Photomedicine and Laser Surgery

Volume 30, Number 5, 2012

ª Mary Ann Liebert, Inc.
Pp. 262–267
DOI: 10.1089/pho.2011.3187

Laser Beams Interaction with Polidocanol Foam:

Molecular Background

Adriana Smarandache

Abstract

Objective: The goal of this study was to investigate the laser light scattering involved in the laser irradiation
process of polidocanol foam samples. Background data: Clinical experimental results proved that exposure of
tissues impregnated with foaming polidocanol to laser radiation emitted at 1064 nm improved the efficacy of the
treatment. Previous absorption studies on Aethoxysclerol 2% solution before and after exposure to Nd:YAG
(1064 nm) laser beam have not shown important spectral modifications of it. Materials and methods: To achieve
the purpose of this work, we produced polidocanol foam using the Tessari method. The batch was passed
between the two syringes *40 times. The resulting foam was stable for 5-6 min. A 10 mm optical cell containing
the foam sample was introduced into a home-made Raman spectroscopy system, in which the laser radiation
used to excite the Raman emission was the second harmonic (532 nm) of a pulsed Nd:YAG laser beam. The
detection was made by a high resolution spectrograph and ICCD camera. Results: The obtained Raman spectra
were more intense in foam form than in simple solution. The laser light elastic scattering produced a larger
optical path of the beam in the sample, and consequently, a larger absorption of it by the foam components that
enhance the laser Raman scattering. Conclusions: The effect of the laser light may be expanded if the polidocanol
is used as foam, because then the light scattering in the tissue becomes more important and the beam absorption
becomes larger.

Introduction Medical observations prove that foam sclerotherapy is

preferable to the use of liquid sclerosing substances.8 De-

A lthough the main approach in the treatment

of small diameter veins, in venulectasias, and retic-
ular veins of < 4 mm in diameter (class I/II and III) is
sclerotherapy,1–4 lasers, especially the Nd:YAG laser, have
shown interesting and non-negligible capabilities in treating
these cases.5–7
Sclerotherapy is the targeted elimination of varicose veins
by injection of a sclerosing substance into the vein lumen.
Regularly, it is performed using sclerosing detergents such as
polidocanol (POL). With their introduction in the 1920s and
1930s, detergent sclerosants, also known as fatty acids and
fatty alcohols, soon became and are still the most popular
sclerosant types used worldwide for the treatment of vari-
cose veins. Detergent sclerosants, with increasingly favorable
risk-to-benefit ratios, rapidly replaced older sclerosants
thought to be ineffective if they could not produce tissue
necrosis or significant thrombosis at vasodestructive con-
centrations. After intravenous injection, liquid detergent
sclerosants become protein bound and are inactivated when
mixed with blood.
tergent-like sclerosing agents can be transformed into fine-
bubbled foam by special techniques.9–19 The ability to be
agitated and foamed increases the potency of detergents two
to four times by mechanically displacing blood and thus
maximizing the surface area and the contact time with the
endothelium. When the foam sclerosant is injected, it fills the
vein completely; it also displaces blood from the vein and
ensures that all endothelium is exposed to the sclerosant
agent and destroys it.5 This process has the advantage of
using small and presumably less allergenic or less tissue-
toxic concentrations and volumes of sclerosant, although
greater risks may occur if foam passes in the ocular or ce-
rebral circulation.20
The understanding of the interaction between POL and
the target veins’ tissues is important in using it in varicose
veins treatment. Clinical experimental results prove that
the exposure of the tissues impregnated with POL foam to
laser radiation emitted at 1064 nm improves the efficacy of
the treatment.21 It combines the effect of sclerotherpy with
that of the laser therapy and, also, with the capabilities of

Laser Department, National Institute for Laser, Plasma and Radiation Physics, Magurele, Romania.

