Journal of Biomedical Engineering Research 43: 271-279 (2022)
http://dx.doi.org/10.9718/JBER.2022.43.4.271
학 술 논 문
Skin-Mimicking Phantom for Measurment of Cosmetic
Transdermal Absorption and Temperature Changes by
Sonophoresis
Gahee Kimǂ, Hwijin Jangǂ, Seonmin Choi, Sanghyo Park,
Woo Cheol Kim and Jaehong Key*
Department of Biomedical Engineering, College of Software and Digital Healthcare Convergence, Yonsei University,
Wonju, South Korea
(Manuscript received 8 August 2022 ; revised 19 August 2022 ; accepted 23 August 2022)
Abstract: Functional cosmetics containing various ingredients that improve skin health are currently being developed.
In addition, technologies that help increase the absorption rate of such cosmetics have recently gained significant
attention. Sonophoresis is a method to increase the transdermal absorption of cosmetics using ultrasound. A skinmimicking phantom was fabricated using polydimethylsiloxane, Strat-MTM membrane, and thermochromic pigments.
Gel-type cosmetics used in skin mask packs and epidermal-growth-factor-based nano-cosmetics were tested for their
absorption rates at ultrasound frequencies of 1, 3, and 10 MHz in the single frequency mode, and 1/3 and 3/10 MHz
in the dual frequency mode. The gel-type cosmetics and epidermal-grow-factor-based nano-cosmetics showed the highest
absorption rate at 3/10MHz dual frequency. The size of the cosmetic particles decreased by 5-9 %. Furthermore, the
temperature rise caused by ultrasound could be visually recognized by the thermochromic pigment in the phantom
turning white. We presented a skin-mimicking phantom. The device can be customized according to the size of the ultrasound probe and has the advantage of quantitatively evaluating the transdermal permeability of cosmetics at a low cost.
The development of the skin-mimicking phantom will be useful for determining the suitable conditions required to
increase the absorption rate of cosmetics using ultrasound.
Keywords: Nano-cosmetic, Sonophoresis, Skin absorption, Skin-mimicking phantom
I. Introduction
continued to grow at a compound annual growth rate (CAGR)
of 6.4% from 2015 to 2020 and reached approximately
In recent years, the cosmetics market has shown a
$8.1 billion in 2019 [1]. Functional cosmetics, which
substantial growth worldwide, and it has great poten-
include active ingredients that provide benefits such
tial. In particular, the functional cosmetics market is
as wrinkle improvement, anti-aging, skin whitening, and
growing rapidly. In fact, the size of the European market,
skin protection, are being developed and commercia-
the largest cosmetics market, was 96.37 billion euros
lized. Furthermore, technologies that help increase the
in 2018, an increase of 3.2% compared to the previous
absorption rate of the active ingredients into the skin
year and is expected to reach 110.19 billion euros in
have recently gained significant interest [2].
2022. Moreover, the second largest market in the U.S.
The skin has low permeability, and only a few components in limited quantities are absorbed by it. In par-
*Corresponding Author : Jaehong Key
Department of Biomedical Engineering, Yonsei University,
1 Yonseidae-gil, Wonju, Gangwon-do, 220-710, Korea
Tel: +82-33-760-2587
E-mail: jkey@yonsei.ac.kr
ǂ
Contributed equally to this work.
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (grant
no. 2022RIS-005, and 2022R1F1A1069516).
ticular, a hydrophilic molecule or a large molecular-weight
compound is hardly absorbed [3]. Although ionized drugs
and some water-soluble drugs are absorbed faster through
the skin appendages than through keratin, these appendages occupy only 0.1% of the skin surface area [4]. This
low permeability of the skin is predominantly caused
by its outermost layer, namely, the stratum corneum,
271
Skin-Mimicking Phantom for Measurment of Cosmetic Transdermal Absorption and Temperature Changes by Sonophoresis - Gahee Kim et al.
which is composed of keratin cells, which are protein
absorption of cosmetics under the effect of ultrasound
cells with hard crystal structure. These cells are sur-
and has the advantage of being easily customizable
rounded by a lipid bilayer; hence, cosmetics must pass
even when the ultrasound probe size is 5–25 mm or
through this lipid bilayer to be absorbed into the human
more. Therefore, this study proposes a cost-effective
body through the stratum corneum [3,5,6]. The skin is
device that can assist in repeated quantitative mea-
an effective biological barrier, which blocks the absorption
surements of the transdermal absorption rate of various
of cosmetics. Therefore, formulation and physical approaches
cosmetics and in the evaluation of the temperature
are used to effectively penetrate these barriers. The
changes in the skin.
