Study on In-vivo Measuring Method of Solubility for
Cerebral Thrombus Dissolution.
Zhongwei JIANG*, Minoru MORITA *, Tetsuyou WATANABE*,Shoichi KATO**, Michiyasu SUZUKI*** Dept of Mechanical Engineering, Yamaguchi University, 755-8611, Japan
Tel : +81-00-111-2345 Fax : +81-00-111-6789
E-mail: {jiang, a089fb, t-wata}@yamaguchi-u.ac.jp**Dept of Neurosurgery, School of Medicine, Yamaguchi University, 755-, Japan
Tel : +81-75-999-8765 Fax : +81-75-999-4321
E-mail: kato-ygc@umin.ac.jp; michi@yamaguchi-u.ac.jp
Abstract: A cerebral thrombus or blood clot might cause cerebral stroke and even decease if the clot
could not be dissolved within several hours after it was formed. This paper presents a fundamental
study on development of a new type of mechanical micro stirrer for assisting the dissolution of thethrombus with a few amount of thrombolytic agent. The micro stirrer is made of a slight beam
embedded with a piezocell. An efficient excitation method for stirring up the thrombus to get a quick
dissolution is investigated. Furthermore, to evaluate the dissolution state in vivo, the method using
the piezo-stirrer as both the stimulator to beat the clot and the probe to evaluate its solubility isproposed. The potential of the piezo-stirrer has been validated experimentally.
Keywords: Micro-stirrer, Beam, Piezocell, Thrombus, Clot, Stroke, Dissolution, Solubility, Measurment

1. INTRODUCTION
The cerebral stroke is one of the sicknesses fromwhich many elderly people are being to suffer. The
cerebral stroke is happened due to a thrombus formed in
the vessel blocks the blood flow in the brain and induces
the brain cell necrosis. Due to enhancement of people’sliving standards, many people recently suffer from thehypertension,
thehyperlipemia
andthehypercholesterolemia, which means there exists highpossibility of the cerebral stroke. Furthermore, themortality or the complication rate due to the cerebral
thrombus would be very high if the cerebral blood vessel
is not recanalized in time. The complication rate could
become lower, if the clot is taken away in the early stage
or within the therapeutic time window at which theischemic organ is still reversible. In the present clinicaltreatment, the thrombus within the vessel is dissolved byinfusion of the thrombolytic agent directly into the artery.
The direct infusion needs a large amount of the agent todissolve the clot, so it has a high risk of intracerebral
hemorrhage, or some kind of adverse reactions. There aresome attempts on this problem, such as using transcranial
Doppler stimulator to assist the dissolution effect, andusing a ultrasonic catheter device to deliver the drugs tothe affected area and to stimulate the clot for a quick
recanalization.[1-3] This method is considered efficient touse a few drugs but how to deal with the ultrasonic energy
for fast dissolution needs advanced investigation.
In consideration as mentioned above, this paper isconcerned with the study on development of a mechanicalmicro stirrer that can be used in the catheter to assist theclot dissolution speed with a few agents. The proposedstirrer is made of a slight beam embedded with thepiezocell. An excitation method for the stirrer, how to beatthe clot to get an efficient dissolution of the clot with a few
thrombolytic agents, is investigated.
Furthermore, evaluation of the solubility of the bloodclot in vivo is a still unsolved problem. It is well known
that the piezoelectric material has both actuator function
and sensor function. It come an ideal to use the samestirrer for beating the blood clot and at same timeevaluating its dissolution state. In common sense, as theclot is dissolving the contraction to the motion of thestirrer goes weakly, which leads a change in the stirrer
mechanical impedance. So the problem to be solved comesto that how to measure the mechanical impedance change
easily and precisely. The piezoelectric impedance based
technique is therefore introduced for this study and its
potential is validated experimentally.

Fig.1. Schematic of piezo-stirrer.