262
LASER BEAM INTERACTION WITH POLIDOCANOL FOAM
modifications induced in the drug following exposure to the
laser radiation. Sometimes, the exposure of a medicine to
laser radiation yields a product that is more biologically ac-
tive than the unexposed parent.22, 23
Dermatologic application of laser technology was initiated
by Leon Goldman. His work was further elucidated by some
authors,24 who described the principle of selective photo-
thermolysis. The application of this principle shows how
laser energy is preferentially absorbed by the intended target
tissue or chromophore, resulting in its controlled destruction
while minimizing collateral thermal damage to surrounding
normal tissue. To achieve selective photothermolysis, a
wavelength that is preferentially absorbed by the intended
target tissue (in our case the vein tissue) or chromophore is
selected.
The pulse duration of the irradiating beam is also impor-
tant for selectivity. If the pulse duration is too long, heat
absorbed by the veins will diffuse out in the surrounding
tissues so that the veins will be not selectively heated to the
necessary degree in order to be destroyed. If the pulse du-
ration is too short, the light-absorbing chemical species such
as hemoglobin (Hb) in the blood will be heated causing va-
porization. This effect can cause purpura. Theory dictates
that the proper pulse width should match the thermal diffuse
time of the targeted structure. For smaller vessels, for ex-
ample, this thermal diffusion time can be of the order of
hundreds of microseconds to several milliseconds, whereas
for larger leg veins it could be 5–100 ms.25
The light absorption of whole blood is different depending
upon the osmolarity, hematocrit, hemodynamics, and red
cell morphology variables. The methemoglobin (MetHb) and
protoporphyrin IX (PpIX) have an absorption coefficient at
1064 nm four times greater than Hb. It is shown that one
pulse of the Nd:YAG laser causes substantial transformation
of Hb into MetHb, followed by a drastic decrease in blood
circulation speed.26 Subsequently, a second Nd:YAG laser
pulse, shortly after the first one, would be four times more
effective. Following this theory, a system was manufactured
with two different lasers built into the same console. The
energy of the two lasers is sequentially pulsed. First, a pulse
of a dye laser emitted at 585 nm produces an increase in the
rate of intraerythrocytic MetHb, changing the coefficient of
absorption of the Nd:YAG laser beam, which is delivered
after the first sequence. The long pulse emitted by the
1064 nm Nd:YAG laser induces vessel damage at lower flu-
ence. In reality, the pulsed dye laser has low penetration and,
therefore, its efficacy is limited to the most superficial dermal
plexus, as the vessels located at a greater depth than 1.5 mm
are not reached by these laser pulses. Hence, significant rates
of MetHb cannot be formed in the deepest veins.27
In this respect, the data reported in this study represent a
step toward better understanding of the interaction of POL
with the target tissues in the context of its exposure to pulsed
laser beams emitted at 1064 nm by the Nd:YAG laser.
Materials and Methods
POL or lauromacrogol 400, C14H30O2(CID 24750, molecu-
lar weight 230.3868 [g/mol]), is the pharmaceutical active
ingredient of commercially available Aethoxysklerol (Kreuss-
ler & Co. GmbH, Germany). It is polyethylene glycol ether
of lauryl alcohol, for which the average value of polymer
263
FIG. 1. 3D image of polidocanol molecule.
is nine.28 This chemical compound is a viscous liquid at room
temperature, having a melting point of 15–21C. It is miscible
in water, has a pH of 6.0–8.0 and a density of 0.97 g/cm3 at
room temperature.
The 3D image of this molecule is shown in Fig. 1, where
the carbon atoms are represented in dark gray, the hydrogen
atoms are light gray and the oxygen atoms are red.
POL should be stored at room temperature (15–250C). No
special precautions are necessary when disposing of this
material. POL at concentrations of 0.5% to 1% is stable for 3
years and should be stored between 150C and 300C (59–
860F). There are no special precautions for the disposal of
unused POL (product insert).
The common pharmaceutical presentation form of Ae-
thoxysklerol 2%, that was used in the experimental study is
as ampoule of 2 mL injection solution whose composition is a
mixture of the following substances: lauromacrogol 400 (ac-
tive), 40 mg; sodium hydrogen phosphate (buffer, inactive);
potassium dihydrogen phosphate (buffer, inactive); ethyl
alcohol (inactive), 0.10 mL, and pure water (inactive), 2 mL.
For this reason, when the solution is exposed to laser radi-
ation, one should consider the interaction of all the above-
mentioned compounds that exist in the commercial grade
substance.
Using the Tessari method – two disposable 5 mL syringes
(Luer Slip) connected to a three-way stopcock – we produced
foam from a mixture of Aethoxysklerol solution and atmo-
spheric air; the mixture ratio was 1:4 (Fig. 2). This batch was
passed between the two syringes *40 times and the result-
ing handmade foam was stable for 5–6 min.
Foam and solution samples of POL were investigated by
Raman spectroscopy using the experimental setup shown in
Fig. 3. This arrangement consists of a laser source, used to