physical approaches include iontophoresis, electroporation and sonophoresis. The formulation approaches
II. Materials and Methods
include polymer hydrogels, polymer micelles, nanoemulsions, ethosomes, and elastic liposomes [4,7]. In this study,
sonophoresis was employed to effectively promote per-
PDMS is used to make a skin-mimicking phantom
cutaneous absorption. Ultrasound is a sound wave above
(shown in Fig. 1). PDMS (Silicone Elastomer Kit, Dow
the audible range, i.e., beyond 20 kHz and is known to
corning, Midland, USA) and an elastomer were mixed
promote the absorption of substances into the skin.
in a weight ratio of 10:1 and placed into a mold to
Sonophoresis increases the skin temperature and improves
obtain a transparent layer of a skin-simulating phan-
the skin permeability by instantaneously changing the
tom. The 10:1 mixture was further mixed with a ther-
lipid bilayer [8,9].
mochromic pigment and arranged as a temperature-
However, the absorption of cosmetics cannot be directly evaluated in humans, and animal testing involves
272
1. Fabrication of a skin-mimicking phantom
sensing layer to produce a two-layered skin-simulating
phantom.
serious ethical issues. Furthermore, several laws are
being enforced against animal testing across the globe
2. Measurement of temperature variation using skin-
[10]. Therefore, the Franz diffusion cell is generally
mimicking phantom
used to indirectly check the absorption of cosmetics
Using thermochromic pigments of 40, 50, 60, and 70 °C,
[11,12]. Generally, Franz diffusion cells use glass and
temperature changes were measured using 1 MHz
have a standard diameter of 5–25 mm. However, when
ultrasound according to the conditions listed in Table 1. A
ultrasound is directly processed, glass may break at
non-sonicated control was compared with the control
the resonance point. Moreover, because a Franz diffusion
after being subjected to 3 min and 9 min of sonication.
cell has a donor in its structure, it is difficult to directly
subject the membrane to ultrasound. In addition, fre-
3. Ultrasound
quency fluctuations via the glass might influence per-
An ultrasound device for dermatology, SONOCARE
meability and the use of ultrasound can drastically
(Newpong Co., Ltd., Seoul, South Korea), was used to pro-
change the temperature of the skin. Therefore, a skin-
mote percutaneous absorption. This device produces
mimicking phantom capable of observing these chan-
ultrasound of 1, 3, and 10 MHz in the single frequency
ges in the skin temperature when it is subjected to
mode and frequencies of 1/3 and 3/10 MHz in the dual
sonophoresis is required. Hence, a skin-simulating
frequency mode. The safest temperature that could be
phantom was manufactured using polydimethylsiloxane
achieved was 45–48°C. Changes in the skin surface
(PDMS) and thermochromic pigments. PDMS has been
temperature owing to ultrasound exposure were observed
widely used over the past 10 years to fabricate phantoms
in real-time using the thermochromic pigment, which
that mimic the optical, physical, and thermal properties
was used in the PDMS production.
of biological tissues and to evaluate various performances
[13-15]. In addition, PDMS has good molding processability,
4. Strat-MTM membrane
durability, and flexibility; thus, the phantom designed
Strat-MTM membrane (Merck KGaA, Darmstadt, Ger-
in this study can safely measure the degree of skin
many) was used as a skin substitute on the skin-mim-
Journal of Biomedical Engineering Research 43: 271-279 (2022)
Fig. 1. PDMS (Polydimethylsiloxane) skin mimicking tissue phantom. (A)Schematic illustration of the skin mimicking
phantom for evaluation of transdermal absorption of cosmetics and measurement of temperature change by ultrasound
treatment. (B) The skin-mimicking phantom measured under ultrasound exposure and magnetic stirring.
Table 1. Ultrasound conditions for each frequency
273
Single Frequency
Output (W/cm2)
Dual Frequency
1 MHz
3 MHz
10 MHz
1/3 MHz
3/10 MHz
1.22
1.44
1.46
1.36/0.86
1.52/1.52
icking phantom in the transdermal diffusion test mode
(Daewoong, Co., Ltd., Seoul, South Korea), the ultrasound
[16-24]. The thickness of the Strat-MTM membrane
device was placed directly above the phantom. The
was approximately 300 µm and it had a multi-layered
space at the bottom of the Strat-MTM membrane was
structure with layers that mimicked human skin tissues
filled with a 1:1 aqueous solution of deionized water
such as the epidermis, dermis, and subcutaneous tis-
(D.W) and Ethanol.
sue [25,26].
