|

Received: 20 January 2021    Accepted: 1 March 2021

DOI: 10.1111/jocd.14047

REVIEW ARTICLE

Mechanism and clinical applications of needle-­free injectors in

dermatology: Literature review

Hye Sung Han MD1  | Ji Yeon Hong MD, PhD2  | Tae Rin Kwon MD, PhD1 |
Sung Eun Lee BS1 | Kwang Ho Yoo MD, PhD1 | Sun Young Choi MD, PhD3 |
Beom Joon Kim MD, PhD1

1
Department of Dermatology, Chung-­Ang
University College of Medicine, Seoul,
South Korea
2
Department of Dermatology, Seoul
National University College of Medicine,
Seoul, South Korea
3
Department of Dermatology, Seoul
Paik Hospital Inje University College of
Medicine, Seoul, South Korea
Correspondence
Beom Joon Kim, Department of
Dermatology, Chung-­Ang University
College of Medicine, 102, Heukseok-­ro,
Dongjak-­gu, Seoul 06973, South Korea.
Email: beomjoon74@gmail.com
Abstract
Background: Needle-­free jet injectors are devices that deliver drugs using a high-­
speed jet without a needle. Recent studies have significantly increased our under-
standing of the mechanisms of needle-­free jet injectors, and technical advancements
have broadened the scope of application of the device.
Aims: We aimed to provide an up-­to-­date review of previous literature regarding the
mechanism of action and clinical applications of needle-­free jet injectors in dermatol-
ogy field.
Methods: We conducted a PUBMED search for studies on needle-­free jet injectors
using the following parameters: “Pneumatic injector” OR “needleless injector” OR
“needle-­free injector” OR “jet injector.” Among 191 results, 72 articles focusing on
their mechanisms of action, cutaneous delivery patterns, and clinical applications in
dermatology were selected for review.
Results: Significant clinical evidence has been published confirming the potential of
needle-­free jet injectors in treating various dermatologic conditions. In particular,
these devices have the potential to be used in various skin remodeling treatment,
especially in skin rejuvenation procedures by injecting various esthetic materials.
Conclusion: As proven by accumulated experience, the applications of NFJIs are not
restricted to vaccine or insulin delivery in dermatology field. However, this literature
review shows that until now, there are no clinical guidelines that standardize the opti-
mal parameters when using NFJIs on various clinical settings. Therefore, further stud-
ies should be performed in order to investigate the full potential of these devices in
dermatology, to ensure safe and effective outcomes in clinical practice.

KEYWORDS
jet injector, needle-­free injector, pneumatic injector

1  |  I NTRO D U C TI O N puncture the skin and deliver drugs to the necessary depth without
the use of a needle.1 Since the mid-­20 th century, NFJIs have been
Needle-­free jet injectors (NFJIs) are devices that are capable of extensively used for vaccinations and insulin injection.1-­3 However,
noninvasive drug delivery. These devices use a high-­velocity jet to due to the risk of cross-­contamination owing to splash-­black, the use

J Cosmet Dermatol. 2021;00:1–9. wileyonlinelibrary.com/journal/jocd© 2021 Wiley Periodicals LLC     1 |

