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DOI 10.1007/2882_2008_103
© Springer-Verlag Berlin Heidelberg 2008
Published online: 11 September 2008 NANOPARTICLE S , COLLOID SY STEMS
Árpád Figyelmesi
Béla Pukánszky Jr.
Preparation and Characterization of Barium
Kristóf Bagdi
Zsuzsa Tóvölgyi
Sulfate Particles as Contrast Materials for
József Varga Surgery
Lajos Botz
Stephan Hudak
Tamás Dóczi
Béla Pukánszky
the treatment takes place directly in the blood vessel, show bility of the suspension is determined by particle size and
better results than micro-neurosurgical methods. Micro density, and by the viscosity of the dispersion [37, 38]. The
balloons and spirals are frequently applied [10–13], but contrast materials available in the open market come in
liquid embolizing agents are the newest materials used various particle sizes. The stability of the suspension pre-
for the treatment [14, 15]. These are less invasive than pared with them is very often not sufficient; the particles
earlier methods and result in very high recovery ratios, frequently separate from the dispersion by sedimentation.
but appropriate contrast is needed to carry out the opera- Separation of the contrast material in the body is very dan-
tion [16–19]. gerous, since the operation cannot be safely completed; the
Several contrast materials are used in medical prac- contrast material may block the arteries and cause dam-
tice. The degree of contrast and the suitability of a ma- age [39–41]. The proper adjustment of the above men-
terial for surgical purposes depend on its electron dens- tioned factors, i.e. electron density, particle characteristics,
ity [20–22] and on the stability of the suspension. Gold, solution viscosity and density, may result in more efficient
tantalum and barium sulfate (BaSO4 ) are added the most contrast materials than those available presently.
frequently to improve contrast in the body during endovas- The goal of our research was to explore the possibil-
cular surgery [20, 23–25]. Gold is extremely expensive, ity of finding efficient and economically viable materials
while a larger amount of BaSO4 is needed in order to for contrasting purposes. We also wanted to investigate the
achieve the necessary contrast. Barium sulfate suspension effect of the main factors on contrast and dispersion stabil-
in water is the universal contrast medium used also for the ity. Since gold and tantalum are very expensive and BaSO4
examination of the upper gastrointestinal tract [26]. How- is also used in medical practice, we decided to prepare
ever, a simple barium sulfate/water mixture has several such particles under different conditions and to character-
undesirable properties including the tendency to sediment. ize them with various methods. In this report we discuss
BaSO4 particles are also the principal additive used to ad- the effect of reaction conditions on particle characteristics
just the density of drilling mud for controlling the pressure and on the stability of suspensions.
gradients in drilling operations, where it is very import-
ant to avoid it completely [27]. Flocculation and sedimen-
tation of suspended solids in a liquid phase are one of Experimental
the most central problems in colloid science. A number
of studies have been devoted to the understanding of the In this study BaSO4 particles were prepared from solution
stability of colloidal suspensions and especially on aggre- by mixing barium chloride (99.0%, Spektrum 3D, Hun-
gation [28–32] or settling phenomena [33] from a funda- gary) and sodium sulfate (99.5%, Reanal, Hungary). The
mental point of view. Information on particle size, packing reagents were used as received. The reaction was carried
density and the mechanism of settling for both flocculated out under various conditions; we changed the concentra-
and deflocculated systems have been discussed by sev- tion of the solutions, reaction temperature, the order and
eral authors [34–36]. Different approaches have been pro- way of mixing. The solution of the reactants was either
posed to describe the settling process; some of them extend put into dropping funnels or into the collection beaker in
the hydrodynamic calculations developed for macroscopic which the reaction took place. The conditions of the reac-
particles to flocculated suspensions. Accordingly, the sta- tions are summarized in Table 1. Ethanol (96%, Spektrum
Table 1 The conditions of the preparation of BaSO4 particles for contrasting purposes
Sample T (◦ C) a
csol Beaker b Funnel 1 b Funnel 2 b EtOH c
(mol/dm3 )
3D, Hungary) was added to the suspension in order to pre- angle in ethanol and DMSO, the solvents used in en-
vent aging either at the beginning (before) or at the end dovascular surgery. The concentration of the suspension
(after) of the reaction (see last column of Table 1). Always was 0.1 g/100 ml and the suspension was treated with ul-
50 ml was used from both reactants and the suspension trasound for 10 min before the measurement. The sedi-
was stabilized with 100 ml ethanol. Altogether 9 samples mentation of the particles was studied by recording the
were prepared and characterized in this study. movement of the sedimentation front. The initial rate of
Since we found that the dried particles cannot be resus- sedimentation and the sedimentation volume were used for
pended again for further study, we used solvent exchange their characterization. 1 g material was suspended in 10 ml
to transfer the particles from water to other suspension li- solvent in a closed graduated cylinder and the suspension
quids. The solid particles were separated in a centrifuge, was shaken vigorously for 5 min before the measurement.