excite the Raman effect, a specific geometry of the sample
investigation (the collection of Raman emission is made at
900, with respect to the laser excitation beam), a spectrograph
(Spectra PRO 750, Acton Research, Princeton Instruments,
NJ), coupled with an ICCD camera (PI-MAX: 1024, Princeton
Instruments, NJ) to record and evaluate the Raman signal
FIG. 2. (a) The Tessari foaming method and (b) foam
consistency.
264
FIG. 3. The Raman spectroscopy setup.
using an appropriate software. Our laser source is a Q-
switched laser, Continuum Surelite II (Continuum, Santa
Clara, CA). The head of the laser consists of a 115-mm-long
rod of Nd3 + doped YAG pumped by a linear flash lamp. The
high pumping efficiency is achieved through a closed cou-
pled configuration surrounded by a high brilliance magne-
sium oxide diffuser. The flashlamps are Xe discharge lamps,
working at a pressure of (1–3) atm. The active Q-switch is
performed by the combination of a polarizer, Pockels cell
and k/4 wave plate. The Q-switch allows the accumulation
of high energy in the laser resonator until it opens and
produces cavity oscillations. Therefore, fast and high peak
power laser pulses are produced. The fundamental laser
beam emitted at 1064 nm (maximum peak energy of 685 mJ)
can be doubled, tripled, and quadrupled by using high
harmonic generation BBO crystals. The characteristics of
the beams obtained are: 532 nm, maximum energy per pulse
340 mJ; 355 nm, maximum energy per pulse 180 mJ; 266 nm,
maximum energy per pulse 120 mJ.
The laser radiation effectively used in this experiment to
excite the Raman emission is the second harmonic of the
Nd:YAG laser emitted at 532 nm; the laser pulsed radiation
has a 10 Hz repetition rate, pulse duration at half maximum
is 5 ns, and the average energy of the emitted beam is 250 mJ.
Results and Discussion
It is important to provide a thorough understanding of the
basic physical principles that underlie the use of coherent light
in therapeutic applications. In this way, with respect to this
method of treating varicose veins by combining POL micro-
foam and pulsed Nd:YAG laser beam, we must consider three
factors: the drug’s sclerosis abilities, the action of the laser
beam on the surrounding tissues, and the possible increasing
of the drug’s potency under exposure to laser light. Of course,
in practice it is important to adjust each of the parameters
involved in the exposure of the substance to laser radiation in
order to obtain the best (most effective) results.
As a sclerosant detergent, POL produces endothelial
damage by multiple mechanisms associated with a decrease
in the endothelial cell surface tension, the interference with
cell surface lipids, a disruption of intercellular cement, and
an extraction of cell surface proteins. It is most effective in the
form of micelles (molecular aggregates) of the kind drawn in
Fig. 4.29,30
At low concentrations and temperatures, most of the POL
molecules are individually dissolved in solution, the micelles
SMARANDACHE
FIG. 4. Scheme of a micelle.
are not formed and the toxicity to the endothelium is con-
sidered minimal. By increasing sclerosant concentrations
at temperatures encountered in living tissue, a predictable
threshold for endothelial damage occurs with a commensu-
rate increase in sclerosing potency. The degree of damage
can be controlled by varying the active pharmaceutical in-
gredient concentration and the length of time of the scler-
osant contact with the vessel wall. Unfortunately, because of
the dilution with blood, it is not possible to determine the
quantity of the sclerosing agent in intimate contact with the
endothelial surface and the quantity that remains in circu-
lation. Therefore, the effects obtained are not always in direct
proportion to their concentration; ‘‘downstream’’ effects with
unintended damage to interconnecting vessels can always
occur.20
Lasers used for the percutaneous treatment of varicose
veins of the lower limbs must fulfil the principles of selective
photothermolysis, 31 which are:
 a wavelength that is, preferably, more absorbed by Hb
than by other similar chromophores;
 sufficient penetration as to reach the depth at which the
vessel for treatment is found;
 the appropriate energy to damage the vessel without
damaging the skin;
 slow release of energy so that the heat reaches the vein
wall without damaging the adjacent tissues.
In order to achieve the above mentioned, the following
variables must be taken into account: the laser beam spot
size, the fluence, the pulse width, the pulse repetition rate,
and the technique used for treatment application.
The experimental measurements described in this article
were made with experimental setups that utilized time width
pulses, energies, and irradiation doses, which are different
with respect to those used in medical practice. However,
they are made in order to better understand the molecular
processes specific to the interaction of the laser light with the
tissues of medical interest and the foam introduced in them
in the treatment of the varicose veins.
The light propagation in turbid biological media is jointly
governed by the absorption and scattering properties of the
medium. The optical properties (absorption and scattering of
light) of the marketed sclerosing substance may be a subject
LASER BEAM INTERACTION WITH POLIDOCANOL FOAM 265