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2      SUNG HAN et al.
of many NFJIs was discontinued. Despite this, recent technological
advancements such as the use of disposable nozzles and syringes
in order to prevent cross-­contamination have widened the scope of
their application.1
In dermatology, NFJIs have a broad scope of use because not
only can they be used as a drug delivery system but these devices
have the potential to be used in various skin remodeling treatment,
especially in skin rejuvenation procedures by injecting various es-
4,5
thetic materials. Here, we aimed to provide an updated review on
NFJIs based on the published reviews, case reports, and observa-
tional studies to give clinicians inspiration.
2  |  BA S I C U N D E R S TA N D I N G O F TH E
D E S I G N A N D M EC H A N I S M O F N FJ I S
A conventional NFJI is composed of three key constituents: an injec-
tion chamber to hold the drug, a nozzle, and a pressure source that
produce high-­velocity jets (Figure 1).
The pressure source uses direct pressure or more commonly,
indirect pressure by using a piston to create a high-­velocity jet of
fluid. The force required to drive the piston can be generated by
a compressed spring, Lorentz actuators, piezoelectric actuators, an
1
expanding gas (usually CO2 or N2) or air. Traditional jet injectors
such as the Dermojet (Akra Dermojet, Pau, France) and Madajet
(Mada Medical Products, Inc) have a stationary driving pressure be-
cause they are spring-­loaded. However, recently developed NFJIs
that use expanding gas as the driving pressure source (pneumatically
controlled) are more versatile because the driving pressure can be
adjusted. Thus, the penetration depth can be controlled for different
uses in different locations with varying skin thickness by changing
the driving pressure.
2.1  |  Factors affecting jet penetration
characteristics
Jet injection outcomes can be described by changes in the skin sur-
face, penetration depth, and dispersion shape created by the jet
inside the skin (Figure  2). In particular, the dispersion pattern and
penetration depth greatly affects drug absorption and injection-­
associated pain.6
Several factors affect drug dispersion and penetration char-
acteristics (Figure 2). These include the jet profile, physical or me-
chanical properties of the injected material and the medium to be
penetrated.1 Among them, the jet profile is the most important and
modifiable factor that determine the characteristics of jet penetra-
tion through the skin.1,6-­9
2.2  |  Jet profile
The jet profile depends on factors such as the nozzle diameter, jet
velocity (driving force), and to a lesser degree, the volume of fluid
injected.10 To date, various previous studies have examined the ef-
fects of each parameter on jet profile (Table 1).
Schramm-­Baxter et al6 investigated the effects of nozzle di-
ameters and jet velocities on jet penetration depth and shape. At
a fixed jet velocity and volume, the penetration depth increased as
the nozzle diameter increased. At nozzle diameters below 76 μm, the
Lm (the distance from skin surface to the point with maximum fluid
dispersion width) was 0.5 mm but at nozzle diameters greater than
100 μm, Lm was 2 mm. Furthermore, with a fixed nozzle diameter
of 152 µm, the penetration depth was <2 mm when the jet velocity
was 110 m/s, which increased to >4 mm when the jet velocity was
190 m/s. The shape of dispersion varied by the nozzle size and jet
F I G U R E 1  A needle-­free jet injector
consists of an injection chamber, a nozzle,
and a pressure source
SUNG HAN et al.
F I G U R E 2  Factors affecting jet
penetration characteristics
velocity as well, forming a lower hemisphere, sphere, upper hemi-
sphere, or nearly a cylinder as the nozzle size and jet velocity in-
creased (Figure  3). This is because the flow inside the skin begins
at the point source near the center of the sphere. Therefore, if fluid
penetration ends inside the skin and dispersion occurs completely
within the skin, a sphere or part of a spherical shape would occur,
but if the fluid penetrates the entire skin thickness, no point source
is formed; thus, the dispersion shape would look like a cylinder.
Seok et al7 studied the INNOJECTOR™ (Amore Pacific, Seoul,
Korea), an NFJI with a nozzle size of 100  μm and a jet velocity up
to 180  m/s to inject 5% methylene blue (MB) into human cadaver
cheeks. The injection at 6  bars of pressure (estimated velocity of
108 m/s) formed an upper hemisphere-­shaped dispersion that pen-
etrated up to 2.330 mm of the tissue, while injection at 8.5 bars (es-
timated velocity of 144 m/s) created a dispersion that resembles a
cylinder and penetrated up to 8.906 mm.
Similar results were observed in another study using the Airjet
(Union Medical, Gyeonggi, Korea) on a rat model.11 Although jet ve-
locity was not specified, a nozzle diameter of 100 μm with 50% and
100% of maximum power resulted in penetration depths of 2.105
and 2.007 mm, respectively, whereas a nozzle diameter of 150 μm
with 50% and 100% maximum power resulted in penetration depths
of 2.551 and 2.530 mm, respectively.
2.3  |  Optimal parameters for NFJI on the facial skin
Commercially available jet injectors have orifices of 76–­360 μm in di-
ameter and can produce jet velocities between 100–­200 m/s.6 In the
fields of dermatology, most procedures require drug injectate into
the dermis. Thus, an ideal parameter would be that which leads to
the injectate that forms a sphere within the dermis. Average human
facial skin thickness (epidermis +dermis) varies at 0.8–­2  mm. As
summarized in Table 1, a nozzle diameter of 76–­100 μm with a fluid
velocity of 110–­160 m/s resulted in a penetration depth of around
2 mm with an Lm of 1 mm in the human skin (marked as a green back-
ground in the table), which would be a generally suitable parameter
for various procedures on the facial skin. However, as skin thickness
or other mechanical properties of skin including Young's modulus
varies between individuals, there is a need for individualized injector
settings, which is suggested by most NFJI manufacturers.
|
      3
2.4  |  Clinical applications of NFJIs-­Skin remodeling
The efficacy of NFJIs in neocollagenesis is an area of active research
(Table 2).7 This is because during various procedures using NFJIs on
the skin, the injection system not only delivers the drug to a par-
ticular depth but also breaks the pull fibers in the dermis (subcision
effect). This is also called “subdermal minimal surgery.”1 An accel-
erated jet can stretch the fibroblasts, activate growth factors and
reduce collagen breakdown.5,12 For effective subdermal minimal
surgery, normal saline (NS) can be injected, but esthetic materials
such as hyaluronic acid (HA) dermal fillers or placental extracts can
also be utilized to maximize skin remodeling effects.
2.5  |  Depressed scar
Seok et al13 reported a case of tissue necrosis following filler injec-
tion successfully treated with NFJI combined with a radiofrequency
(RF) device. After 6-­month treatment of NS injection using NFJI
combined with RF device, the depressed scar significantly improved.
We recently reported a case of a depressed scar in a pediatric pa-
tient successfully by eight monthly treatment of NS injection using
NFJI.14 During the treatment, applying a topical anesthetic cream
sufficiently controlled the treatment-­induced pain, even in a pedi-
atric patient. Another study showed the clinical efficacy and safety
of Airjet (Union Medical, Gyeonggi, Korea) for facial atrophic acne
scars.15 Two months after a single treatment of HA injection using
NFJI, scar volumes significantly reduced compared with baseline
volumes. In another study, ten Korean patients with acne scars were
successfully treated after three sessions of HA injection using the
Airgent™ (PerfAction Ltd).16 HA injection using the Airgent™ also ef-
fectively treated herpes zoster-­induced depressed scars.17
2.6  |  Hypertrophic scar
In a previous case report, treatment using an NFJI device demon-
strated efficacy on a hypertrophic scar of the forehead.18 With only
two monthly treatments of NS injection using NFJI, the Vancouver
scar scale score (VSS) was reduced from 6 to 1. A thyroidectomy
scar was also successfully treated with a combination of NS injection
4     | SUNG HAN et al.

