Advanced Drug Delivery Reviews 127 (2018) 35–45

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Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Device-assisted transdermal drug delivery☆

Hyunjae Lee a,1, Changyeong Song a,b,1, Seungmin Baik a,b,1, Dokyoon Kim a,
Taeghwan Hyeon a,b,⁎, Dae-Hyeong Kim a,b,⁎
a
Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Republic of Korea
b
School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: Transdermal drug delivery is a prospective drug delivery strategy to complement the limitations of conventional
Received 12 May 2017 drug delivery systems including oral and injectable methods. This delivery route allows both convenient and
Received in revised form 19 August 2017 painless drug delivery and a sustained release profile with reduced side effects. However, physiological barriers
Accepted 29 August 2017
in the skin undermine the delivery efficiency of conventional patches, limiting drug candidates to small-mole-
Available online 1 September 2017
cules and lipophilic drugs. Recently, transdermal drug delivery technology has advanced from unsophisticated
Keywords:
methods simply relying on natural diffusion to drug releasing systems that dynamically respond to external stim-
Transdermal drug delivery uli. Furthermore, physical barriers in the skin have been overcome using microneedles, and controlled delivery by
Microneedles wearable biosensors has been enabled ultimately. In this review, we classify the evolution of advanced drug de-
Wearable biosensors livery strategies based on generations and provide a comprehensive overview. Finally, the recent progress in ad-
Controlled drug delivery vanced diagnosis and therapy through customized drug delivery systems based on real-time analysis of
Soft bioelectronics physiological cues is highlighted.
© 2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2. Advancement of transdermal drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.1. First generation: diffusion-based transdermal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.2. Second generation: non-invasive transdermal drug delivery with actuation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.3. Third generation: minimally invasive transdermal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3. Fourth generation: controlled and feedback-induced transdermal drug delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.1. Transdermal drug delivery based on physiological/electrophysiological monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.2. Transdermal drug delivery based on biochemical signal monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.3. Smart microneedle systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

1. Introduction
Abbreviations: RF, radiofrequency; DMF, dimethylformamide; DMSO, dimethyl
sulfoxide; MSN, mesoporous silica nanoparticle; NP, nanoparticle; PCM, phase change
material. The growing demand for patient-friendly therapies has led to the de-
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Skin- velopment of transdermal drug delivery that has several advantages
Associated Drug Delivery". over conventional drug delivery methods. For instance, transdermal de-
⁎ Corresponding authors at: Center for Nanoparticle Research, Institute for Basic Science
(IBS), Seoul 08826, Republic of Korea.
livery enables sustained and controlled drug release, and promotes pa-
E-mail addresses: thyeon@snu.ac.kr (T. Hyeon), dkim98@snu.ac.kr (D.-H. Kim). tients' compliance and convenience with its non-invasiveness and
1
These authors contributed equally to this work. painlessness [1]. In particular, transdermal route is a good alternative

http://dx.doi.org/10.1016/j.addr.2017.08.009
0169-409X/© 2017 Elsevier B.V. All rights reserved.
36 H. Lee et al. / Advanced Drug Delivery Reviews 127 (2018) 35–45

to needle injection or oral intake of medication. Transdermal delivery
often requires a lower dosage of drugs than oral administration. With
a short diffusive pathway to reach vasculature, transdermal mode
helps the patients to circumvent side effects due to digestion and me-
tabolism of the drug in the gastrointestinal tract. Transdermal delivery
is painless and non-invasive, the advantage which is prominent against
intravenous or intramuscular administration. The non-invasiveness al-
lows repeated administrations of the drug over the same region of the
body for a long-term treatment, and thus provides patients with com-
pliance and convenience.
However, transdermal drug delivery is not a flawless drug transport
method. The stratum corneum, the outermost barrier of the skin against
foreign materials, imposes an obstacle to the transdermal diffusion of
drugs [2]. Since only a few small-molecule drugs with high lipophilicity
can naturally permeate through the hydrophobic stratum corneum, a
vast majority of hydrophilic drugs have been ruled out against transder-
mal delivery. Even after the drug successfully penetrates the stratum
corneum, it may be degraded prematurely by epidermal enzymes,
resulting in decreased bioavailability. Latency in the onset of action as
well as a lack of pharmacokinetic control may also undermine the reli-
ability of the transdermal delivery.
The endeavor for a better transdermal delivery has evolved towards
overcoming such limitations, and the innovation has been seen in sever-
al generations, namely, focusing on drug formulation, external actua-
tion, and minimally invasive microneedles. The first generation of
transdermal delivery focused on refining the drug formulation to max-
imize its diffusion through the skin as manifested by emulsions, nano-
carriers, and chemical enhancers. The second generation has sought ex-
ternal forces, such as heat and electricity, to energetically fuel the drug
to cross the epidermal layers and reach the vasculature. The third gen-
eration incorporated microneedles, which puncture the outer skin
layer but preserve the dermis, to provide the drug with a physical short-
cut bypassing the epidermal barriers. The breakthroughs of previous
generations have greatly improved the efficiency of transdermal drug
delivery.
Although the betterment of transdermal delivery so far has focused
on maximizing the delivery efficiency, transdermal drug delivery is
yet to see another breakthrough by adopting a paradigm shift towards
personalized therapy [3–5]. Furthermore, transdermal delivery is set
to adopt an advanced paradigm of device-assisted personalized therapy
where the precise control of the amount and duration of a drug dose in
response to the patient's physiological condition is a key to maximizing
the therapeutic efficacy (Fig. 1a and b). The controlled and on-demand
administration of a drug tailored to the needs of each patient requires
extensive innovation. Wearable devices may be a viable and useful
strategy because they can collect an assortment of physiological [6–
15], electrophysiological [16–21], and biochemical [22–27] cues, and
thereby, facilitate drug delivery via energetic actuations.
In this review, we recapitulate the major breakthroughs of four gen-
erations of transdermal drug delivery strategies, providing the reader
with the detailed advantages and challenges of each generation. In ac-
cordance with a growing interest in controlled drug release for person-
alized medical treatment, we also emphasize the recent progress on
wearable devices that support device-assisted transdermal drug deliv-
ery. This review concludes with case presentations to demonstrate the
wearable biosensors and advanced transdermal delivery schemes that
are seamlessly integrated. Thereby, we hope to present a novel potential
protocol and foundation for the next generation of personalized
therapy.
2. Advancement of transdermal drug delivery systems
Among the anatomical layers and appendageal structures of the skin
(Fig. 2a), the epidermis and its outermost stratum corneum are the most
challenging barriers to transdermal delivery [28,29]. The brick-and-
mortar assembly of keratinocytes and intercellular lipids renders the
epidermis impregnable to most foreign materials. Therefore, a cursory
observation of transdermal delivery can regard it as a counterintuitive
strategy for delivering a drug systematically. However, a detailed analy-
sis reveals that transdermal delivery provides a number of advantages
over oral intake or hypodermic injections. Compared with oral delivery,
transdermal delivery requires a lower dosage and has fewer side effects
because transdermal diffusion circumvents the digestion and first-pass
metabolism of the active drug in the gastrointestinal tract and liver
[30]. Moreover, transdermal delivery is less painful, minimally invasive,
and convenient to patients so that the compliance with drug adminis-
tration increases to a great extent. Because such advantages offset the
drawbacks of transdermal delivery, studies continue to develop reliable