An aqueous solution of D.W and Ethanol (1:1) was
injected and discharged using syringes on both sides
5. Measurement of transdermal absorption using a skin-
of the phantom, following the in vitro skin absorption
mimicking phantom
guidelines by the Korean Ministry of Food and Drug
A Strat-M
TM
membrane was placed on the PDMS-
based phantom. The membrane was fixed using tape
Safety. A magnetic stirrer was used to circulate the aqueous solution inside the well of the phantom.
to prevent the penetration of cosmetics through the
Furthermore, the membrane and mixed solution were
space between the membrane and phantom, as well as
ensured to be in direct contact such that the cosmetic
the movement of the membrane due to ultrasound. After
that passed through the membrane was mixed with the
applying 200 µL of gel-type cosmetics from an MK Mask
aqueous solution. Ultrasound was applied according
pack (Mankil, Co., Ltd., Seoul, South Korea) and epi-
to the conditions for each ultrasound frequency, as
dermal growth factor (EGF)-based ampoule cosmetics
detailed in Table 1. and 1 ml of the aqueous solution
Skin-Mimicking Phantom for Measurment of Cosmetic Transdermal Absorption and Temperature Changes by Sonophoresis - Gahee Kim et al.
was injected and discharged according to the ultrasound
Differences were considered to be statistically significant
treatment time (1, 3, 5, 7, and 9 min). The non-sonicated
when *p<0.05, **p<0.01, ***p<0.005, and ****p<0.001.
group was chosen as the control group and compared
with the experimental group. The aqueous solution
III. Results
discharged for each treatment time was transferred to
a 96-well plate, and the change in absorbance was mea-
1. Evaluation of cosmetics
sured at a wavelength of 290 nm. The absorbances of
The skin-mimicking phantom used in this study was
cosmetics were measured using a Synergy HTX multi-
manufactured using PDMS according to the size of the
mode reader (BioTek Instruments, Inc., Winooski, VT,
ultrasound probe. The skin-mimicking phantom had a
USA). The percutaneous absorption of cosmetics was
diameter of 5.4 cm and a height of 1.3 cm (shown in
obtained by inverse calculations according to the stan-
Fig. 1). The calibration curves of the EGF ampoule
dard curve of each cosmetic. The percentage was obtained
cosmetics and mask pack cosmetics determined by lin-
through the x value of the equation of the standard
ear regression were y = 2.1783x + 0.046 (R2 = 0.9956)
curve.
and y = 1.1314x + 0.0456 (R2 = 0.9974), respectively. The
All experiments were repeated five times to confirm
reproducibility.
x and y axes represent absorbance values for each
concentration of cosmetics (shown in Fig. 2B. and Fig.
3B.). The absorbance value refers to the amount of
6. Statistical analysis
cosmetics that have penetrated the membrane by
The data were expressed as mean ± standard devi-
ultrasounds. The cumulative absorbances of the mask
ation and comparisons were performed using one-way
pack at control 0.024 and single frequencies of 1, 3,
ANOVA tests (SystatSoftware, Inc., Chicago, IL, USA).
and 10 MHz were 0.138, 0.067, and 0.124, respectively,
274
Fig. 2. Evaluation of MK mask pack. (A) Absorbance of cosmetic. (B) Standard curve of cosmetic. (C) The cumulative absorbance of cosmetic over time by ultrasound frequency. (D) Cosmetic penetration percentage by ultrasound frequency.
Journal of Biomedical Engineering Research 43: 271-279 (2022)
275
Fig. 3. Evaluation of EGF ampoule. (A) Absorbance of cosmetic. (B) Standard curve of cosmetic. (C) The cumulative absorbance of cosmetic over time by ultrasound frequency. (D) Cosmetic penetration percentage by ultrasound frequency.
whereas these absorbance values at the dual frequen-
whereas at dual frequencies of 1/3 and 3/10 MHz, the
cies of 1/3 and 3/10 MHz were 0.070 and 0.212, respec-
inverses of the absorbances of the EGF ampoule were
tively (shown in Fig. 2C.). The cumulative absorbance
9.05 % and 16.75 %, respectively (as shown in Fig. 3D).