TA B L E 1  Summary of the effects of nozzle diameter and jet velocity on jet injection (studies on human skin)

Jet velocity

Nozzle diameter 110 m/s 160 m/s 180 m/s 190 m/s

6
31 µm Abdominal skin
Depth 2 mm
(epidermis and superficial dermis)
Shape Lower hemisphere
76 µm Abdominal skin6
Depth 2 mm
(epidermis and dermis)
Lm =0.5 mm
Shape Lower hemisphere
90% of fluid retained in the dermis
100 µm Cadaver cheeks7 Cadaver cheeks7
6 bar (108 m/s) 8 bar (144 m/s)
Depth 2.330 mm 8.906 mm
(penetration to the (penetration to the
SMASa ) masseter m.)
Shape Upper hemisphere Cylinder
6 6
152 µm Abdominal skin Abdominal skin Abdominal
skin6
Depth 2–­4  mm
(Full thickness)
Lm =2 mm
Shape Lower hemisphere Ellipsoid Upper
hemisphere
40% of fluid beyond
the dermis
229 µm Abdominal skin6
Depth Dermis floor
Shape Upper hemisphere
50% of fluid beyond the dermis
559 µm Abdominal skin6
Depth Beyond the dermis
Lm =3 mm
Shape Cylinder
60% of fluid beyond the dermis
a
SMAS; Superficial muscular aponeurotic system.