a b

Body
temperature

Diagnosis

Blood Blood
pressure glucose
Device-assisted
transdermal
drug delivery

Therapy

Microneedle
Iontophoresis
Device-assisted
transdermal drug
delivery Heat

Fig. 1. (a) Schematic illustration of the device-assisted transdermal drug delivery for patient-customized skin-based therapy. (b) The wearable device system conducts real-time
monitoring of vital signs and actuates transdermal drug delivery according to individual health condition.
 H. Lee et al. / Advanced Drug Delivery Reviews 127 (2018) 35–45
a Sweat gland pore
b 1st generation
Hair shaft
Epidermis
Dermis
d 3rd generation
Subcutaneous
layer
Capillary
Tactile
corpuscle
Sweat gland duct
Fig. 2. (a) Schematic illustration of human skin. (b) First generation transdermal drug delivery technology via natural diffusion of drugs. (c) Second generation transdermal drug delivery
technology for actuated drug delivery via external stimulation. (d) Third generation transdermal drug delivery technology for enhanced drug transport via microneedle-mediated
destruction of skin layer and various functionalities accompanying microneedles. (e) Fourth generation transdermal drug delivery technology for patient-customized therapy with the
assistance of wearable devices.
delivery systems and broaden the library of applicable candidate drugs.
Novel designs of transdermal patches to increase the skin penetration of
drugs have been widely investigated, and major breakthroughs have
been observed as the evolving generations of transdermal delivery
systems.
The research on the first generation of transdermal drug delivery
systems focused on tailoring the physicochemical properties of chemi-
cal drugs. Drugs for transdermal delivery are either selected or modified
to have a high partition coefficient and a low molecular weight for facile
diffusion through the skin barrier (Fig. 2b). The second-generation re-
search focused on improving the skin permeability of drugs using chem-
ical enhancers and stimulators through external driving forces (Fig. 2c).
Chemical enhancers [31,32] and emulsion/nano-carriers [33–36] solu-
bilize the drugs and facilitate their easy penetration into the skin. Exter-
nal actuation using heat [37], electricity [38], or noncavitational
ultrasound [39] also facilitates drug transportation. The third-genera-
tion research adopted methods that cause microscopic destruction of
epidermis to facilitate the delivery of drugs. Radiofrequency (RF) abla-
tion [40], ultrasound [41], and lasers [42,43] disrupt the stratum
corneum temporarily and enhance drug penetration through the weak-
ened barrier. Microneedles are another approach of microinvasive
transdermal delivery with vastly diverse drug candidates [44–47]. The
microneedles create micrometer-sized porations in epidermis, which
serve as an unobstructed pathway for incoming drugs (Fig. 2d). Since
the size of the microneedles leaves the dermal and hypodermal layers
untouched, the microneedle is considered virtually painless and mini-
mally invasive.
While breakthroughs in transdermal delivery in previous genera-
tions have focused on maximizing the efficiency of drug delivery, the re-
cent growth in personalized medicine requires a new generation of the
drug delivery system aimed at controlled and feedback-induced trans-
dermal release of drugs. Wearable devices consisting of sensors and ac-
tuators are expected to meet such needs [48–50]. Indeed, novel
materials design and device fabrication have spurred the innovation in
wearable devices for biomedical application, providing a new opportu-
nity in personalized healthcare [51]. By precisely monitoring the key in-
dicators of disease treatment and potential side effects of the delivered
drugs, decisions can be rapidly made on the appropriate amount of drug
to be delivered. The external energy stimulates and controls state-of-
the-art transdermal delivery systems. Device-assisted transdermal de-
livery, an ensemble of soft bioelectronics and a transdermal drug deliv-
ery system, simultaneously controls the release of drugs and monitors
the alteration of the physiological states by the drug (Fig. 2e). The
37
c 2nd generation
Drug-loaded
patch External
stimuli
Natural Actuated
Skin diffusion diffusion
e Wearable 4th generation
Actuation device
Penetration Signal Drug
monitoring delivery
cycle of diagnosis, actuated drug release, and follow-up diagnosis con-
stitute a feedback loop that provides patients with a precise and person-
ally customized medical treatment.
2.1. First generation: diffusion-based transdermal drug delivery
Transdermal drug delivery is an attractive drug delivery option be-
cause it offers several advantages. First, dermal layers provide the
drug a shorter route to the bloodstream than gastrointestinal tract
does [1]. Particularly, transdermal shortcut also enhances bioavailability
and reduces the dosage because the drug avoids the extensive first-pass
metabolism and degradation in liver. Second, patients usually comply
with transdermal drug administration because a drug patch is painless,
non-invasive, and easy to use. A long-lasting patch that provides
sustained drug release for up to several days is convenient for patients,
and its non-invasiveness allows repeated drug application over the
same part of the body. Freedom from pain, compared particularly to
needle-based injections, increases the popularity and acceptance of
the transdermal delivery.
The first generation of simple transdermal patches emerged during
the early 1970s. Following the first approval from the U.S. Food and
Drug Administration (FDA) for the use of scopolamine patch for motion
sickness, approximately 19 patches including nicotine, menthol, and es-
tradiol are commercially available to date [52]. However, the number of
drugs that are suitable for patch formulation is severely limited because
of the physiological barrier of the epidermis. The vast majority of the
first generation transdermal drugs are highly lipophilic with partition
coefficients greater than 104, small particle sizes, and molecular weights
no more than 400 Da [53]. The forerunning system of transdermal deliv-
ery depending on the physicochemical properties of drug molecules has
been effective for its therapeutic purposes but with a limited variety in
applications. Therefore, extensive efforts to render more drug candi-
dates transdermally applicable and to further increase their delivery ef-
ficiency had ensued.
2.2. Second generation: non-invasive transdermal drug delivery with
actuation
The second-generation transdermal delivery strategies seek to max-
imize the permeability of the drug to the skin using chemical enhancers
or external energy sources without damaging the structure of the skin.
Chemical enhancers facilitate the drug to penetrate the skin by
interacting with the proteins comprising the skin and by increasing
38 H. Lee et al. / Advanced Drug Delivery Reviews 127 (2018) 35–45