for study. This would contribute to clarifying the mecha-

nisms involved in the combination of the sclerotherapy with
the light therapy in the treatment of varicose veins.
Previous absorption studies on Aethoxysklerol solution
before and after irradiation with a beam emitted by pulsed
Nd:YAG laser at 1064 nm have not shown important spectral
modifications.32 One may suppose that the clinical positive
results of the combined sclerotherapy and laser therapy
method are mainly caused by photoinduced processes of the
primary photoacceptors (derivatives of blood Hb, molecular
oxygen dissolved in all components of the biological tissue,
different ferments, and other tissue substances that absorb
light). Also, optical absorption in the near-infrared spectral
range is generally caused by combination of overtone bands
of fundamental molecular stretches. For wavelengths near
1000 nm, water is a primary absorber of optical energy. Some
authors have assumed that the molecules of drugs can be FIG. 5. Comparison of Raman spectra of the polidocanol in
photoactivated by assisting the hydrolysis process that re- solution and foam presentation.
sults from excitation of vibration levels of the water molecule
in the spectral range of 1–2 lm, following the absorption of
the result of a longer optical path of the laser beam in the
infrared radiation by the water molecules.33
foam sample. The Raman vibrational lines corresponding to
After the exposure of the Aethoxysklerol solutions at
foam sample are more structured and stronger.
1064 nm pulsed Nd:YAG laser beam with different irradiation
The broad band in 3500–3200 cm - 1 region in the Raman
doses, the absorption spectra plotted at wavelengths > 500 nm
POL solution spectrum is caused by the bonding OH stretch
remain within the measuring error limits. Modifications that,
exhibited in water solutions and in alcohols.
as a trend, are above the error limits are obtained in the
As for the Raman spectra of the foam sample, the signals
spectral range (250–285) nm. In some cases (exposures at
< 3000 cm - 1, especially those centered on 2850 and 2935 cm - 1
4, 6, and 8 min) the absorption curves may be considered
are specific to the methyl C-H asymmetric/symmetric stretch
within the error limits of the measuring system but they are
specific to the long linear aliphatic chain, which is the POL
modified according to the trend.32
chemical structure.
A possible explanation for this behavior of the curves is
The characteristic band profiles in the 3600–3200 cm - 1
that nonlinear absorption effects take place in Aethox-
range indicate the hydroxyl groups, whose presence linked
ysklerol, such as the absorption of four photons at 1064 nm,
with the weak Raman signals in the 1650–1450 cm - 1 interval
which would correspond to a transition at 266 nm. This
are typical for the OH stretch signature.
modification may show that after absorbing four photons at
Also, the Raman signals were acquired at different times
1064 nm the POL molecules change their structure. In
after the preparation of the foam samples (Fig. 6). One may
this article, measurements of the absorption spectra of foam
observe that the Raman spectrum is changing relatively fast,
were not made. Such measurements were previously per-
so that after 5 min from foam production, the Raman lines
formed and have shown that there is most probably a dif-
are 10 times less intense than the initial values.
ference between the absorption of radiation by the liquid
sample and the foam in the spectral range (900–1100 nm).34
This difference seems to show that the absorption of the
foam at 1064 nm is higher than for the corresponding liquid
sample.
According to our data, the effect of the laser light may be
enhanced if the POL is introduced as foam, because the light
scattering in the tissue becomes more important and the ef-
fective absorption of the laser beam becomes larger consid-
ering the Lambert–Beer law. Therefore, one might have, in
this case, a larger number of modified POL molecules or a
larger volume of tissue that is exposed to laser radiation.
Laser energy absorption in the foam can be boosted by the
multiplication of the impacts of the photons at the collisions