using NFJI and the use of silicone gel.19 In another pilot study evalu-
ating the efficacy of HA injection using NFJI among ten patients with
keloids on the upper arm, three sessions of treatment led to success-
20
ful effect in reducing VSS score.
2.7  |  Wrinkles
Wrinkles are one of the most common yet most challenging cosmetic
problems to treat. Numerous energy-­based skin rejuvenation tech-
niques, including lasers, RF, and intense pulsed light, are available,
but these technologies have limitations because they have limited
immediate visible effects and the transfer of energy through the
epidermis often results in side effects such as excessive erythema,
burns, or pigmentary alternations. HA injections using NFJIs may
overcome these problems because they cause less puncture damage
and destruction in the epidermis.18
Airgent™ (PerfAction Ltd.) has been successfully used to treat
wrinkles by the administration of HA injections in a few clinical stud-
ies.5,21 In one study, 34 participants underwent treatments with
HA injection using the Airgent™ on the face, neck, chest and dorsal
hands. After the treatment, short-­term evaluation revealed signifi-
cant reduction in the mean Fitzpatrick–­Goldman scale score by 30%
which lasted up to 18 months.5 Similarly, in another study, 20 partic-
ipants received three treatments of HA injection using Airgent™ on
various sites on the face, and the skin thickness was measured using
ultrasonography. Seven days after the last procedure, skin thickness
was increased in all patients and lasted up to six months after the
SUNG HAN et al.       5|

F I G U R E 3  Schematic diagram that shows the change in fluid dispersion shape with increase in nozzle diameter and jet velocity

TA B L E 2  Clinical applications of NFJIs in skin remodeling

Depressed scar

Skin condition and

Study Intervention Device Parameters # of treatments
13
Seok et al, Tissue necrosis following filler INNOJECTOR™ Nozzle diameter: 100 μm 1
2016 injection Velocity: 108 m/s (6 bars)
0.15 ml of normal saline at a 2 mm distance
Park et al,14 Depressed scar in pediatric INNOJECTOR™ Nozzle diameter: 100 μm 8
2019 patient Velocity: 108 m/s (6 bars) (1-­month interval)
0.1 ml of normal saline at a 2 mm distance
Kim et al,15 Facial atrophic acne scar Airjet Nozzle diameter: 200 μm 1
2019 Pressure: 50% pressure power
85 uL of hyaluronic acid diluted with 20%
hypertonic glucose
Lee et al,16 2010 Facial atrophic acne scar Airgent™ Nozzle diameter: 150 μm 3
10*10 mm square-­shaped tip (1-­month interval)
Pressure: 70% pressure power
0.15 ml of hyaluronic acid
20–­50 shots according to patient scar
condition
Kim et al,17 Herpes zoster-­induced Airgent™ Nozzle diameter: 150 μm 6
2009 depressed scars 10*10 mm square-­shaped tip (1-­month interval)
Pressure: 80% pressure power
0.2 ml of hyaluronic acid
Hypertrophic scar
Seok et al,18 Hypertrophic scar on the INNOJECTOR™ Nozzle diameter: 100 μm 2
2016 forehead Velocity: 180 m/s (1-­month interval)
0.1 ml of normal saline at a 2-­mm distance
Seok et al,19 Thyroidectomy scar INNOJECTOR™ Nozzle diameter: 100 μm 4
2016 Velocity: 108 m/s (6 bars) (1-­month interval)
0.1 ml of normal saline at a 2-­mm distance
Kim et al, 20 Keloids Airgent™ Nozzle diameter: 150 μm 3
2012 10 × 10 mm square-­shaped tip (3-­week interval)
Pressure: 70% pressure power
0.15 ml of hyaluronic acid
Wrinkles
Levenberg et Wrinkles on the face, neck, Airgent™ Nozzle diameter: 150 μm 3–­4
al, 5 2010 chest, and dorsal hands 10–­10-­mm square-­shaped tip (3–­4-­week interval)
Kobus et al, 21 Pressure: 70% pressure power
2010 Approximately 2 mg HA deposited in each
5 cm2 treatment area)
a
INNOJECTOR™ (Amore Pacific, Seoul, Korea); Airjet (Union Medical, Gyeonggi, Korea); Airgent™ (PerfAction Ltd., Rehovot, Israel)
 |

TA B L E 3  Clinical applications of NFJIs for transdermal drug delivery.