a Microemulsion Human skin b c 100

d

Relative release (%)

Solution Nanoparticle Temp. resp. nanogel NPC H+
80 32 oC H+
SC SC 22 oC Farnesol
60 Diclofenac Bacteria
Epidermis Epidermis
40 Biofilm pH 7.2 pH 4.5

Dermis Dermis 20 H+

0 H+
Nucleic acid loaded H+
0.1 µm 100 µm nanoparticle 12 24
Time (hr)

Cumul. release (%)

e 60 f

Rel. amount (µg/mL)

Light on Light off OFF OFF OFF OFF 60 w/o strain
ON ON ON ON
50
40
40 w/ strain
Stretch F F 30
20
20
no light 10
0 w/ light Drug release
0 4 8 12 16 20 24 0
0 100 400 1000
Time (h) Stretching cycles
g IR image Temp. h 70 i Iontophoresis device j Control Iontophoresis
Drug release (%)

50°C 60
50
(+) (-)
40
30 25oC Drug
Current
37oC Drug
20 Skin
Ag NW/SBS heater 0 20 40 60 80 ion
20°C Time (hour)

Fig. 3. (a) TEM image of microemulsion in hydrophilic gel (left). Cross-sectional fluorescent image of dye permeation through human skin (right). (b) Confocal images of solution-based
(left) and nanoparticle (NP)-based (right) nucleic acid delivery via transdermal route. (c) Temperature responsive drug release from nanogel. (d) Schematic illustration of pH-responsive
drug release. (e) Optical images of light responsive release (left). Drug release profile under visible light irradiation (right). (f) Schematic illustration of stretch-triggered drug release (left).
Accumulative drug release during 1000 cycles of finger flexion (right). (g) Infrared camera image of a wearable heater on the wrist. (h) Cumulative release of drugs from PNIPAM
microparticles embedded on heater before (25 °C) and after (37 °C) thermal stimulation. (i) Schematic illustration of iontophoresis treatment. (j) Optical (top) and fluorescent
(bottom) cross-sectional images of the pigskin taken after 1 h or 6 h of iontophoresis treatment.
Adapted and reproduced with permission from (a) Batheja et al. [55], Copyright 2011, Elsevier; (b) Desai et al. [63], Copyright 2013, Elsevier; (c) Carmona-Moran et al. [65], Copyright
2016, Elsevier; (d) Horev et al. [66], Copyright 2015, American Chemical Society; (e) Kim et al. [67], Copyright 2015, Wiley-VCH; (f) Di et al. [68], Copyright 2015, American Chemical
Society; (g) Choi et al. [69], Copyright 2015, American Chemical Society; (h) Bagherifard et al. [70], Copyright 2016, Wiley-VCH; (i) Kim et al. [24], Copyright 2016, American Chemical
Society; (j) Ogawa et al. [71], Copyright 2015, Wiley-VCH.

the drug solubility [1]. Presently, more benign chemical enhancers (e.g.,
fatty acids, urea, and pyrrolidone) compared to skin irritants such as di-
methyl sulfoxide (DMSO), dimethylformamide (DMF), and
oxazolidinone are available to use [54].
Emulsion is one of the major strategies in non-invasive transdermal
delivery because they solubilize a wide range of both lipophilic and hy-
drophilic drugs in a transdermal formulation (Fig. 3a) [55]. The absorp-
tion profile of an emulsion is determined by the droplet size,
composition, and surface charge. Particularly, reducing the size of vehi-
cle particles to micrometer or nanometer level has been a popular strat-
egy because smaller droplets can easily permeate the tight junctions of
the skin barrier [56,57]. Recently, nanomaterials have been studied as
potential systems for the delivery and controlled release of various
drugs (e.g., nucleic acid, antibacterial, and cancer drugs) [58–62]. For ex-
ample, drug-loaded nanoparticles (NPs) effectively overcome the epi-
dermal barrier and deliver an encapsulated cocktail of anti-
inflammatory siRNAs and capsaicin. In contrast, the delivery of siRNA-
capsaicin cocktail in solution form was hindered by the stratum
corneum (Fig. 3b) [63]. The efficiency of drug delivery control can be en-
hanced by using nano-sized vehicles responsive to physicochemical
stimuli [64]. One example is the temperature-responsive nanogel that
significantly increases the release of the drug as the temperature ele-
vates from room temperature to that of the outer skin (Fig. 3c) [65].
The pH-sensitive release of antibacterial drugs into the skin in response
to the acidic microenvironment of a virulent biofilm is another approach
for the stimuli-responsive drug release (Fig. 3d) [66].
Stimuli-responsive nano-vehicles are incorporated into patches to
yield a synergetic efficacy in transdermal delivery. External stimuli
(e.g., light, mechanical force, and magnetic field) promote not only a
higher rate of drug absorption but also a facile initiation and termination
of drug administration [58,67,68]. Visible light can trigger release of the
drug from a transdermal patch. For example, drug-loaded hydrogels can
respond to the temperature change induced by light irradiation (Fig. 3e,
left) [67]. Along with the increase in cumulative delivery, drug transport
can be easily triggered on and off by controlling the external stimuli
(Fig. 3e, right). Alternatively, mechanical force can control the release
of the drug from transdermal patch. The patch is fabricated with a
drug-laden elastomer (Fig. 3f, left), which can be conformally attached
to the finger joints [68]. When the joints flex, the patch experiences lat-
eral strain and releases the drug (Fig. 3f, right).
External devices, particularly in the wearable forms, can be integrat-
ed with drug-laden patches. The devices deliver a sufficient level of en-
ergy to promote drug diffusion through the skin. Devices that operate
with heat and electricity are frequent drug-delivering locomotives. For
example, local heat from a wearable heater (Fig. 3g) can enhance the
skin permeation of the drug [69]. When the heat is applied, solubility
and diffusivity of inorganic and organic drugs increase from the drug-
containing layer (Fig. 3h) [70]. The applied heat also increases the circu-
lation of body fluid, the permeability of blood vessel walls, and the rate-
limiting membrane permeability, which in turn increases the perme-
ation of the transdermal drugs. For example, the effect of temperature
was evaluated in vitro by estimating the flux of transdermal fentanyl
(a potent opioid analgesic) at temperatures of 32 and 37 °C. The flux
of the drug approximately doubled over the 5 °C increment in temper-
ature. Further studies indicate that a temperature change of 5 °C is nec-
essary to cause a measurable enhancement in permeability between cell
membranes and transport of the drug.
Iontophoresis uses an electrical current to enhance and control the
penetration of charged drugs into tissues through the skin barrier (Fig.
3i) [24]. The dose is easily controlled by changing the magnitude and
the duration of the stimulating current. Iontophoretic administration
of the drug can be applied to pain relief, diagnosis of inflammation,
 H. Lee et al. / Advanced Drug Delivery Reviews 127 (2018) 35–45 39

