components and the results of 3D-probe steering experiments
to evaluate the fabricated prototype will be shown.
Current
amplifier ×6
II. MODEL ANALYSIS OF THE 3D-MT Target
Position/Force

Fig. 1 illustrates the composition of the sextuple 3D-MT Inverse


system. The workspace of the system is a spherical volume of model analysis
several hundred micro meters diameter in which a magnetic Target
probe is included, and is surrounded by six sharpen-tipped Current

magnetic poles having actuation coils and connected to each DAC


other by a yoke ring. By exerting drive current on each coil, (#1-6)
magnetic field gradient in the working space is generated. Probe

Since the magnetization of the probe is dominated by the field


position

gradient in the working space, noncontact magnetic force DAC Piezo


(#7) driver
exertion can be achieved by controlling the driving current.
A mathematical model of this actuation system can be
Image
constructed by using a closed loop magnetic circuit shown in Grabing,Processing

Fig. 2. Since the modeling scheme has already been proposed


by Zhang et al. [11], derivation of the direct and inverse model Figure 1. Composition of the 3D magnetic tweezer system
will be briefly explained. In the expression below, a
coordinate system having each two magnetic charges on its
x,y and z axis as shown in Fig.3(a) will be used.
Transformation between the two coordinate, actuation and
measurement coordinate frames, shown in Fig.3(b) is easily
done by using a rotation matrix.
First of all, a magnetic flux due to an a driving coil
excitation is diverged strongly in the air among the workspace
from the sharp tip of the pole, each magnetic pole can be
represented by a lumped magnetic charge, surrounding a
workspace at a same distance h from the center. In the figure,
Fj NcIj [j=1,2,...,6] is the magnetomotive force generated by a
coil with Nc turns and a current I. The force is diverged into the
workspace through the circuit including Ry, Rp and Ra , that are
representing the reluctance of yoke, magnetic pole, and air
among workspace respectively. By considering Hopkinson’s Figure 2. Schematic drawing of the sextuple 3D-MT system
law, which is equivalent to Ohm’s law for electric circuit,
magnetic flux  is described as

1,..., 6 T  Φ  Nc K I I (1)
Ra

where I = [i1,...,i6]T is an input current vector, and KI is a


distribution matrix of magnetic flux, satisfying the constraint
that the net magnetic flux is always zero, determined by (a) Actuation frame (b) Measurement frame
Gauss’s law for magnetism. Since a magnetic charge is
Figure 3. Coordinate transformation between two frames
defined as q=0, magnetic charge and input current
relationship can be written as
Nc 3V     0  (4)
Q  q1 q2  q6  
T
KI I . (2) m  B ,
0 Ra  0    2 0 

By using superposition principle, a magnetic field where  and V are permeability and volume of the particle,
generated by the six magnetic charges can be written as respectively, and the magnetic force due to this magnetization
is written as
6 qj
B   km 2
uj , (3) written as
j 1 rj
1 3V    0 
where km = μ0/4π = 1.0×107 [N/A2], rj and uj are the distance F m  B    B  B   k Q FQ , (5)
2 2 0    2 o 
between the j-th charge and the particle, and its directional
unit vector. Since a magnetization of a particle is proportional The above equation can be written in quadratic form as
to the external magnetic field, it can be written as

1746
 u j uk  Namely, an approximate solution of eq. (13) is written as
5 6 6
FQ  B  B    q k  2 2   Q T LQ , (6)
km
2  rˆ rˆ  ( Fˆcx , Fˆcy , Fˆcz )  ( Fˆx  8 x, Fˆ y  8 y, Fˆz  32 z ) . (14)
j 1 k 1
 j k 

where rˆ  r / h is a normalized distance. By substituting eq. From eqs. (10) and (14), linearized inverse model is finally
(2) in eq. (6), the direct model in quadratic form is obtained as obtained as
2  3  Fˆ  8 x 4  3  Fˆ  8 x 4 
 N   Iˆ1   x   Iˆ2    x  
F  kQ  c  I T K I LK I I
T
 4 6 9 4 6 9
  0 Ra   . (15)
, (7) ˆ 3 y  ˆ
F  8 y 4  3  ˆ
F  8 y 4 
 N 
2
 3I   Iˆ   y