water was removed from the upper phase and it was ex- The movement of the sedimentation front was followed by
changed to the required solvent. Separation in the cen- a camera, visualized with the Vision GS software, recorded
trifuge did not change the morphology of the particles by Bulent’s Screen Recorder and evaluated by the BSR
in any visible way and they could be easily resuspended Movie Lab software. Sedimentation was studied in water,
after separation. The particles were suspended in the new ethanol and DMSO.
solvent by vigorous stirring and then separated again. Sol-
vent exchange was repeated three times in order to achieve
perfect exchange of the solvent. Even a superficial visual Results and Discussion
inspection indicated significant differences among the pre-
The results of the measurements are presented in three sec-
pared particles; the sample prepared without ethanol could tions. First we describe the size and shape of the particles
be resuspended much easier than the others. Commercial
and the effect of reaction conditions on them. Then we dis-
barium sulfate particles were used as reference contrast cuss the results of the light scattering measurements and
materials; one is offered specifically for medical purposes
finally the stability of the suspensions, which is extremely
(BR1), while the other, a general purpose sample, was pur- important from the medical point of view.
chased from Aldrich (BR2).
The size of the particles was determined by scanning
electron microscopy (SEM) and laser light scattering. 1 g Particle Size and Shape
material was suspended in 100 ml ethanol for SEM. One
droplet was placed on a sample holder, the solvent was The particle size and shape of the contrast material strongly
evaporated and the particles were coated with gold. Mi- influences the stability of the suspensions. As mentioned
crographs were taken with a JEOL JSM-6380 apparatus. before, different reaction conditions resulted in various par-
Dynamic laser light scattering measurements were done ticle sizes and shapes. A few examples are shown in Fig. 1.
using a Brookhaven BI 9000 apparatus at 90◦ scattering The reference samples (BR1, BR2) are also included for
Fig. 1 Size and shape of selected BaSO4 samples; a B3, b B6, c medical grade (BR1), d general purpose (BR2)
60 Á. Figyelmesi et al.
Fig. 3 Bimodal size distribution of the commercial BaSO4 sample Fig. 4 Rate of sedimentation of samples B3 and B8 in ethanol.
(BR2) obtained from Aldrich. Laser light scattering in DMSO Symbols: () B3, () B8
for sample 9 to 1.97 nm for the commercial reference sam- where vs is the sedimentation rate of the particles, g grav-
ple. The width of the distribution also varies, but it seems itational acceleration, ρp and ρs is the density of the par-
to depend on the actual value of particle size. These results ticles and the solvent, respectively, and η is the dynamic
indicate that at least some of the particles will form sta- viscosity of the suspension. Equation 1 clearly shows that
ble suspensions and can be applied as contrast material in the main factors determining sedimentation are the size of
endovascular surgery. the particles, the density difference between the particles
It is also worth to compare the results obtained by the and the liquid, and the viscosity of the media. Particle size
two different methods, i.e. SEM analysis and laser light has an especially dominating effect on sedimentation rate
scattering. The general tendency between the quantities since it appears on the square in the equation. In the case
determined by the two techniques compares well, but the of small particles, the solvate layer adsorbed onto the sur-
exact values are quite different and considerable contra- face of the particles also influences particle size and must
dictions can be also observed occasionally. Large sizes be taken into consideration. The results and their analysis
were determined for both reference samples (BR1, BR2), presented above clearly show that the size of our particles
as well as for sample B3 by both methods. On the other cover a wide range thus we may expect considerable dif-
hand, the size of the B1 particles proved to be very large ferences in the stability of the suspensions.