chronic edema, cystic fibrosis, and cosmetic applications. A weak elec-
trical current below 500 μA cm−2 is applied to the skin area of a few cen-
timeter squares to prevent pain, irritation, or skin burns. The electrical
field increases the rate of drug transport compared to that of passive dif-
fusion-based methods (Fig. 3j) [71]. Recently, a cryoelectrophoresis
technique was introduced to increase the electrophoretic efficacy by ap-
plying a strong current to locally frozen skin to eliminate the risk of skin
burns [72]. However, the non-invasive transdermal delivery does not
drastically increase the efficiency of drug delivery, particularly for high
molecular weight (e.g., proteins) and hydrophilic drugs.
2.3. Third generation: minimally invasive transdermal drug delivery
As the limitations of non-invasive transdermal delivery have been
recognized, an alternative approach of minimally invasive transdermal
delivery is rapidly adopted. Minimal invasion of the skin involves
destroying the stratum corneum so that epidermal disruption is limited
to clinically safe level while a large number of hydrophilic drugs and
macromolecules are more effectively delivered into the inner skin
[73]. High power energy modalities (e.g., radiofrequency (RF), ultra-
sound, and laser) and various types of microneedles are currently
used to disrupt or puncture the skin and enhance drug delivery. Howev-
er, destruction of the skin should be minimized and carefully controlled
to allow its rapid recovery [74]. A comparative study using ibuprofen as
a model drug indicates that the biodistribution and the bioavailability of
differently formulated microneedles can be significantly different, and
minimally invasive microneedles have advantages over non-invasive
iontophoresis in terms of bioavailability [75].
Disruption of the epidermis by high power energy broadens the
range of drugs that can be delivered through the skin [73]. Because a sig-
nificantly high level of energy is required to damage the outer layers of
skin, it is necessary to carefully control the amplitude and exposure time
of the applied energy to prevent unwanted damage to the inner skin
layers. RF ablation uses a high-frequency electrical current (100–
500 kHz) for localized heating of the outer skin layer (Fig. 4a) [76].
Sonophoresis uses ultrasound which generates heat and promotes
drug delivery into the skin [41,77,78]. Recently, double frequency ultra-
sound was used to enhance the skin permeability and shorten the treat-
ment time compared to single frequency ultrasound (Fig. 4b) [79]. Laser
ablation is also commonly used in cosmetics for procedures such as hair
removal, skin resurfacing, and acne treatment. The laser targets a high
level of energy at a designated location to penetrate the skin (Fig. 4c)
[80,81]. Gold nanorods absorb near-infrared light and generate an in-
tense heat, which can damage the outer layer of the skin. The pulsed
laser only increases the temperature of the skin surface and causes
less damage to the inner skin than continuous-wave laser does (Fig.
4d) [82–84].
Although RF ablation, sonophoresis, and laser ablation methods
show reasonably high potentials, they need bulky and expensive equip-
ment and thus can only be performed at clinics. As an alternative,
microneedles have attracted considerable attention because they can
transport drugs in a minimally invasive manner via the transdermal
route, and are relatively simple and cheap [74,85]. Microneedles are
easier to use and less painful to the skin than high-power energy modal-
ities. In addition, microneedles enable the controlled and sustained
release of drugs depending on the patients' needs. Microneedles are di-
vided into several types according to their shape and use including solid,
surface-coated, dissolvable, hollow-shaped, and smart microneedle
[86]. Solid microneedles are fabricated from hard materials such as sili-
con and metals (Fig. 4e) [87–90]. The hardness of the materials enables
the solid microneedles to easily create micropores, which are the micro-
inlet through which drugs are transferred. The micropores are recov-
ered a short period after the creation and, therefore, additional patches
or drugs (e.g., diclofenac) can be used to extend the duration of the
formed micropores.
Microneedles may also incorporate a drug coated onto the surface of
the solid needle substrate (Fig. 4f) [91–93]. Since the coating layer de-
creases the physical strength and sharpness of needles, the drug load
on the needle surface is limited to a small amount. Accordingly, coated
microneedles are used for treatments where large amounts of drugs
are not required to be delivered (e.g., vaccine delivery and cosmetic pro-
cedures) [94,95].
Dissolvable microneedles are formulated from water-soluble and
biocompatible polymers. In dissolvable microneedles, drugs are embed-
ded in the polymeric matrix and released as the matrix degrades or dis-
solves slowly in body fluids (Fig. 4g) [96–103]. The temporal drug
release profile can be controlled from several seconds to several months
by selecting appropriate polymers. However, there are also challenges
associated with this technique. For example, the use of ultraviolet
(UV) irradiation or elevated temperature to cure the polymer for
microneedles during the fabrication process can denature the drugs
loaded in the polymeric precursor. The drug quantity that can be loaded

a Feedback Control
b Double frequency ultrasound c Ablation Laser poration d
RF energy US1
Ablated area CW-laser Pulsed laser
US2
Au NR