2. MICRO STIRRER & EXCITATION
Figure 1 shows the schematic of a hand-made stirrer
in a size suitable for fundamental test in the laboratory.
The base beam is aluminum cut in size of 60x5x0.5mm
and the piezocell of 6x2x0.3mm is bonded on it as anactuator and also sensor. The experimental system for
driving the stirrer is shown in Fig.2. The beam is driven in
the following way. The input signals, such as sine andpulse waveforms, are formed by a waveform generator(HIOKI 7050) and amplified to 50V through a power
amplifier (FN 4010), then added to the piezocell. Figure 3
shows a picture in which a micro-stirrer is fixed on ahand–made fixator and the vessel filled with the testing
liquid is set on a three-dimension manipulator (M-152) sothat the inserting depth of the stirrer could be easilyadjusted.
In the experiment, the depth of the stirrer tip is set at
7mm from the liquid surface. Instead of blood, water isused in the experiment say about 1.8ml. In order toinvestigate the stirring effect, four resonant frequencies at
0.155, 0.228, 0.55 and 2.56kHz, is selected and two kindwaveforms, sine and pulse waveforms, were tested, andthe stirrer is driven for 10 minutes. Further, as for pulse
waveform, its duty ratio is changed by 10, 30 and 50%.

Fig.3. Experimental setup photo.

Table 1. Stirrer or excitation effect.

The obtained results are summarized and described inTable 1. Since the motions of the stirrer is difficult tomeasure in the experiment, the whirlpool or ripple on thewater surface is observed for evaluation of the stirring
effect. Further, the sound from the stirrer is also used as animportant factor. The mark ‘ ’ in the table means the casethat the ripple has been observed and mark ‘×’ means theripple was not observed by eyes. Furthermore, mark ‘ ’means the case that the whirlpool has been observed on thewater surface. In the column of Sound mark ‘ ’ means
one can hear the sound form the stirrer by ears and mark‘×’ means not. Furthermore, mark ‘ ’ represents a strong
sound has been observed. It is found that the excitation
using pulse waveform with 50 % duty ratio at 2.56 kHz
seems most effective for stirring the liquid.
Note : × not observed,observed,

I = i sin(ω t + φ )well observed

Coupled electro-mechanicaladmittance Y=Re(Y)+jIm(Y)KV = v sin(ω t)

PZTmC

Fig.2. Experimental setup for the stirrer driving test.

Fig.4. Concept of piezoelectric impedance based
measuring technique.

3. THROMBUS SOLUBILITY MEASURMENTAs mentioned above, the thrombus solubility might
be estimated according to the ripple on the water surface
observed by eyes or to the sound by ears in the present
condition. It is firmly difficult to evaluate the dissolution
effect in vivo when a catheter type stirrer is used. Also no
efficient method has been established in present literature
to measure or evaluate the thrombus solubility in vivo. In
this section, an ideal using the same stirrer to beat the clot
and also to measure its solubility is thereat proposed. This
ideal is based on a change in the piezoelectric effect due tothe thrombus dissolution, when a change of theconcentration in the blood existed.

Fig.5. Experimental setup for impedance measurement.

In common sense, as the clot is dissolving thecontraction to the motion of the stirrer goes weakly, whichleads a change in the stirrer mechanical impedance. This
stirrer mechanical impedance change can be measured bya piezocell bonded on it, because the mechanical
impedance induces a change in the piezoelectric
impedance. The thrombus solubility is therefore inferredby the piezoelectric impedance. The piezoelectric
impedance based technique is expressed as follows.
The model of the stirrer with the piezocell can be
simplified as shown in Fig.4. Therefore the admittance ofthe piezocell is then represented as:[4]Y = iω

wala  T
Z S (ω )d32xYxxE ε 33 (1 − iδ ) −ha 
Z S (ω ) + Z a (ω )
(1)where Z a and Z S are mechanical impedance of the piezocell
and the stirrer, Y xxE is the complex modulus of the piezocell
at zero electric field, d 3 x is piezoelectric constant, ε 33T iscomplex dielectric constant, δ is the dielectric loss factor
and wa , l a and ha are the width, length and thickness. The
admittance is reciprocal of piezoelectric impedance. The
mechanical impedance of the piezocell is assumedconstant. In the equation (1), the piezoelectric impedanceis therefore controlled by the mechanical impedance of thestirrer. The mechanical impedance of the stirrer isinfluenced by the testing liquid. Therefore, the conditionof the liquid could be estimated by measuring the stirrer
piezoelectric impedance, which means the solubility ofblood clot could be assessed by measuring thepiezoelectric impedance of the stirrer.
The experimental impedance measuring system isshown in Fig.5. The piezocell is connected to theimpedance analyzer (HP 4192), so that a sweep sine
voltage generated by the analyzer is added to the piezocell.
The piezoelectric impedance change due to different kindof the testing liquid is measured and transmitted to acomputer for data processing. Some obtained results areplotted in Figs.6 and 7. Therefore, the impedance and thefrequency shift of the responses are used for assessment.
In the experiment, the volume of the testing liquid, theposition of stirrer and the vessel type are fixed for
obtaining the measurement repeatability. Figure 6 shows
the real part of piezoelectric impedance obtained along aselected frequency region 2-100kHz.

