Journal Innovention

Journal of Cosmetic Dermatology, 0, 1--5

A potential relationship between skin hydration and stamp-type

microneedle intradermal hyaluronic acid injection in middle-aged
male face
Joon Seok, MD,1 Ji Yeon Hong, MD,1 Sun Young Choi, MD,1,2 Kui Young Park, MD, PhD,1 &
Beom Joon Kim, MD, PhD1
1
2

Department of Dermatology, Chung-Ang University College of Medicine, Seoul, Korea

Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Summary

There is an increasing interest in skin rejuvenation using hyaluronic acid (HA) fillers
beyond the improvement of deep wrinkles and volume deficiencies, which have been
primary research foci in the past. We conducted a pilot study using a sample of six
middle-aged male subjects. Using an automatic intradermal injector with 0.020 mL of
material contained in each injection point with a total of 100 points, 2 mL of noncross-HA filler was injected into the entire face at every treatment session. We
administered injections of HA for a total of three sessions per subject at 2-week
intervals and evaluated the results using a corneometer, TEWL, cutometer, measures of
patient satisfaction, and the global aesthetic improvement scale (GAIS). Corneometer
values increased steadily at each measurement, while the average value of TEWL
increased in comparison with baseline after each application of the procedure.
However, values returned to readings similar to those at 4 weeks after complete
termination of the procedures. Cutometer values differed between the baseline and after
procedures. All patients were assessed as very much improved or much improved
according to GAIS, and all were pleased with the outcomes of treatment in terms of the
enhancement of moisture, elasticity, and brightness.
Keywords: hyaluronic acid, hydration, intradermal injector, skin rejuvenation, stamptype microneedle

Introduction
As HA diminishes in the skin with aging, the skins
elasticity and capacity to hold water are also reduced.
This effect is directly related to a decreased dermis volume and an increased tendency for wrinkles and skin
laxity to occur, particularly on the facial skin.1
Correspondence: Beom Joon Kim, MD, Department of Dermatology,
Chung-Ang University Hospital 224-1 Heukseok-dong, Dongjak-ku, Seoul
156-755, South Korea. E-mail: beomjoon@unitel.co.kr
Accepted for publication May 11, 2016

2016 Wiley Periodicals, Inc.

Changes in skin hydration over the lifetimes of patients

show that the peak is reached around the age of 40
50 years in males on both the face and the forearm.2
These changes often cause middle-aged male patients
to complain about dry, tired-looking facial skin. There
is also an increasing interest in skin rejuvenation
beyond the improvement of deep wrinkles and volume
deficiencies, which have been primary research foci in
the past. In this article, we describe the efficacy and
safety of automatic intradermal injections of HA to
improve skin hydration for rejuvenation of the skin in
East Asian males.

Skin hydration and stamp-type HA injector

. J Seok et al.

Methods
Patients

Six male subjects in their 40 s with facial skin and

with no prior exposure to other forms of skin rejuvenation treatments were enrolled in the study. This study
was performed at Chung-Ang University Hospital in
accordance with the principles of the Declaration of
Helsinki and Korean Good Clinical Practice and conformed to local regulatory requirements. All subjects
provided written informed consent prior to study participation.

Germany), and cutometer (MPA 580, Courage and

Khazaka Electronic Co., Germany) and assessed a total
of four areas: 2 cm below the lateral canthus of each
eye and the two points where the lateral canthus
meets the alar of the nose bilaterally. We also assessed
the level of aesthetic satisfaction through a patient survey at 4 weeks following the procedure. We defined
patient satisfaction using a point system from 1 to 5
(1, highly unsatisfied; 2, unsatisfied; 3, ok; 4, satisfied;
5, highly satisfied). In addition, two dermatologists
scored the patients in accordance with the Global Aesthetic Improvement Scale (GAIS). We assessed degrees
of pain according to the visual analog scale (VAS) after
each operation.