4  6 9  4  9 
4
 kQ  c  I T NI  k I I T NI  6
  0 Ra   3  Fˆ  32 z 16  ˆ 3  Fˆz  32 z 16 
 Iˆ5    z   I 6    
where kI = kQ[Nc/(0Ra)]2 is a lumped coefficient related to the  8  6 9 8 6 9
property of the particle and the magnetic circuit. A
normalized input current with saturation current, Imax, III. IMPLEMENTATION
simplifies eq. (7) as
A. Design of a 3D-MT with pole positioning mechanisms
F  k I I NI  k I I T 2
max Iˆ T NIˆ  k Iˆ Fˆ In the above theoretical modeling of the magnetic tweezer,
. (8) the magnetic charges were aligned onto the three axes of the
 Fˆ x , y , z  Iˆ T N x , y , z Iˆ actuation coordinate system. To minimize the difference
between the actual setup and the theoretical model, the tips of
Here, a constraint condition that summation of the six input the magnetic poles should be precisely aligned onto a target
currents is always zero is introduced to limit the possible circle on the top and bottom layers respectively as shown in
solutions and further simplification of the forward model as Fig.3(b), and the shapes of the tips should be identical to each
other. In order to make the actual assembly as close to this
Fˆcx  6( Iˆ1  Iˆ2 ), Fˆcy  6( Iˆ3  Iˆ4 ), Fˆcz  6( Iˆ5  Iˆ6 ) , (9)
2 2 2 2 2 2
ideal condition as possible, positioning mechanisms were
implemented in the base block of each magnetic pole.
where Fˆc  Fˆcx , Fˆcy , Fˆcz  is a normalized force at the center of the
Fig. 4(a) shows the composition of the developed MT. Each
working space. Since a linear solution which satisfies eq.(9) is magnetic pole unit is composed of four pieces, a base block, a
written as moving block, a rocker pin and a magnetic pole as shown in
 1/ 8 0 0   1/ 3  Fig.4(b). This composition is common between the three
 0 1 / 8 0   1/ 3  upper units and the three lower units. In-between the base
    block and the moving block, a couple of micrometer heads are
 1 / 8 0 0   1/ 3 
ˆI  DFˆ  E , where D   , E    . (10) attached. By using them, the tip of the magnetic pole can be
c
 0  1/ 8 0   1/ 3  turned around the rocker pin and can be fed forward or
 0 0  1 / 16  2 / 3 backward as shown in Fig.4(c). By using this mechanism, the
   
 0 0 1 / 16   2 / 3 tips of the poles can be aligned onto a target circle. The height
of each pole was aligned by inserting a few sheets of shim
Substituting Eq. (10) to Eq. (8) gives a normalized force as between the baseplate and the pole block before doing
 Fˆ x  Fˆ cT N 2 x Fˆ c  N 1x Fˆ c  N 0 x  N 2 x, y, z  D T N x, y, z D
horizontal alignment.
ˆ 
 F y  Fˆ c N 2 y Fˆ c  N 1 y Fˆ c  N 0 y , where  N 1x , y , z  2 E N x , y , z D . (11)
T T
In order to evaluate many specimens quickly, introducing a
 Fˆ  Fˆ T N Fˆ  N Fˆ  N N specimen holders should be easily done while the alignment of
 0 x, y , z  E N x, y, z E
T
 z c 2z c 1z c 0z
the pole tips is guaranteed. To satisfy this requirement, the
First order Taylor expansion of F̂x in two dimensions near upper poles are fixed to the yoke ring so that they can be easily
removed from the bottom unit. In order to guarantee the fine
Fˆ cx0  0 0 0 and probe position P  0 0 0 can be
T 0 T
alignment between the lower three poles and upper three poles,
derived as Three of coupled v-groove and hemisphere convex were made
on the bottom surface of the yoke ring and on the top of base
Fˆx y , z  blocks respectively. Since each couple of v-groove and
  
