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Confocal laser scanning microscopy to estimate

nanoparticles’ human skin penetration in vitro
This article was published in the following Dove Press journal:
International Journal of Nanomedicine
31 October 2017
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Ying Zou 1,2,* Objective: With rapid development of nanotechnology, there is increasing interest in
Anna Celli 2,3,* nanoparticle (NP) application and its safety and efficacy on human skin. In this study, we utilized
Hanjiang Zhu 2,* confocal laser scanning microscopy to estimate NP skin penetration.
Akram Elmahdy 2 Methods: Three different-sized polystyrene NPs marked with red fluorescence were applied to
Yachao Cao 2 human skin, and Calcium Green 5N was used as a counterstain. Dimethyl sulfoxide (DMSO)
and ethanol were used as alternative vehicles for NPs. Tape stripping was utilized as a barrier-
Xiaoying Hui 2
For personal use only.

damaged skin model. Skin biopsies dosed with NPs were incubated at 4°C or 37°C for 24 hours
Howard Maibach 2
and imaged using confocal laser scanning microscopy.
1
Skin & Cosmetic Research Results: NPs were localized in the stratum corneum (SC) and hair follicles without penetrating
Department, Shanghai Skin Disease
Hospital, Shanghai, People’s the epidermis/dermis. Barrier alteration with tape stripping and change in incubation temperature
Republic of China; 2Department of did not induce deeper penetration. DMSO enhanced NP SC penetration but ethanol did not.
Dermatology, School of Medicine,
Conclusion: Except with DMSO vehicle, these hydrolyzed polystyrene NPs did not penetrate
University of California San
Francisco, San Francisco, CA, USA; intact or barrier-damaged human “viable” epidermis. For further clinical relevance, in vivo
3
San Francisco Veterans Medical human skin studies and more sensitive analytic chemical methodology are suggested.
Center, San Francisco, CA, USA
Keywords: nanoparticles, skin penetration, stratum corneum, confocal laser scanning micros-
*These authors contributed equally copy, tape stripping
to this work

Background
Nanotechnology, a rapidly emerging field, provides new techniques and tools.1
Nanomaterials including nanoparticles (NPs), nanoemulsions and nanosomes are
widely used in pharmacology, cosmetics, medicines, etc.2 NPs, defined as particles
at least one dimension smaller than 100 nm, have been engineered for carrying drug
payloads, imaging contrast agents, or gene therapeutics for diagnosing and treating
diseases, and ingredients in cosmetics.3–5 With increasing NP applications, investi-
gations focus on optimization in therapeutic/cosmetic use and their health hazards.
Since skin is a major target tissue for the exposure of NPs, the assessment of NP skin
penetration has attracted great attention.2
General pathways of skin absorption occur via appendages and through stratum
corneum (SC) to underling layers.6 Skin conditions and NP properties, such as size,
shape and charge, are crucial for skin permeability.7 Investigation of skin penetration
versus different parameters should provide valuable knowledge on promotion or
Correspondence: Ying Zou minimization of NP skin penetration.
Skin & Cosmetic Research Department,
Shanghai Skin Disease Hospital, Qualitative microscopy visualization techniques, including scanning electron
1278 Baode Road, Shanghai 200443, microscopy (SEM), transmission electron microscopy (TEM), fluorescence microscopy
People’s Republic of China
Tel +86 139 1648 1856
and confocal and multiphoton laser scanning microscopy, offer opportunities of nonin-
Email [email protected] vasiveness, high sensitivity and high spatial resolution analysis of NP skin penetration.7