6     

Jet anesthesia

Study Skin condition Device Parameters # of treatment

Benohanian et al, 22 2006
Benohanian et al, 23 2005
Benohanian et al, 24 2007
Ellis et al, 26 1993
Intralesional corticosteroid injection
Abell et al, 27 1973
Sparrow et al, 28 1975
Nantel-­Battista et al, 29 2014
Intralesional bleomycin injection
Agius et al, 32 2006
Bodokh et al, 33 1996
Saray et al, 34 2005
Intralesional 5-­aminolevulinic acid (ALA) injection
Li et al,35 2013
Barolet et al, 36 2011
a
MED-­JET MBX (Medical International Technologies); Syri-­jet Mark IV (Mizzy Inc); Dermojet (AKRA Dermo Jet, Pau); Madajet® (Mada Medical Products, Inc); INJEX (Rösch AG Medizintechnik).
Jet anesthesia prior to MED-­JET MBX Nozzle diameter: 120 μm 1
palmar BoNT injection Pressure: 130–­150 psi (Injections at 1.5–­2-­cm intervals over the whole palm)
Volume: 0.02 ml of 2% lidocaine per spurt to
produce superficial skin wheals
Digital blocks Syri-­jet Mark IV Nozzle diameter: 152–­220 μm 1
Pressure: 2,600 lb/in2 (First injection on the ulnar aspect of proximal phalanx
Volume: 0.15 ml of 1% lidocaine per spurt midway between palmar and dorsal surfaces/
Second injection placed anterior to this site/Third
injection placed posterior to the site)
Alopecia areata Porto-­jet Nozzle diameter: unknown 3
Velocity: unknown (1–­2-­week interval)
0.1 ml triamcinolone acetonide (5 mg/ml)
Granuloma annulare Porto-­jet Nozzle diameter: unknown 3–­16 total
Necrobiosis lipoidica Velocity: unknown (3 injections in 2-­week interval and additional injection
0.1 ml triamcinolone acetonide (5 mg/ml) by clinical situation)
Psoriatic fingernail MED-­JET MBX Nozzle diameter: 120 μm 4
Pressure: 130–­140 psi (4-­week interval)
Volume: 0.07 ± 0.02 ml volume per spurt
Recalcitrant plantar warts Dermojet Nozzle diameter: 200 μm Up to 5
Pressure: 1400 psi (5-­week interval)
Volume: 0.1 mL bleomycin (1 IU/ml) intralesionally
to cover an area of about 0.25 cm2 of plantar
warts
Keloids and hypertrophic Madajet® Nozzle diameter: 200 μm 2–­6
scars Pressure: 1800 psi (4-­week interval)
Volume: 0.1 ml bleomycin (1.5 IU/ml) per spurt
with injection sites spaced 0.5 mm apart
Condyloma acuminatum INJEX Nozzle diameter: 170 μm 1–­2
Velocity: 140 m/s (1-­week interval)
Volume: 0.4 ml of 20% ALA solution
Basal cell carcinoma Madajet® Nozzle diameter: 200 μm 1
Pressure: 1800 psi
Volume: 0.4 ml of 20% ALA solution intradermally
SUNG HAN et al.
SUNG HAN et al.
treatment. These results were also consistent with the results of the
Global Improvement Assessment questionnaire at six-­month post-­
treatment where 59.9% of participants reported of at least a slight
improvement in their appearance. 21
3  |   C LI N I C A L A PPLI C ATI O N S O F N FJ I S -­
TR A N S D E R M A L D RU G D E LI V E RY
NFJIs can also be used to treat various dermatological conditions re-
quiring transdermal drug delivery (Table 3). NFJIs can deliver various
drugs into the skin in a standardized manner that allows for an in-
stant and controlled allocation of the drug with minimal side effects.
3.1  |  Local anesthesia using NFJIs (jet anesthesia)
Jet anesthesia has been successfully used before botulinum toxin
(BoNT) injection for palmar hyperhidrosis (HH) in a few case
reports.22-­24 Local anesthesia of the palms using NFJIs can reduce pain
and possible injury to the underlying nerves or vessels.25 Other studies
26
have also reported the efficacy of NFJIs for performing digital blocks.
Compared to the nerve blocks using needles, using NFJIs caused sig-
nificantly lower pain scores than needles at the time of injection.
3.2  |  Intralesional corticosteroid injection
NFJIs are a useful alternative to corticosteroid needle injections be-
cause they can diminish pain and also allows for a uniform spread of
corticosteroids in the intradermal lesions. Using NFJIs, corticoster-
oids may spread more evenly into intradermal lesions, such as alo-
pecia areata (AA), rather than remaining alongside the needle track.
However, the blockage of NFJI by corticosteroid agglomerates may
occur during injection. This can be prevented by shaking the triamci-
nolone suspension using a large-­diameter nozzle.
Abell et al reported of the successful treatment of alopecia
27 28
areata (AA), granuloma annulare (GA), and necrobiosis lipoid-
28
ica with triamcinolone injection using the Porto-­jet needleless in-