Fˆx y , z  Fˆc , P  Fx y , z  Fc0 , P 0   P
P  P  0
(12) convex is fit when the yoke ring is placed onto the bottom base
Fc0 , P 0 block, alignment can be well guaranteed, and removal of the
Fˆx y , z  N 0 x y , z  upper poles together with the yoke ring can be easily done as

Fc
 Fˆ  F  
c c
0

P
 P  N1x y , z 
P0
 Fˆc shown in Fig. 5. The fabricated prototype is shown in Fig. 6,
Fc0 , P 0 P0 and the close-up image of the six pole tips when they were
aligned around a circle of 900μm, which was equivalent to a
By substituting N1x,y,z and N0x,y,z into eq. (12), inverse force spatial gap distance of 1.1mm, is shown in Fig. 7. In this figure,
model can be expressed as three poles with fine focus are located on the upper side, and
three blurred poles are on the lower side. During a 20 cycles
( Fˆx , Fˆ y , Fˆz )  ( Fˆcx  8 x, Fˆcy  8 y, Fˆcz  32 z ) . (13)
removal and placement of the yoke and upper pole assembly,

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the alignment error of the upper pole tips against an exact
target position were no larger than 20μm. Upper positioning unit

B. Visual measurement and servo system


For the establishment of a noncontact 3D precision
measurement of a probe particle, visual servo system using an
inverted optical microscope was built. A CMOS image sensor
(GS3-U3-23S6M-C, Point Grey Inc.) of which pixel size is
5.86μm was mounted under an 50x magnification objective
lens (M-PLAN NIR 50x, Mitsutoyo corp.) to acquire the Lower positioning unit
image of the workspace. Position of the probe is measured by
analyzing this image of 0.12μm/pixel resolution. A sub-pixel (a) The entire assembly
in-plane analysis and an out-of-plane analysis [13] were Spring for stopper
sequentially applied to achieve a 3D position measurement of Pole and Pole block
Fixing with tapered bore
the probe. In the in-plane analysis, the center of the probe can Pin and Slotted hole
be easily identified from the centroid of the intensity 10 mm h7/H7
distribution projected onto the horizontal (X) and vertical (Y) ×
axes of the image.
On the other hand, the out-of-plane (Z) position Micrometer head x 2

measurement was done by using a calibration-based algorithm (b) Composition of the lower unit (c) Tip rotation and translation
corresponding to the micrometer operation
as shown in Fig.8. As the first process of the out-of-plane
position measurement, images with respect to known Figure 4. 3D-CAD drawing of the pole positioning mechanism
out-of-plane displacements should be recorded. In order to
give a known Z displacement to the probe, a piezo driven
flexure stage shown in Fig. 9 was fabricated and mounted V-groove
under the objective lens. The flexure mechanism of the stage
magnifies the piezo actuator’s input stroke 5 times to achieve
200μm stroke. Displacement of this stage was measured by a Semi spherical convex
capacitance sensor having sub-micrometer resolution to
establish a PI feedback position control. Fig.10 plots an
obtained result during a calibration process in which a stepped Replace
command trajectory within +/-40μm was given. During the
calibration process, positioning error was within +/-0.1μm.
Although it can be seen that positioning error has a ripple
spiky peak of approximately 100nm amplitude, that only
occurred when the target position of the stage was stepped.
Figure 5. Alignment mechanism for specimen replacement
The image acquisition for the calibration was done when the
target position remained stable, and the positioning error of the
stage was under 20nm at that time.
By substituting the measured probe position and the target
force calculated by the PI feedback controller into eq. (15), a
visual servo system can be established. In the current
implementation, the control frequency of the visual servo is
approximately 300 FPS.