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Conventional microscopy such as light microscopy, SEM fixed flatly on diffusion cells (PermeGear Inc., Hellertown,
and TEM have limitation of artifacts due to sample staining PA, USA) with the dermal side in contact with media.
and/or mechanical section, whereas confocal and multipho- Red fluorescent polymer microspheres of varied size
ton laser scanning microscopy enable researchers to obtain and/or dissolved in different vehicles were dosed on the
three-dimensional image of NP distribution at micrometer surface of samples from the dosing hole on diffusion cell
resolution by way of “optical sectioning.”8 Occupied fluo- and then incubated at 4°C for 24 hours. After clearing excess
rescence confocal laser scanning microscopy can detect NP NPs with PBS, specimens were mounted with SC in contact
distribution in lifetime information. with a glass coverslip and secured on the stage for imaging.
Despite increasing studies on penetration and mechanism For each experiment, a sample without NP dosing was used
of NP distribution in skin, behavior of NPs remains sub as blank control. Imaging of NPs in DMSO and ethanol was
judice with conflicting results reported.2,8 Factors affect- compared with that of original NPs.
ing NP skin penetration, including physicochemical NP To observe the impact of incubation temperature, higher
properties, formulation and environmental and skin condi- temperature (37°C) was compared with routine one (4°C),
tions, make it difficult to draw general conclusions on NP skin both incubated for 24 hours. For skin barrier-damaged
penetration.8 studies, the specimens were tape stripped 20 times on the
In the present study, penetration pathway of fluorescence- area of interest before securing on the perfusion chamber.
marked NPs in ex vivo human skin samples was tracked The intact skin without tape stripping was used as control.
utilizing spectral confocal microscopy; the impact of skin Imaging was performed using a Zeiss LSM 780 confocal
condition, incubation temperature, NP size and vehicles on microscopy system (Carl Zeiss Meditec AG, Jena, Germany).
NP distribution in skin were assessed visually. About 488 nm and 561 nm laser lines were used as excitation
sources for CG5N and NP fluorescence, respectively. The
Materials and methods emitted fluorescence was detected in two separate spectral
Calcium Green 5N (CG5N; Thermo Fisher Scientific, channels centered at 550 nm and 637 nm, respectively, for
Waltham, MA, USA) was employed as skin staining for CG5N and NPs.
autofluorescence. Polystyrene NPs sized 25 nm, 50 nm
and 100 nm, namely red fluorescent polymer microspheres Results
R25/R50 and R100 in water, were obtained from Thermo NPs of different size distributions in
Fisher Scientific. Dimethyl sulfoxide (DMSO; Acros, human skin (water vehicle)
Morris Plains, NJ, USA) and 99% ethanol (Sigma-Aldrich Figure 1 depicts the pattern of NP distribution in human skin.
Co., St Louis, MO, USA) were used as alternative vehicles About 24 hours after topical application, red fluorescence of
for NP dissolution. DMSO and ethanol concentration in NP NPs was clearly observable and especially pronounced on the
dispersion was 80%. topmost skin layers. No penetration was observed in stained
Human skin was excised from five donors (age “viable” epidermal layers (green channel). A prominent NP
42–55 years) with no medical history of dermatological signal was noticeable tracing hair follicles without spreading
disease undergoing abdominal plastic surgery after their to the neighboring cells and tissues.
written informed consent was completed. The procedures
were performed under protocols approved by the University Vehicles (DMSO and ethanol)
of California, San Francisco, and in accordance with the prin- Figure 2 shows NP distribution in human skin when 80%
ciples expressed in the Declaration of Helsinki. This study DMSO and 80% ethanol are used as vehicles. NPs dissolved
was approved by the University of California Institutional in DMSO penetrated deeper; red fluorescence was detected
Review Board. After excision, the subcutaneous fatty tissue in stratum granulosum layer but not in stratum spinosum.
was removed by surgical scalpel. Imaging of specimens dosed with NPs in ethanol showed NPs
After cutting into rectangular pieces, each sample was incu- deposited in SC layer without entering “viable” epidermis.
bated with a 50 μM solution of CG5N with the dermal side in
contact with dye solution. Samples were incubated overnight in Incubation temperature
the dark at 4°C to enable dye penetration. Samples were rinsed Figure 3 shows NP distribution in dosed specimens incubated
in PBS three times to remove excess dye and dried with paper at 4°C or 37°C for 24 hours. Higher temperature did not
tissue. After cutting into 2×2 cm2 pieces, specimens were enhance the penetration depth of NPs.

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 Dovepress CLSM to estimate the skin penetration of nanoparticles in vitro

QP QP QP

6&VXUIDFH
'HUPLV
+DLUIROOLFOH

Figure 1 NPs of different size distributions in human skin.

Notes: Three different-sized NP distributions are shown. Red fluorescence shows the NPs and green fluorescence shows the skin samples. NPs (in red) distribute on the
surface of SC and hair follicles. No penetration to deeper layer was observed. Scale bars =50 μm.
Abbreviations: NPs, nanoparticles; SC, stratum corneum.

NP distribution in barrier-damaged skin of NPs, the mechanism and relative factors remain unclear
Figure 4 shows the image of skin penetration after tape strip- with some conflicting results reported.8
ping. Tape stripping permitted deeper SC penetration. The Several factors may affect skin penetration such as
no-NP location gap between SC layer and granulosum layer physicochemical properties of NPs, formulation (vehicle)
became smaller in tape stripped skin than intact skin, but no and experimental factors.8
traces of NPs presented in granulosum or deeper. Physicochemical properties, such as size and surface
charge of NPs, are key factors of NP skin penetration. 9
Discussion Negatively charged NPs had a greater diffusion coeffi-
NPs have wide applications in cosmetics, pharmaceutics and cient10 and penetrated skin more rapidly,11,12 while positive
biomedicine. Penetration studies provided conflicting data.8 charges acted in an opposite way. Since there is negatively
It is crucial to understand the skin permeability of NPs and charged electrostatic interaction on skin surface, the
its behavior in different skin layers. Clarification of factors potential incentive of charge effect could be a repulsive
that either hinder or enhance NP skin penetration may benefit or attractive force between skin surface and negatively or
the design of an “ideal” carrier or agent of NP for drugs and positively charged NPs, respectively.13 This study focused on
cosmetics. Moreover, since not only intentional applications the effect of particle size on NP skin penetration; neutrally
of drugs and cosmetics were the routes for the exposure of charged polystyrene NPs were chosen to eliminate influences
NPs but also non-intentional ways and environmental expo- of surface charge.
sure could introduce NPs on the skin, there is increasing focus Converse results were reported on skin permeability of
on health risks of NPs. In spite of studies on skin penetration NPs with different sizes.14–17 Studies using animal skin rather

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'062 (WKDQRO
$

% 

 ; —P
      
  
—P
< 




 


= QP 



P


< —
 

= QP
 
; —P 




Figure 2 Distribution of NPs dissolved in DMSO and ethanol.