Skin 300 µm 300 µm

e Solid microneedle f Coated microneedle g Dissolvable microneedle h Hollow microneedle

2 mm

100 µm 100 µm 100 µm 100 µm 100 µm

Fig. 4. (a) Schematic illustration of radiofrequency (RF) ablation on skin. (b) Schematic illustration of double frequency ultrasonic treatment for transdermal drug delivery. (c) Histological
image of ablated skin after 30 min of delivery of sulforhodamine (left). Optical image of skin after laser poration (right). (d) Schematic illustration of gold nanorod (AuNR) assisted
photothermal ablation with continuous-wave (CW) (left) and pulsed laser (right). (e) SEM image of silicon-based solid microneedles. Optical image of solid microneedle array (inset).
(f) Optical microscopic image of sucrose-coated polylactic acid microneedles. Schematic illustration of coated microneedles (inset). (g) Optical image of dissolvable microneedles (left).
Fluorescence microscopic image of porcine skin after poration of microneedles (right). (h) SEM image of hollow microneedles.
Adapted and reproduced with permission from (a) Sintov et al. [76], Copyright 2003, Elsevier; (b) Schoellhammer et al. [79], Copyright 2012, Elsevier; (c) Lee et al. [80], Copyright 2011,
Elsevier and Weiss et al. [81], Copyright 2012, Elsevier; (d) Tang et al. [82], Copyright 2013, Elsevier; (e) Li et al. [90], Copyright 2010, Elsevier; (f) DeMuth et al. [92], Copyright 2013, Nature
Publishing Group; (g) Sullivan et al. [97], Copyright 2010, Nature Publishing Group; (h) Vazquez et al. [104], Copyright 2014, Elsevier.
40 H. Lee et al. / Advanced Drug Delivery Reviews 127 (2018) 35–45

into the polymeric matrix is also limited because a high percentage of
drug in the precursor mixture would undermine the mechanical
strength of the needles.
Hollow microneedles have a hollow core inside the needle through
which the drug solution flows (Fig. 4h) [104–107]. The drug solution
can be delivered passively by diffusion or actively by pressure-driven
flow through the needle hole. A drug reservoir attached to the back of
the microneedles releases the drug by the action of a pump. Hollow
microneedles have a merit in controlling the amount of injected drug.
However, one disadvantage of this approach is that additional equip-
ment (e.g., drug reservoir and pump) assisting the microneedles is re-
quired for drug delivery [73].
With increasing variety of applicable drug candidates, microneedles
represent a major breakthrough in transdermal delivery in terms of ef-
ficiency and versatility. However, the fabrication process for mass pro-
duction is yet to be established. Furthermore, even the microneedles
share the same limitation of transdermal patches in which the only
way to control the offset of drug release is to detach the patches. A
more dynamic control on the release profile (e.g., pulsatile, variable,
and feedback-controlled) of the drug could be envisioned with incorpo-
ration of other technological elements.
3. Fourth generation: controlled and feedback-induced transdermal
drug delivery
Personalized therapy is distinguished from conventional medical
treatments by its ability to optimize the treatment based on each
individual's pathophysiological conditions [49]. Establishment of per-
sonalized therapy requires systematic control of the administered
dose based on an accurate real-time observation of the patient's physi-
ological parameters to determine the progression of disease and efficacy
of the drug. In response to an increasing need for personalized treat-
ment, the advanced transdermal delivery system empowered by soft
bioelectronics has been spotlighted as a strategy for the next generation
drug delivery method.
Rapid advances in soft and ultrathin devices in wearable forms have
facilitated the seamless integration of bioelectronic devices in a skin-
mounted patch domain with unprecedented functionalities [108–110].
Specifically, sensors accurately measure the physiological [6–15], elec-
trophysiological [16–21], and biochemical [22–27] signals, actuators
transfer energy to the drug-laden patch in a controlled manner, and
the sensors subsequently gather information on the therapeutic efficacy
of the drug. The synergetic performance of wearable devices and drug-
delivering patches according to a complete feedback loop provides a
novel platform for personalized therapy.
To maximize the performance of device-assisted transdermal drug
delivery, it is crucial to safeguard a conformal contact between the de-
vice and the skin which stems from the stretchability and flexibility of
the device. The softness and deformability of the system minimize the
local detachment and microscopic spaces between the device and the
skin due to the curvilinear morphology of the skin and bodily move-
ments [16]. Conformal integration of a device onto the skin also pro-
motes precise measurements of the biological signals with minimal
motion-induced noise, enhancing the accuracy of wearable sensors
monitoring physiological (e.g., blood pressure, strain, and temperature)
[6–15], electrophysiological (e.g., electrocardiogram and electroenceph-
alogram) [16–21], and biochemical (e.g., pH, blood glucose, and oxygen
levels) [22–27] signals from the skin. Based on the collected informa-
tion, a co-integrated actuator controls the drug diffusion rate. This pro-
cess is also enhanced by the conformal contact because a stable
interface between the patch and the skin ensures homogeneous and ef-
ficient energy transfer, and provides a uniform drug release profile
throughout the entire patch area [111,112].
3.1. Transdermal drug delivery based on physiological/electrophysiological
monitoring
To diagnose the health condition of an individual, an assortment of
physical and electrical cues must be collected first. The collection of pre-
cise health information with high spatiotemporal resolution is impor-
tant in controlling drug delivery. Since the surface of the skin is soft,
curvilinear and movable, skin-mounted sensors necessitate physical
characteristics similar to those of the skin to obtain high-quality infor-
mation without motion artifacts or background noises from the skin
surface. Flexible and stretchable devices in ultrathin and serpentine
structures facilitate a conformal contact with the skin, which is crucial
for high fidelity measurement of bodily signals [48–50]. Therefore, soft
wearable biosensors that are attached conformally to skin contours en-
able the precise real-time monitoring of an individual's physiological
biomarker without hindering bodily motions. Accurate diagnosis
based on the conformal contact also increases the efficacy of controlled
drug release in response to physiological feedback.