Treatment

We applied topical anesthetic (EMLA cream) to each

subject before treatment. Using an automatic intradermal injector (Dermashine Balance, Huons, Seongnam,
Korea), 2 mL of non-cross-HA filler (Elravie Balance,
Humedix, Anyang, Korea) was injected into the entire
face at every treatment session. Each injection point
contained 0.020 mL of material, and 100 total points
were injected at each session. Non-cross-HA filler is
suitable for use with an intradermal injector because of
its low elastic modulus (G), shear viscosity (N), and a
behavior closer to that of a viscous liquid (tand  1)
relative to other HA fillers (Table 1).3 Subjects were
given multiple injections of equivalent depth to the
intradermal layer. We used the automatic intradermal
injector with nine microneedles (32-gauge needle,
injection depth: 0.82.0 mm) to provide precise injections of small quantities of HA filler to the intradermal
layer. We administered injections of HA over a total of
three sessions per subject at 2-week intervals. We
observed progress at four and 12 weeks after the procedures were completed.
Measurement

Each patients face was evaluated prior to treatment

sessions as well as at four and 12 weeks after the last
treatment session. We utilized a corneometer, TEWL
(MPA 5, Courage and Khazaka Electronic Co.,

Statistical analysis

We used the statistical analysis tool SPSS 19.0 (IBM

SPSS, Armonk, NY, USA) to assess the efficacy of the
test product. Paired sample t-tests were used to determine statistically significant differences, corresponding
to P < 0.05, between the test group and the control
group upon parametric tests. We interpreted P-values
less than 0.001 as highly significant.

Results
Compared with baseline, the average value measured
by the corneometer for the six subjects at 4 weeks following the final procedure (Week 8) had increased
from 44.31 to 55.94 (P < 0.001).
At 12 weeks after the final procedure (Week 16),
the corneometer value reached 51.79, which is lower
than the values 4 weeks following the final procedure
(Week 8), but still representative of a higher degree
of hydration than at baseline (P = 0.02). Corneometer
values increased steadily at each measurement, suggesting enhanced skin hydration (Fig. 1a). The average value of TEWL increased in comparison with
baseline (27.13) after each procedure (Week 2:
46.13, Week 4: 40.12), but returned to readings similar to those at 4 weeks after the complete termination of procedures (Week 8: 30.73, Week 16: 28.20)
(Fig. 1b).

Table 1 The rheological properties of HA filler (Elravie Balance)

Elravie Balance

G(Pa) (1 Hz)

G(Pa) (1 Hz)

G*(Pa) (1 Hz)

N*(Pa s) (1 Hz)

d() (1 Hz)

N(Pa s) (450s)

tand

100.9

107.0

147.0

23.46

46.68

50.08

1.06

G, storage modulus, elastic modulus; G, loss modulus, viscous modulus; G*, complex rigidity modulus; N*, complex viscosity; d, phase
angle; N, shear viscosity; tand, damping factor.

2016 Wiley Periodicals, Inc.

Skin hydration and stamp-type HA injector

. J Seok et al.

Figure 1 (a) Corneometer values (A.U.). As measurements steadily increased after treatment, we confirmed that skin hydration was
improved after the procedure. (b) TEWL values (g/m2/h1). The average value increased in comparison with baseline after each application of the procedure, but returned to readings similar to those at 4 weeks after the complete termination of procedures. Statistically
significant results are indicated by *P < 0.05 and highly significant results by ***P < 0.001.

According to the cutometer, R2 (gross elasticity), R5

(pure elasticity), and R7 (firmness) values did not differ
between baseline or after the procedures were completed. According to the GAIS evaluation, four patients
were assessed as very much improved and two
patients were much improved. All patients were
pleased with the outcomes of treatment in terms of the
enhancement of moisture, elasticity, and brightness
(average of 4.25 points) (Fig. 2). The average VAS
score after each procedure was 2.9, indicating mild
pain. There were no serious adverse events during the
course of treatment. One patient experienced temporary mild erythema after treatment, which subsided
after 1 day and resolved without any further adverse
effects.

Discussion
Man et al.2 demonstrated that the average corneometer
value in Asian males aged 40-50 is around 43.0. In
this study, the average corneometer value at baseline

(a)

(b)

was similar at 44.31. After the hydration procedures

were completed (Week 8, 16), the highest skin hydration values (55.94, 51.79) were significantly higher
than the average for Asian male subjects aged 1335
(about 44.5). We therefore confirmed the skin rejuvenation effect of HA administered with an automatic
stamp-type microneedle intradermal injector to
improve skin hydration.
Injections of HA within the intradermal layers create
an effect comparable to that of a basin of hydration in
the dermis by bringing water into the extracellular
matrix.4 Existing as a poly-anionic polymer at physiologic pH, HA is thus highly charged in the skin. This
particular characteristic of HA in its natural state
makes it soluble and enables it to bind water.5 This
should increase skin turgor and lubricate the tissues.
During the present study, we were able to confirm that
the moisture content in the skin increased due to automatic intradermal injections of HA through corneometer measurements. The cutaneous micro-injury itself
can stimulate epidermal HA synthesis through

(c)

Figure 2 Clinical photographs. (a) Before treatment. (b) 8 weeks later (4 weeks after 3rd treatment). (c) 16 weeks later (12 weeks after
3rd treatment).