IV. PROBE STEERING EXPERIMENT


By using the fabricated prototype, a monodisperse
superparamagnetic micro particle which is a cluster of Figure 6. The developed 3D-MT with positioning mechanisms
nanometer-sized particles aggregated in 4.5μm diameter
(Dynabeads M-450 Epoxy, Thermo Fisher Scientific Inc.)
was successfully manipulated in standard viscosity silicon oil
of 50, 100 and 200cSt. Manipulation of a particle of 2.8μm
diameter (Dynabeads M-270 Epoxy) was also achieved in 900μm
pure water. Among these various viscosity medium and
different size particles, high viscosity silicon oil and 4.5μm
particle were used at first due to the ease of establishment of
the trapping and position control of the particle because of the
large force strength and less Brownian motion. Pure water and
2.8μm diameter particle were used at last as the most difficult
Figure 7. The developed 3D-MT with positioning mechanisms
case to achieve the steering.

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Figure 8. Out-of-plane visual measurement algorithm utilizing a
calibration of off-focus blurred image
Figure 11. A result of a trajectory tracking experiment
Lens mount
(M25 x 0.75mm thread) Lens displacement

Piezoelectric actuator Displacement magnification


Expansion (input) mechanism
Figure 9. 3D-CAD drawing of the piezo objective lens stage

Figure 12. A result of a trajectory tracking experiment

Figure 10. Commanded trajectory for the objective lens stage (right
upward slope) and positioning error (spiky line) during a calibration

Fig. 11 plots an example of trajectory tracking experiment


using a 4.5μm probe in 50cSt silicon oil. Position tracking
error is plotted in Fig. 12. During the experiment, in-plane
error (X and Y) was always less than 800nm. Out-of-plane (Z)
was also less than 500nm while the probe was moved on a Figure 13. Averaged generated force strength distribution (the error
horizontal plane, which is the half (0 to 225 sec.) of the graph. bars indicate the range of measured values among the five trials).
However, when the probe began to trace a target trajectory
drawn on a slope of 30 degrees inclination, it became larger, F  6rv , (16)
approximately up to 2μm, as seen in the latter half (225 to 450
sec.) of the graph. Although spiky peaks are also seen in that where  and r are the viscosity of the silicon oil and the radius
period, it is because of the incorrect convergence of Z position of the bead, respectively. The obtained result is plotted in Fig.
search algorithm. 13. The error bar and center dot represents the fluctuation of
In order to evaluate the homogeneity of the magnetomotive the measured force strength while iterating the same
measurement 5-times for each pole and the averaged value,
force generation of each pole, a probe in silicon oil of 100cSt
respectively. It can be seen that the force strength was close
viscosity was dragged by exerting a constant current, 500mA, each other in-between the three upper and lower poles, but
on each coil at a time. Since the velocity of the probe is steady there was a difference between those two layers. This means
when the exerted force and the viscous resistance force were that the machining error and assembling error seem to be small
balanced, the strength of exerted force, F, can be easily enough to obtain the almost homogeneous distribution in the
calculated from the measured constant velocity v, as same layer, but the balance between the upper and lower poles
were imperfect to achieve same force strength.