a b c Patch Surface (°C) d 5 min/40 °C 60 min/40 °C

Strain gauge Heater 45
42
39
m-silica Skin
Heat Patch 36 Thermal
diffusion
TiO2 NM/Au NPs 33
Drug
RRAM 5 mm 40 nm Interface 100 µm 100 µm
30
Penetration depth (µm)

e f Iontophoresis g 3 cycles 12 cycles h 400

Iontophoresis
Skin Amplifiers
Memories + electrode

_
-0 300 Thermal diffusion
Control
200
- 100
100

- 200 (µm) 0
ECG Drugs 0 3 6 9 12
electrodes 5 mm 1 mm 30 nm # of stimulus

Fig. 5. (a) Optical image of a wearable electronic patch which can detect movement disorder and store detected signals. (b) Transdermal drug delivery using a wearable heater. Drug
loaded in mesoporous silica NPs (MSNs) is released by thermal stimulation. (c) Finite element modelling of the three-dimensional thermal profile of a heater on the patch and at the
interface between the patch and the human skin. (d) Cross-sectional fluorescence images show enhanced drug diffusion into pig skin via thermal actuation. (e) Skin-mounted device
used for heart-rate measurement, signal amplification and data storage. (f) Transdermal drug delivery using the iontophoresis. (g) Cross-sectional fluorescence images for the drug
(doxorubicin) diffusion into the mouse skin with different stimuli of iontophoresis; 3 cycles (left) and 12 cycles (right). (h) Stimulus number versus drug diffusion length into the
mouse skin with different actuators (black: none, blue: thermal actuator, and red: iontophoresis electrode).
Adapted and reproduced with permission from (a)–(d) Son et al. [3], Copyright 2014, Nature Publishing Group; (e) Kim et al. [19], Copyright 2016, AAAS; (f)–(h) Choi et al. [5], Copyright
2016, Wiley-VCH.
 H. Lee et al. / Advanced Drug Delivery Reviews 127 (2018) 35–45 41

Physiological signals such as body temperature [6], and dynamic in-
formation including tremors [3,9,10] and cardiac movements [5,7,8,19]
are the key information required for diagnosing the health condition of
an individual. Collected signals can be used for patient-customized
transdermal drug delivery. For example, a multifunctional and wearable
patch continuously monitors movement disorders using silicon mem-
brane-based strain gauges, and stores the recorded information on the
activities and tremors in the memory module (Fig. 5a) [3]. Continuously
operating sensors collect vital signals and the cumulative information is
processed to operate a co-integrated drug delivery unit (Fig. 5b). Ac-
cording to the patient's health condition, wearable drug actuators trig-
ger drug delivery through the skin. To maximize the amount of loaded
drugs, mesoporous silica NPs (MSNs) serve as the drug delivery vehicles
in the patch because their large surface area allows greater drug adsorp-
tion. The programmable thermal actuators control the drug delivery
through the skin by enhancing drug diffusion (Fig. 5c). The generated
heat degrades the binding of the MSNs and the loaded drugs, which sub-
sequently diffuse transdermally (Fig. 5d). The integrated temperature
sensor conducts real-time monitoring to prevent any low-temperature
burns.
Electrical signal is also an integral part of health monitoring that en-
ables relevant information to be collected continuously. The time-re-
solved amplitude and wave pattern of electrophysiological signals
such as those of an electromyogram, electroencephalogram, and elec-
trocardiogram reflect the real-time condition of the muscles, brain,
and heart, respectively. These signals can be detected from the outer
skin noninvasively using wearable electrodes and a co-integrated am-
plifier (Fig. 5e) [19]. To investigate the reliable long-term monitoring
of signals, studies have focused on the interface between wearable de-
vice and biological tissues to establish a robust mechanical coupling
for a highly sensitive and accurate biometric detection [5,8]. The design
motifs based on bio-inspired interfaces provide sufficient adhesion to
the skin so that the devices do not require adhesive glues, which are po-
tential skin irritants in the long-term. Based on the measured electrical
signals, the integrated drug actuators can efficiently deliver the loaded
drug through the skin (Fig. 5f) [5]. For electrostatically charged drugs,
iontophoresis can serve as an efficient delivery method. In a study,
MSNs were used as drug delivery vehicles to prevent oxidation, dena-
turation, and unstimulated diffusion of drugs. Iontophoretic delivery ac-
celerates the deep permeation of the drug into the skin, mediated by the
charge repulsion between the electrodes and drugs (Fig. 5g). Iontopho-
retic actuation of drug-loaded MSNs enhanced the dermal penetration
significantly compared to those of the control and thermal diffusion
(Fig. 5h). Iontophoresis also has advantages over thermal diffusion by
preventing low-temperature burns on the skin and thermal denatur-
ation of the loaded drugs.
3.2. Transdermal drug delivery based on biochemical signal monitoring
Biochemical analysis of biofluids can provide ample information on
an individual's health condition and disease progression [22–27]. For
wearable devices, sweat is a frequently used specimen to monitor the
physiological and biochemical conditions such as glucose level because
it contains voluminous metabolic data (Fig. 6a) [113–116]. In accor-
dance with the versatility of sweat analysis in disease diagnosis, wear-
able sweat sensors are developed to conveniently measure the
analytes of interest.
Wearable and disposable chemical sensors are recent examples of
colorimetric and electrochemical analyses. Colorimetric analysis is
widely used for simple and disposable sensing instruments because
the presence of biomarkers is easily confirmed by color changes (Fig.
6b) [117,118]. Although this method can be used to monitor various

a Sensor Glucose, b Colorimetric sweat sensor c Tattoo-type glucose sensor d

Lactate, ions

Smart
5 mm 5 mm wristband
Sweat duct Sweat

e Sweat glucose f Integrated Sweat glucose

Temp. Heater
monitoring patch patch system sensor
e-

Hand
pH Sens. Glu. Sens.
Sweat 5 mm [Wearable diabetes patch] [Sweat analysis] [Transdermal drug delivery]

8 35
g R.T. h Initial i j
Rel. release (a.u.)