2016 Wiley Periodicals, Inc.

Skin hydration and stamp-type HA injector

. J Seok et al.

upregulated hyaluronan synthase expression.6 It is

possible that the increased hydration of dermis could
affect that of epidermis through the tunnel by injection. The injected HA of dermis might also migrate to
epidermis through the tunnel by injection. We hypothesize that these mechanisms could explain why the
value of corneometer, which determines the hydration
state of epidermis, increased steadily after intradermal
injections of HA.
We also observed that the microneedle devices
TEWL increased at the beginning of the procedure and
later returned to normal, as Park et al.7 previously
reported. We therefore concluded that although the
TEWL rises temporarily after the procedure due to the
damage caused to the skin barrier by the stamp-type
injector, it returns to baseline as the skin barrier recovers in Asian male subjects.8
Wang et al.9 found that an injection of HA filler in
the intradermal layer is capable of bolstering the production of collagen. In comparison with a control
group, increased collagen accumulation was found in
areas surrounding the filler. In another study, injecting
small quantities of HA filler over extensive areas of the
dermis resulted in improved elasticity and alleviation of
rough skin surface.10 Based on cutometer values, we
were unable to identify any significant increases in
contrast to previous reports, probably due to a phenomenon that Wang et al. previously verified in which
the collagen generation effect after HA injection was
not reflected by changes in cutometer values.4,9
According to recent reports, although the diameter of
collagen decreases after mesotherapy using vitamins and
hyaluronic acid, there are no differences in the quantity
of collagen or total elastin, and no histological
changes.11,12 When using a micropuncture injector
device to inject 0.010 mL at each injection, the skin
quality improved based on assessments via blinded evaluation and subject satisfaction questionnaire.13 Therefore,
it appears that when injecting HA into the skin in quantities lesser than 0.020 mL, skin hydration is improved
rather than activating an increased synthesis of collagen
or elastin. As hydration, skin thickness, and elasticity all
increased during a study in which patients were injected
with 0.030 mL of HA, qualities such as elasticity may be
affected if injection quantities are increased to values
higher than in the current study.14 Injecting high quantities of HA to increase effectiveness may result in the formation of noninflammatory nodules that are palpable
and possibly also visible. Therefore, bolus injections of
HA are contraindicated, and as such, nodules may occur
soon after injection and clinicians should perform vigorous massage and hyaluronidase injection immediately.15

Using hypodermic needles, it is difficult to inject HA

filler at a consistent depth. Such injections can also be
painful, and the procedure times can be excessive.
Automatic intradermal injectors use a needling stamp
system with nine microneedles (32 gauze needles) to
bypass the stratum corneum barrier. The skin varies in
its thickness depending on the region of the face being
treated.16 The thickness of the epidermis in the thinnest area, the eyelid, is a mere 54.4  9.6 lm, while
at the forehead and the cheek, it is 93.6  22.3 lm
and 98.2  26.7 lm, respectively.17 The depth of
injection by microneedles can be adjusted from 0.8 to
2.0 mm. In the present study, the epidermis was penetrated at a depth of 0.8 mm when injecting HA in the
periorbital region and at a depth of 1.52.0 mm when
injecting other areas.
The use of microneedles effectively increases the variety of compounds, including HA, that can be applied
across the skin. The release rate tends to increase
when the solution is divided into portions injected over
multiple injections.18 The delivery of HA into intradermal layers by means of infiltration through microneedles is relatively painless when compared with
procedures using hypodermic needles.19 According to
data from animal and human studies, there are few
concerns regarding serious adverse reactions to
microneedles. Furthermore, previous studies indicate
that any resulting skin irritation is both mild and temporary.9,20,21
In conclusion, administering HA with an automatic
stamp-type microneedle intradermal injector improves
skin hydration for rejuvenation of the skin in East
Asian male subjects. Our results should be validated by
a follow-up in vivo study, as well as a large-scale
research study, to establish standard protocols.

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