Notes: Red fluorescence of DMSO-dissolved NPs (size 25 nm) is detected in stratum granulosum layer. Arrows show the penetration of NPs to deeper layer in longitudinal
section (A, left) and 3D images (B). No red fluorescence of ethanol-dissolved NPs (size 25 nm) was observed in granulosum and deeper layers (A, right). Scale bars =50 μm.
Abbreviations: 3D, three-dimensional; DMSO, dimethyl sulfoxide; NPs, nanoparticles.

QP QP QP

°&
°&

Figure 3 Distribution of NPs incubated in different temperatures.

Notes: Three different-sized NP distributions are shown. NPs (shown in red fluorescence) distribute in SC after incubation under both 4°C and 37°C. No red fluorescence
is shown in deeper layers. Scale bars =50 μm.
Abbreviations: NPs, nanoparticles; SC, stratum corneum.

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 Dovepress CLSM to estimate the skin penetration of nanoparticles in vitro

QP QP QP

,QWDFWVNLQ
7DSHVWULSSHG

Figure 4 Distribution of NPs in barrier-damaged skin.

Notes: Three different-sized NP distributions in both intact and barrier-damaged skins are shown. The no-NP location gap between SC layer and granulosum layer became
smaller in barrier-damaged skin than in intact skin, but no red fluorescence of NPs presented in granulosum and deeper layer. Scale bars =50 μm.
Abbreviations: NPs, nanoparticles; SC, stratum corneum.

than human skin showed a positive result of skin penetration.8 skin layers. However, ethanol did not alter NP penetration in
Zvyagin et al18 suggested that animal skin represents a poor the size range of 25–100 nm in human skin. Being absorbed
model for human skin for the studies on NP transdermal into corneocytes, DMSO may change keratin conformation
penetrability. Differences between these skins, especially hair and then enhance NP penetration.23
follicle density, SC thickness, whole skin and skin lipid mass,19 Temperature is considered a critical factor in chemical
could lead to different results. Due to structural and morpho- penetration;25–27 however, no previous study investigated
logical differences between human and animal skin, excised the influence of temperature on NP penetration to our best
human skin is regarded as a “gold standard” for in vitro skin knowledge. In the current study, skin samples were incubated
penetration studies.20 Therefore, we employed excised human at 4°C and 37°C after dosage. No further penetration was
skin in this study. Three different-sized polystyrene NPs detected at higher temperature, indicating that NP penetration
(25 nm, 50 nm and 100 nm) were assayed on their distributions was stable under different temperature conditions.
in SC and hair follicles. Permeability of each sized NP made no There are two general pathways for skin absorption:
difference in excised human skin, and no “viable” epidermal through SC and the underlying layers and along skin append-
penetration was observed. The results were consistent with ages. No NP penetration through SC was observed in this
some reports using human skin8,18,21 and animal skin.16,17 study, except when DMSO was used as an enhancer. Via hair
Barrier function of SC against molecule penetration in follicles, NPs may reach deep into subcutaneous fat; however,
general depends on its protein, lipid and water compartments.22 hair follicle also contains an efficient barrier, which is similar
Vehicle may alter the nature of skin barrier or even the physi- to SC in upper part and features tight junction in lower part.
cal state of NPs, which makes it another factor affecting NP This barrier inhibits NPs invading into viable cells. Thus,
penetration.15 Labouta et al23 studied the effect of DMSO on traces into hair follicles are not yet a deep absorption process,
the penetration of gold NPs (AuNPs, φ=10 nm) in human as they remain on the outside of the body by definition.
skin and showed enhanced NP transport in the presence of NPs stored in hair follicles could also be extruded by hair
DMSO. Kuo et al24 demonstrated ethanol as an enhancer growth and sebum flow. Lademann et al28 found that NPs
of zinc oxide NPs (φ=10 nm) in animal skin. Our study located in SC were removed after 24 hours, while that in hair
evaluated the effect of DMSO and ethanol on aqueous NP follicles remained more than 10 days, whereas non-particles
penetration. NPs dissolved in DMSO penetrated into deeper only stored in hair follicles up to 4 days.29 Therefore, hair

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follicles, representing an efficient reservoir for NPs, can be

a potential target of NP carrier system for drug delivery,
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