T>Tc: transition Release No patch w/o drug

Blood Glu. (mM)

30 Dose1 Dose2
PCM 6 w/ heater
25
Left on 4 20
PVP/
drug drug 15 * *
2 **
elution
10 **
Left/right on 0 N=4
i ii iii iv v vi vii viii 5
0 2 4 6
2 mm Heater actuation Time (hr)

Fig. 6. (a) Schematic illustration of sweat monitoring system on the skin. Biomarkers such as glucose, lactate, and ions secrete from epithelial cells along the sweat ducts inside the skin,
reflecting a subject's physiological state. (b) Optical image of colorimetric sweat sensor mounted on the forearm. (c) Optical image of a sweat glucose monitoring tattoo device applied to a
human subject. (d) Optical image of smart wristband on subject's wrist, integrating the multiplexed sweat sensor array. (e) Optical image of multifunctional electrochemical devices on the
human skin with perspiration. (f) Schematic illustrations of operation process of skin-based diabetes monitoring and therapy system. (g) Schematic illustrations of drug-loaded
bioresorbable microneedles. The phase change material (PCM) coating prevents unwanted drug release before programmed thermal actuation. (h) Optical images of the stepwise
dissolution of the microneedles for drug dose control. (i) Multistage drug release profile by using three-channel thermal actuator for stepwise transdermal drug delivery. (j) Blood
glucose levels of the db/db mice for the treated groups (microneedles with the drugs) and control groups (without the patch, microneedle without the drugs).
Adapted and reproduced with permission from (a) Heikenfeld [113], Copyright 2016, Nature Publishing Group; (b) Koh et al. [117], Copyright 2016, AAAS; (c) Bandodkar et al. [114],
Copyright 2015, American Chemical Society; (d) Gao et al. [26], Copyright 2016, Nature Publishing Group; (e)–(h) Lee et al. [115], Copyright 2016, Nature Publishing Group; (i) and (j) Lee
et al. [116], Copyright 2017, AAAS.
42 H. Lee et al. / Advanced Drug Delivery Reviews 127 (2018) 35–45

biomarkers such as perspiration rate, total sweat loss, pH, chlorides, and
lactates, it is difficult to accurately quantify the color changes to deter-
mine the concentration of the biomarkers. Wearable electrochemical
sensors have been devised to quantifiably detect biomarkers in the
sweat. The concentration of target biomarkers is directly measured
from the electrical signals of the redox reaction of the markers in a
short time. The wearable electrochemical sensors fabricated by screen
printing have simple structures and enable the facile measurement of
a single biomarker (Fig. 6c) [114]. An array of electrochemical sensors
is also available for the simultaneous detection of multiple biomarkers
(Fig. 6d) [26]. The information acquired from the sweat is wirelessly col-
lected and continuously stored in mobile devices for long-term health
monitoring.
Accurate monitoring of the sweat glucose level is of primary interest
because of its direct correlation to the blood glucose level [119]. Further-
more, this correlation inspired the development of a skin-based diabe-
tes control system that combines sweat glucose detection with
microneedle-based drug delivery for minimally invasive blood glucose
regulation (Fig. 6e) [115,116]. Conventional blood glucose monitoring
for diabetes inflicts pain and stress during the blood withdrawal and
drug injection steps. Therefore, device-assisted glucose monitoring
and feedback therapy could improve the quality of life of patients with
diabetes by managing blood glucose level more conveniently. The min-
imally invasive glucose monitoring system is initiated by perspiration
after the patch is applied (Fig. 6f, left). To measure the sweat glucose
level more accurately, data collected from the glucose sensor are
corrected by integrated pH, temperature, and humidity sensors. It en-
sures that corrections are made for the activity variation of glucose ox-
idase, which is the primary detection moiety (Fig. 6f, middle). When
hyperglycemia occurs, the microneedles are triggered by the sensor sig-
nal to transdermally administer the antidiabetic drug (Fig. 6f, right).
In the case of conventional microneedles, it was difficult to control
the duration and amount of the drug dose released because the drug dif-
fusion is irreversible once the microneedles are inserted into the skin. In
addition, data to determine the drug delivery rate are unavailable. Re-
cent studies have demonstrated the prospect of controlled transdermal
drug release based on real-time health monitoring using a wearable de-
vice-assisted thermo-responsive microneedles system [115,116]. Phase
change materials (PCMs) protect the drug and dissolvable microneedle
matrix from biofluids below the critical melting temperature (Fig. 6g).
When multi-channel heaters initiate patterned thermal actuation, the
PCM coating on the microneedles melts, and thereby, the transdermal
drug delivery proceeds by partial or total dissolution of the
microneedles (Fig. 6h). The amount of delivered drug can be controlled
by the area of the applied heating, which is determined by the integrat-
ed wearable biosensors. Temperature sensors near the heater simulta-
neously monitor the temperature variation of the heaters to
sequentially control the drug release and prevent low-temperature
burns. By using additional PCMs combined with drugs and multichannel
heaters, the drug delivery system features a precisely controlled trans-
dermal release of drugs at up to six different release amounts (Fig. 6i).
The effectiveness of the wearable microneedle system was demonstrat-
ed in diabetic (db/db) mice by triggering controlled transcutaneous
drug release using thermal actuators. Animal experiments with diabetic
mice confirmed the efficacy of the microneedles in reducing blood glu-
cose levels (Fig. 6j).
3.3. Smart microneedle systems
Smart microneedles represent the culminating point of advanced
transdermal delivery since they incorporate the aforementioned ele-
ments of sensors, actuators, and enhanced drug formulation into a com-
plete feedback loop of personalized therapy. Sensors monitor the
physiological conditions and trigger the medication, and actuators ma-
nipulate the release profile and dose of the administered drug. Without
further medical intervention, automated microneedle patches continue
to respond to the progression of the disease until symptoms are allevi-
ated. Smart microneedles can provide a patient-friendly and feedback-
controlled drug delivery, which has not been accomplished with previ-
ous microneedle systems. Microneedles that are responsive to external
stimuli (e.g., heat, laser, and mechanical strain) provide an on/off trigger
for drug administration, which can be easily controlled by patients [44,
68]. An example is the mechanically responsive microneedles whose
drug release is modulated by lateral strain (Fig. 7a, left) [68]. The
microneedles that release the drug payload following lateral pulling
were successfully tested in vivo (Fig. 7a, right). Smart NPs that are re-
sponsive to biochemical stimuli (e.g., pH change, glucose concentration,
and hypoxia) can also be loaded in microneedles (Fig. 7b, left) [46,120,
121]. Microneedles facilitate the entry of NPs into the bloodstream, and
the delivered NPs respond to the patient's physiological state and re-
lease the drugs accordingly. The concept has been demonstrated by
NPs containing glucose oxidase, which release insulin in response to a
high blood glucose concentration to modulate its level (Fig. 7b, right)
[120]. Thrombin-responsive microneedle array can prevent the un-
wanted blood coagulation as thrombin-cleavable peptides interlinked
within hyaluronic acid hydrogel scaffolds trigger the drug release