Fig.6. Real part impedance response and its
repeatability. (a) 2-100kHz, (b) 2.3-2.6kHz,(c) 19-21.5, (d) 54-60, (e) 80-95

The measurement
repeatability is verified bycomparing the data obtained twice before and after 30
minuets in the same experiment condition. Figure 7 shows
the impedance response variations along the frequency
region [2.5-2.6]kHz obtained when the concentration of
the sugar solution is confected with water and sugar syrup
at 10, 20, 30, 40, 50 and 60% respectively. It is clear thatthe impedance waveform shifts to left and its amplitude
goes lower monotonously with an increase of theconcentration. Therefore, it comes to a conclusion that thesolubility could be estimated by evaluation of theimpedance waveform variation. In following, threeparameters are introduced for evaluation of the solubility
by analyzing the waveforms.
Now, suppose the peak frequency of the waveform
for water is given by FW and its amplitude by AW and theones for sugar solution at x % are Fx and Ax as definedin Fig.8. Then the parameters named as peak frequency
shift ratio δ F and peak amplitude ratio δ A are defined by
δ F = 20 log

Fw − Fx
Fw(2)δ A = 20 log

Aw − AxAw(3)Fig.7. Impedance variation corresponding toconcentration of sugar solution.

Further, the concentration of sugar solubility might affectthe damping effect as the stirrer is under drive. According
the waveforms in Fig.7, their damping coefficient ζ canbe easily calculated byζ =Fx2 − Fx1
2 Fx0

(4)

where, F 0 is the peak frequency, and F 2 and F 1 are
obtained from the peak amplitude Amax as described in(a) Value of peakFig.9. Imitating the above definitions Eqs.2 and 3, thethird parameter is then given byδ ζ = 20 log

ζw −ζxζw(5)

Figure 10-12 show the plot of the parameters δ F , δ A andδ ζ calculated from the data in Fig.7. It is found theparameters δ F , δ A and δ ζ are almost linear to the sugar
solution concentration and their approximate lines isthereat calculated by the least mean square method andplotted in superposition to the figures. Therefore, thesolubility, if defined as x (%), could be estimated by
x = 2.5δ F + 145.(6)x = 2.5δ A + 82.5

(7)

x = 2.5δ ζ + 72.5

(8)(b) Frequency shiftFig.8. Parameter definition of frequency shift and peakratio.

Fig.9. Definition for damping ratio.

Fig.12. Damping ratio vs. sugar solution concentration.
Finally, an experiment is carried out to validate thedissolution effect with the aid of the proposed measuringmethod. For excitation of the stirrer, the pulse waveform at
2.56kHz and with 50% duty ratio is selected. The input
amplitude is 50V, and the stirrer is driven for 10 minutes.
The testing liquid is confected by 1.3ml water with 0.5ml
sugar syrup and the stirrer is inserted about 7mm from its
surface. At the beginning, the sugar syrup is precipitateddown the vessel. Figure 13 shows the obtained impedance
waveforms for three cases, (1) before the excitation, (2)after excited the stirrer for 10 minutes and (3) completely
dissolved by hand. It is evident that the stirrer driven by
the piezocell is powerful for the dissolution of sugar syrup
and the solubility measurement using the same stirrer
shows its potential to in vivo measurement.

Fig.10. Frequency shift as a function of sugar solution
concentration.

Fig.11. Peak ratio vs. sugar solution concentration.

Fig.13. Stirring effect validation.

4. CONCLUSION
A novel method using a mechanical excitation for
dissolving the cerebral thrombus and a impedance based
measurement for evaluating the solubility are proposed
and the fundamental experiments show that thepiezo-stirrer has high potential to be used both fordissolving the blood clot and for evaluating the thrombus
solubility in vivo.
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Monitoring”, Stroke, Vol.31, 2000, 610-614.
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Circulation Ischemia With Extranial Percutaneous Balloon
Angioplasty and Stent Placement” Stroke, 1999.
[3] David Russell, MD and Rainer Brucher, Phd. “Online
Automatic Discrimination Between Solid and Gaseous
Cerebral Microemboli With the First Multifrequency
Transcranial Doppler.” Stroke, August 2002.
[4] C.Liang, F.P.Sun and C.A.Rogers, “Couples ElectroMechanical Analysis of Adaptive Material Systems
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