of the EGF ampoule at control was 0.068; at single fre-
After ultrasound of the mask pack and EGF Ampoule,
quencies of 1, 3, and 10 MHz, these values were 0.212,
it was confirmed through Scanning electron microscope
0.237, and 0.190, respectively; whereas, at the dual
(SEM) that there were cosmetics in the D.W+Ethanol
frequencies of 1/3 and 3/10 MHz, the absorbances were
aqueous solution (Fig. 5). Fig. 2D. and Fig. 3D. show a
0.243 and 0.410, respectively (as shown in Fig. 3C.).
comparison of the results, including the statistical sig-
Inverse calculations were performed to convert the
nificance of the cosmetic penetration effect with varying
absorbance values into percentages (%). In the case of
frequencies. In the case of the MK mask pack, there is
the MK mask pack, the inverse of the absorbance at
a significant difference at all frequencies when com-
control was 0 %; at single frequencies of 1, 3, and 10 MHz,
pared to the control (p<0.001). In the case of EGF Ampoule,
these values were 8.17 %, 1.94 %, and 6.94 %, respec-
there is a significant difference compared with the control
tively; whereas at dual frequencies of 1/3 and 3/10
(1MHz, 1/3MHz, and 3/10MHz: p<0.001;3 MHz: p<0.005;
MHz, the inverses of the absorbances were 2.23 % and
10 MHz: p<0.01). As a result, the penetration rate changed
14.75 %, respectively (as shown in Fig. 2D.). The inverse
according to each frequency. Interestingly, the highest
of the absorbance of the EGF ampoule at control was
cosmetic penetration was confirmed at a dual frequency of
0.48 %; at single frequencies of 1, 3, and 10 MHz, these
3/10 MHz for both the MK mask and the EGF ampoule.
values were 7.65 %, 8.78 %, and 6.61 %, respectively;
Skin-Mimicking Phantom for Measurment of Cosmetic Transdermal Absorption and Temperature Changes by Sonophoresis - Gahee Kim et al.
2. Variation in size and zeta potential of the EGF ampoule
cosmetic using ultrasound
Nanoemulsion is a method of synthesizing nanoparticles that generally have a size of 20–500 nm. Nanoparticles that are fabricated as a nanoemulsion penetrate
the skin much faster than macroemulsion [27,28]. This
experiment examined whether the average particle size
of the EGF ampoule cosmetics, which was 227 nm, was
changed by the ultrasound. Here, the EGF ampoule
cosmetics were exposed to ultrasound for different
durations. The results were confirmed by dynamic light
scattering (DLS). The particle sizes of the cosmetics at
single frequencies of 1, 3, and 10 MHz decreased by
5.89 %, 6.93 %, and 6.73 %, respectively, whereas at the
cross frequencies of 1/3 and 3/10 MHz they decreased
by 7.46 % and 9.2 %, respectively. Thus, the cosmetic
particle size decreased as the sonication time increased
at both the single and dual frequencies. In particular,
the largest change in particle size was observed at a
dual frequency. This result supported the explanation for
increased penetration rate when using a dual frequency
276
(shown in Fig. 4). In the case of mask pack cosmetic, it
was hard to accurately measure the size with DLS
due to problem in gel formulation and its viscosity.
The exact size was confirmed through SEM.
The zeta potential of the EGF ampoule was -40.53 mV
before sonication; after 3 min ultrasound at frequencies of
1, 3, and 10 MHz, these values were -47.2, -46.56, and
-41.06 mV, respectively. Further, the zeta potentials
after ultrasound at the dual frequencies of 1/3 and 3/
10 MHz were -47.73 and -47.43 mV, respectively. Moreover, after 9 min ultrasound at frequencies of 1, 3, and 10
MHz, the zeta potentials were -48.23, -51.6, and −54.6 mV,
respectively. Further, after ultrasound at the dual frequencies of 1/3 and 3/10 MHz, these values were -47.73
and -48 mV, respectively. Thus, after ultrasound, the
zeta potential decreased to a higher negative value in
all frequency conditions, which can be explained by the
decrease in the particle size and increase in the surface
area of the particle, consequently inducing a more
negative shift in the charge (Fig. 4).
3. Skin-mimicking phantoms, including various thermochromic pigments
Thermochromic pigments that change color accord-
Fig. 4. Variation in size and zeta potential of the epidermal
growth factor (EGF) ampoule cosmetic using ultrasound
sonication. (A) Single frequency of 1,3,10 MHz. (B) Dual frequency of 1/3MHz, 3/10MHz.
Journal of Biomedical Engineering Research 43: 271-279 (2022)
range frequencies is known to increase the temperature up to 65°C [29], and the experiments were conducted at 40, 50, 60, and 70°C. The color changes of
the phantom as a function of temperature were observed
up to 60°C (as shown in Fig. 6).