1749
The reason of the imbalance between the two layers needs [5] F. J. Alenghat, B. Fabry, K. Y. Tsai, W. H. Goldmann and D. E. Ingber,
to be further investigated and solved. Saturation of Analysis of Cell Mechanics in Single Vinculin-Deficient Cells using a
Magnetic Tweezer, Biochemical and Biophysical Research
magnetization of the pole tip, magnetic conductivity between
Communications, Vol. 277, No. 1, pp. 93-99, 2000.
the gaps of the magnetic pole, pole support block and yoke [6] M. Weicheng, F Niu, X. Li, H. Ji, J. Yang and D. Sun, Automated
ring and the unbalance of excitation coil characteristics, e.g. Manipulation of Magnetic Micro Beads with Electromagnetic Coil
resistance and inductance, are currently under investigated. It System, Proc. of the 7th IEEE Intr. Conf. on Nano/Molecular Medicine
is also necessary to take the nonlinearity of the magnetization and Engineering, pp. 47-50, 2013.
phenomena against the excitation current, e.g. saturation and [7] D. Kilinc and G. U. Lee, Advances in magnetic tweezers for single
hysteresis, into account either theoretical or experimental. molecule and cell biophysics, Integrative Biology, Vol. 6, No. 1, pp.
27-34, 2014.
After solving these problems, the setup will become capable
[8] F. Amblard, B. Yurke, A. Pargellis and S. Leibler, A Magnetic
of generating several hundred pico-newton force by reducing Manipulator for Studying Local Rheology and Micromechanical
the gap distance in between each pole by using the adjustment Properties of Biological Systems, Review of Scientific Instruments,
mechanism. Regarding the strength of the magnetic force, Vol. 67, pp. 818-827, 1996.
large-size particles would be suitable to achieve it easily. [9] A. H. B. de Vries, B. E. Krenn, R. van Driel, and J. S. Kanger, “Micro
However, when the bead diameter becomes too large, magnetic tweezers for nanomanipulation inside live cells,” Biophys. J.,
vol. 88, no. 3, pp. 2137-2144, 2005.
gravitational force and inertial force will become too large to
[10] F. Niu, X. Li, H. K. Chu, J. Yang, H. Ji and D. Sun, Modeling and
be ignored, and it will also influence the resolution of the Development of a Magnetically Actuated System for Micro-particle
Z-position measurement since the measurement is utilizing the Manipulation, Proc. of the 14th IEEE Intr. Conf. on Nanotechnology,
blur of the particle image with respect to the displacement on pp. 127-130, 2014.
Z axis. The capability of the usage of various-size particles for [11] Z. Zhang, and C. H. Menq, Design and Modeling of a 3-D Magnetic
making it possible to select an optimum diameter particle for Actuator for Magnetic Microbead Manipulation, IEEE/ASME Trans.
each experimental plan is an important engineering problem to on Mechatronics, Vol. 16, No. 3, pp. 421-430, 2011.
make the MT system more practical. [12] D. Matsuura, Z. Zhang, C. H. Menq, Development of Noncontact
Micro Particle Manipulation System Using Three-Dimensional
Magnetic Tweezer and Three Axis Piezo Stage, Proc. of the 15th Intr.
V. CONCLUSIONS Conf. on Mechatronics Technology. pp. 514-519, 2011.
[13] Z. Zhang and C. H. Menq, Three-Dimensional Particle Tracking with
In the present paper, development of a prototype 3D Subnanometer Resolution using Off-Focus Images, Applied Optics,
magnetic tweezer (MT), which aims to establish non contact Vol 47, No. 13, pp. 2361-2370, 2008.
precise manipulation of a probe’s position and the exerted
force on it has been discussed. All essential components
including the MT, the inverted microscope for 3D visual
measurement with a piezo objective stage and the
measurement/control software were developed. Especially, a
pole positioning mechanism was implemented in each pole
support block to minimize the undesirable effect of pole
misalignment. By using the developed prototype, the bead
steering experiment to trace a spatial trajectory tracking was
successfully demonstrated. In case of horizontal tracking, the
tracking error was almost less than 500nm. The homogeneity
of the six magnetic poles for generation of magnetomotive
force was evaluated by exerting a constant current on each
coil one by one. From the obtained results, it can be said that
poles located on the same level established sufficiently close
strength, but the imbalance between the poles in different
layers needs to be solved. After further investigation and
improvement, the developed prototype will provide position
and force control for bioengineering experiments and other
micro-manipulation tasks.

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