a Microneedle b
Blood glu. (mg/dl)

Without strain With strain Glu. 600

F 500
400
300
Force 200 GRV(E,I)
Force GRV(0.5E,I)
100
GRV(I)
F 0 Insulin Blank
Skin 0 2 4 6 8 10 12
Drug release 200 µm Time (hr)

c 400 0 U/ml Thrombin d 100mg/dL 400mg/dL

Heparin rel. (a.u.)

0.5 U/ml 12
Insulin rel. (µg/ml)

300 1 U/ml
10
200 8
Skin
100 6
Disass
Thrombin -embly 4
0
2
0 1 2 3 4 12 Dual-sensitive Insignificant
Time (hr) 0
Heparin release d-GRP inflammation Time

Fig. 7. (a) Schematic illustration of strain-responsive microneedles (left). Optical image of stretch-triggered drug release on shaved dorsal skin of mouse (right). (b) SEM image of smart
NP-loaded microneedles (left). Schematic illustration of glucose-responsive drug release (inset). Changes in the level of blood glucose after treatment with microneedle patch (right). (c)
Schematic illustration of thrombin responsive microneedle array (left). Release profile of heparin at different thrombin concentrations (right). (d) Schematic illustration of hypoxia and
H2O2 dual-sensitive microneedles for delivery of insulin (left). Pulsatile release profile of insulin as a function of glucose concentrations (right).
Adapted and reproduced with permission from (a) Di et al. [68], Copyright 2015, Elsevier; American Chemical Society; (b) Yu et al. [120], Copyright 2012, National Academy of Sciences; (c)
Zhang et al. [122], Copyright 2017, Wiley-VCH; (d) Yu et al. [123] Copyright 2017, American Chemical Society.
 H. Lee et al. / Advanced Drug Delivery Reviews 127 (2018) 35–45
against the increased level of thrombin in a controlled and on-demand
manner (Fig. 7c, left) [122]. Release of heparin in the thrombin respon-
sive hydrogels is promoted as the concentration of thrombin is in-
creased (Fig. 7c, right). For an enhanced glucose-responsive delivery
of insulin, dual-responsive (hypoxia and H2O2) vesicles are embedded
in the microneedle array (Fig. 7d, left) [123]. This microneedle array is
highly sensitive to glucose concentrations and shows a pulsatile release
of insulin according to the glucose concentrations (Fig. 7d, right). The
next-generation transdermal drug delivery systems are a considerable
improvement over wearable devices that have a limited ability to detect
or treat disease conditions. Furthermore, the next-generation transder-
mal drug delivery represents the integration of multiple functionalities
in a single device. In addition, the interactive and complementary co-ap-
plication of sensing and therapy to enable patient-tailored transdermal
drug delivery will likely be available in the foreseeable future through
the next-generation systems.
4. Conclusion
The skin, which has long been perceived as unsuitable for drug deliv-
ery, currently widens the vista on the possibilities for drug delivery
strategies with its physiological significance and convenience. Studies
to overcome the challenges of the skin barrier against drug permeation
and improve the efficiency of transdermal drug delivery have shown
considerable success as demonstrated by the first, second, and third
generations of transdermal delivery strategies. From simple patches to
intricate microneedles, diverse approaches to improve the efficiency
of drug delivery are still in progress. Amidst the rising popularity of
the transdermal drug delivery, the device-assisted transdermal delivery
provides a new paradigm for drug delivery in response to the real-time
progression of disease.
The diagnosis of the health status of patients using wearable sensors
and the drug administration that is finely and timely controlled by actu-
ators are combined with the detection of physiological changes by sen-
sors to provide a complete feedback therapy. This strategy is expected to
enhance the quality and effectiveness of medical therapy. Since the pre-
vious generations of the transdermal drug delivery technology have fo-
cused on maximizing the efficiency of delivery, this novel technological
platform complements the drawbacks of previous transdermal delivery
systems and even yields synergetic results when the most advanced
transdermal patches and devices are combined altogether.
Since the incorporation of wearable sensors and advanced transder-
mal patch formulations is still in the early stage, there is a spacious room
for future research aimed at improving the wearable devices and rigor-
ously optimizing the reliability of the system, as well as their application
to assorted disease models. Continued efforts to enhance the delivery of
drugs that are considered unsuitable for administration through the
skin (e.g., peptides, nucleic acids, and macromolecules) must also be
carried out to broaden the library of transdermally applicable drugs. Al-
though the patient-customized transdermal drug delivery still requires
much development, this approach holds great promise for the conve-
nient management of diseases in daily life and a novel paradigm for
healthcare in the future.
Acknowledgement
This work was supported by IBS-R006-D1, and IBS-R006-A1.
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