IV. Discussion and Conclusion
The stratum corneum of the skin acts as a major
barrier that limits the penetration of substances into
Fig. 5. SEM image of MK-mask pack and EGF ampoule cosmetics
present in D.W+Ethanol aqueous solution through StratMTM membrane after ultrasound (Scale bar: 1 µm).
the skin. The sonophoresis method can increase the
skin permeability of cosmetics non-invasively using
ultrasound [30,31]. Therefore, the absorption rate of
cosmetics was quantitatively evaluated using single
ing to the temperature change were used in this phantom
and dual frequencies. It was confirmed that, compared to
model. The thermochromic pigments exists in the
the untreated control group, there was a statistically
temperature change layer of the two layers of the PDMS
significant increase in the experimental group treated
phantom, and becomes transparent at a certain
with sonication. Both the mask pack and the EGF
temperature or higher. In this experiment, thermochromic
ampoule showed a significant difference at 3/10 MHz.
pigment that change a 40, 50, 60, 70°C or higher were
In the case of a single frequency, the mask pack cos-
prepared, respectively, and the colors for each temperature
metics showed a high absorption rate at 1 MHz, whereas
were set to blue to 40°C, red at 50°C, black at 60°C,
the EGF ampoule cosmetics did not show a statistical
and yellow at 70°C. The thermal effect of ultrasound
difference between 1 and 3 MHz. The results were
was investigated using color change with respect to
expected to be significantly affected by low frequen-
the ultrasound treatment time. Ultrasound at MHz
cies for the mask pack cosmetics. The particle size of
the mask pack was not in the nanoscale; therefore, a
low frequency provided a better penetration. In contrast, for the EGF ampoule cosmetics, which are based on
nanoparticles, the particles were well absorbed in both
1 and 3 MHz frequencies. Nanoparticle-based cosmetics may have had a high absorption rate due to their
small sizes regardless of external stimuli. For the dual
frequency measurements, both the mask pack and EGF
ampoule cosmetics had higher absorption rates at 3/
10 MHz, and the particle size change in the cosmetics
was the largest at the dual frequency mode. The penetration depth was measured as the distance after the
sound intensity is reduced to 50 % of that at the skin
surface. The penetration depths at 1 and 3 MHz were
3 and 1 cm, respectively[32], whereas, in the case of
ultrasound with 10 MHz, the penetration depth was only
0.3 cm. This observation can be expected to have an intensive sonophoresis effect on the stratum corneum. A
Fig. 6. Color change after ultrasound on a skin mimicking
phantom using various thermochromic pigments.
stimulation at 10 MHz has been reported to be mainly
effective for the epidermis and dermis, where aging or
277
Skin-Mimicking Phantom for Measurment of Cosmetic Transdermal Absorption and Temperature Changes by Sonophoresis - Gahee Kim et al.
pathological changes occur[31]. Therefore, although
sound exposure time. Therefore, this skin-mimicking
the frequency penetration depth of 10 and 3 MHz was
phantom can suggest the ultrasound intensity, frequency
lower than that of 1 MHz, the skin stimulation by the
range, and exposure time to optimize the skin per-
dual frequency of 3/10 MHz may be a more efficient
meability of various cosmetics. Since only one ultrasound
combination for penetrating cosmetics. Additionally,
device is used and cosmetics are limitedly evaluated,
increasing sonication resulted in a decrease in par-
it is necessary to apply it to various ultrasound devices
ticle size, and the particle size distribution was narrowed
that are being put into practical use. Accordingly, if a
due to the cavitation force [33]. As a result, the sono-
database is established by evaluating various ultra-
phoresis method using dual frequency could be a non-
sound devices and cosmetics through future research,
invasive method to reduce the particle size of cosmetics
it is expected to be a new tool to evaluate the in vitro
and promote their absorption effectively.
penetration percentage of cosmetics.
Alberti, M., et al. reported a phantom model simulated
on a microfluidic chip by simulating the main functions of
Declaration of Competing Interest
the Franz diffusion cell method, which is a represen-
The authors declare no competing financial interest.
tative in vitro skin permeation measurement method,
to determine the skin drug permeability [34]. In addi-
References
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278
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because the ultrasound device probe in practical use
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However, the skin mimicking phantom presented in
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without multilayer or micropattern, and can be customized according to the size of the ultrasound probe.
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cosmetics at a low cost. In addition, the temperature
rise caused by ultrasound can be visually recognized by
this method, thus providing a guideline of the ultra-
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