with the gas bubbles. Moreover, under these circumstances,
the number of changed POL molecules could also increase.
Attempting to increase the efficacy of the laser beam if the
POL is used as foam introduced in the tissue, the foam
(produced by the Tessari method and the procedure de-
scribed previously) and solution samples of POL were in-
vestigated by Raman spectroscopy. The obtained Raman FIG. 6. The influence of foam separation (in two phases:
signals were more intense for foam than for simple solution liquid and remaining foam) on the Raman spectra of a po-
samples (Fig. 5). This laser light scattering enhancement is lidocanol foaming sample.
266
The results indicate that there are some parameters that must
be taken into account, such as the bubble dimensions referred
to the foam cohesion; these are important with respect to the
time of exposure of the varicose vein injected previously with
foam POL and exposed in the tissue to laser radiation.
Figure 6 shows that the recommended time to apply
laser beam on the tissues impregnated with POL foam is at
2 min after foam preparation, in our experimental conditions.
After a few more minutes, the foam is destroyed and the
intensity of the characteristic vibrational lines decreases
drastically.
Conclusions
Clinical results prove that foam sclerotherapy combined
with photothermolysis based on laser therapy increases the
efficiency of the varicose vein treatment.34
Foam sclerotherapy reduces the dose and concentration of
the injected drug, and assures a better intimate contact of the
active substance with the target tissue.
Concerning the foaming procedure, it is recommended to
achieve a compromise between the bubbles dimension and
the foam stability in time, so that the value of the surface
tension is great enough to produce sclerosis of the target
tissue without the foam self-destructing too quickly and di-
luting in the bloodstream before acting on the vein.
On the other hand, pulsed Nd:YAG lasers emitting at
1064 nm offer important advantages for treating varicose
veins of the lower limbs. A laser pulse at 1064 nm converts
Hb into the more spherically shaped MetHb, which has a
four times greater absorption coefficient. After initial irradi-
ation, further delivering of energy is more effective at heating
blood and the surrounding vessel.35
The effect of the laser light may be enhanced if the POL is
introduced as foam, because then, the light scattering in the
tissue becomes more important and the overall absorption of
the laser beam becomes greater. The Raman spectroscopy
measurements prove that the Raman signals were more in-
tense for foam than for simple solution samples. The laser
Raman scattering enhancement is caused by a longer optical
path of the laser beam in the foam sample produced by the
elastic scattering. The vibrational lines corresponding to the
foam sample are more structured and stronger.
As for the appropriate/most recommended time to expose
the varicose vein injected previously with foam POL to laser
radiation, the results of Raman spectroscopy study, performed
at different moments in the foam’s lifetime, indicate that there
are some parameters that must be taken into account, such as
bubble dimensions referred to the foam cohesion.
Further studies are needed to elucidate the role of POL
microfoam interaction with the Nd:YAG laser beam and
both a possible molecular excitation and light scattering
phenomenon that will enhance the effects to obtain the effi-
cient results observed. It appears to be recommended to
perform measurements of the absorption and Raman spectra
on foams before and after exposure to laser radiation.
Acknowledgments
The author thanks Prof. Mihail-Lucian Pascu for his kind
supervision of this study and Dr. Angela Staicu for technical
advice. Also, she acknowledges Dr. Mario Trelles and Dr.
Javier Moreno Moraga for their clinical assistance.
SMARANDACHE
This research work was supported by the ANCS (RO),
projects LAPLAS 3-PN 09 33.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Adriana Smarandache
Lasers Department
National Institute for Laser, Plasma and Radiation Physics
Str. Atomistilor Nr. 409
077125 Magurele
Judetul Ilfov
Romania
E-mail: adriana.smarandache@inflpr.ro