in the light scattering measurement, while the SEM study Sedimentation experiments were carried out in water,
yielded a much smaller value. This apparent contradiction ethanol and DMSO. Occasionally we could not measure
can be easily explained by the fact that primary particles the sedimentation characteristics of the samples because
were determined by SEM, while light scattering cannot a homogeneous suspension could not be prepared or be-
differentiate between these and the aggregates. Finally we cause sedimentation was excessively fast (samples BR1,
must mention here that much smaller aggregates formed B5 and B6). We present two typical sedimentation curves
in DMSO than in ethanol. The observation was later con- in Fig. 4, which show the progress of the sedimentation
firmed by the sedimentation experiments described below. front as a function of time. The SEM micrograph taken
The different aggregation tendency of the samples must from sample B3 (see Fig. 1a) clearly showed the plate-
be related to dissimilar surface characteristics and interac- like particle geometry and large size of this sample. The
tions, but we did not investigate them in this study. sedimentation curve agrees well with these observations,
the rate of sedimentation is relatively fast, the particles
Sedimentation, Suspension Stability rapidly fall to the bottom of the vessel. Both microscopy
and light scattering experiments indicated that the particle
As a first approximation the sedimentation rate of spheri- size of sample B8 is much smaller. The particle char-
cal particles can be predicted by Stokes’ law: acteristics of this sample can be observed quite well in
Fig. 5. We see that the primary size of the particles is rela-
d 2 g(ρp − ρs )
vs = , (1) tively small and they form small aggregates. This aggre-
18η gate formation appears in the light scattering experiments
62 Á. Figyelmesi et al.
known and the average particle size can be calculated. completely fulfill the strict requirements of medical appli-
This calculation was carried out and we compare par- cation and yield a suspension with appropriate stability.
ticle sizes derived from results obtained in ethanol and The contrasting efficiency of the samples, their effect on
DMSO in order to study the aging phenomena further. The the viscosity of the embolizing fluid and the concentration
results are presented in Fig. 6 for those samples which necessary for surgical application requires further study
could be studied by this technique, i.e. by sedimentation, and optimization.
at all. The commercial BR2 sample was omitted from
the correlation, since the much larger value obtained for
it would have dominated the correlation pushing the rest Conclusions
of the values closely together. Although the number of
points is rather small, a general tendency can be estab- In this study barium sulfate particles were prepared under
lished in the figure. The large difference in the absolute various conditions to explore their potential application
values must be assigned to the inadequacy of the model as contrast materials in endovascular surgery. The results
used (Stokes’ law), since it is supposed to take into ac- showed that the particle characteristics of the samples de-
count changes in the density and viscosity of the solvents pend very much on reaction conditions. Particles were ob-
used. The deviation from the general tendency must be tained in spherical and plate-like shape and in a variety of
related to the aging phenomena mentioned above, which sizes. Primary particles of nanometer size formed aggre-
occur in DMSO. Samples falling above the tendency con- gates in most cases. Some of the samples had bimodal par-
sist of larger, while those below it contain smaller particles ticle size distribution. Particle characteristics determined
than in ethanol indicating aggregation or disaggregation, from SEM micrographs, by laser light scattering meas-
respectively. These results further support our observa- urements and calculated from sedimentation experiments
tions about the aging of BaSO4 particles in DMSO, which often differed from each other. The discrepancy could be
might considerably influence the stability of the suspen- explained by the different behavior of various fractions and
sion. Moreover, the deviations from the general tendency by the dissimilar sensitivity of the measurements to them.
call the attention to the fact that the results of all measure- Some of the samples showed various aging phenomena in
ments must be treated with the utmost care, since some of DMSO leading either to the formation of larger particles
them can be biased by various factors. or to the break down of aggregates. The experiments also
The results presented here unambiguously prove that proved that the appropriate selection of preparation condi-
commercial contrasting agents, like the medical reference tions results in particles yielding stable suspensions, which
sample used in this study (BR1), are not always optimal can be used in the intended application.
and the stability of the suspensions prepared from them Acknowledgement The project was financed by the National Bu-
might be poor. On the other hand, by the selection of the reau of Research and Development (NKFP Grant No. 1/0027/2005)
reaction conditions properly, barium sulfate particles can and the National Scientific Research Fund of Hungary (OTKA
be prepared with proper shape and particle size, which Grant No. K 68748); their support is highly appreciated.
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