jector. Another study has also evaluated the efficacy and safety of
NFJI for corticosteroid matrix injections into psoriatic fingernails. 29
Injecting corticosteroid into the nail matrix using a needle is a tradi-
tional treatment option for nail psoriasis, significant pain often limits
treatment. Corticosteroid matrix injection using an NFJI enabled a
less painful and more successful treatment of psoriatic nail, which
was proven by reduction in the NAPSI score.
3.3  |  Intralesional bleomycin injection
Intralesional bleomycin injection has been successfully used for to
treat recalcitrant planar warts.30,31 Agius et al32 reported of the ef-
ficacy of bleomycin injection using NFJIs among 47 patients (138
|
      7
plantar warts) that have been recalcitrant to 10 cycles of cryosur-
gery. After one to five treatment sessions, a cumulative clearance
rate (complete and partial) was 89.9%. The operators reported that
NFJI seemed to be ideal for penetrating thick acral skin and can also
be easily applied to the curved surfaces especially on the sole.32
Bleomycin injections using NFJIs also successfully treated ke-
loids and hypertrophic scars in a few preliminary studies.33,34 In one
study that evaluated the efficacy of bleomycin injection using NFJIs
among 14 patients with keloids or hypertrophic scars, successful
treatment results were achieved with two to six treatment sessions
using smaller doses of bleomycin (0.4 mL/cm2) compared to injected
doses using needles (2  mL/cm2).34 The authors concluded that by
using NFJIs, bleomycin can be distributed more evenly throughout
the lesions, leading to successful clinical results despite smaller vol-
umes of bleomycin.
3.4  |  Intralesional 5-­aminolevulinic acid injection
The use of photodynamic therapy (PDT) using the topical application
of 5-­aminolevulinic acid (ALA) has been demonstrated effective for
treating anogenital warts. However, the optimal penetration of the
photosensitizing agent (ALA) is often not achieved with topical ap-
plication, especially in patients with thick and extensive warts.
Li et al35 compared the efficacy of ALA injection using NFJI with
the topical application of ALA when performing PDT for the treat-
ment of condyloma acuminatum (CA). The complete response rate
was significantly higher and recurrence was significantly lower in
the NFJI group. Also, the incubation time prior to the irradiation was
considerably reduced (1.5 h) using NFJI compared to when using the
conventional topical application method (3 h).
Barolet et al36 also used NFJI to inject 5-­ALA 20% before PDT
to treat nodular basal cell carcinomas (BCCs), which led to complete
remission for several years. Also, the treatment resulted in minimal
side effects. When treating nodular BCC using ALA-­PDT, the suc-
cess rate is highly dependent on the sufficient penetration of the
photosensitizing agent into the lesion. The authors reported that
NFJIs can secure an instant and far-­reaching allocation of the drug.36
4  |  CO N C LU S I O N
As reported by various clinical studies and case reports, the
clinical use of NFJIs is not limited to vaccine or insulin delivery
in dermatology field. However, despite much accumulated posi-
tive experience of the use of NFJIs in dermatology field, clinicians
must also be aware of undesired effects of failed jet injections
including blebs due to large volumes in a single spot, misalignment
of the injector leading to suboptimal injections, or development
of epidermoid implantation cysts. Furthermore, this literature re-
view shows that until now, there are no clinical guidelines that
standardize the optimal parameters when using NFJIs on various
clinical settings. Therefore, well-­d esigned randomized controlled
 |
8      SUNG HAN et al.
studies are necessary to determine the efficacy and safety of this
technology for various clinical indications in the future to insure a
safe and effective outcome.
AC K N OW L E D G E M E N T S
This research was supported by the Chung-­Ang University Research
Scholarship Grants in 2019
C O N FL I C T O F I N T E R E S T
No conflict of interest.
AU T H O R C O N T R I B U T I O N S
Hye Sung Han, Ji Yeon Hong, Sun Young Choi, and Beom Joon Kim
contributed to conception and design. Hye Sung Han, Tae Rin Kwon,
Sung Eun Lee, and Kwang Ho Yoo contributed to acquisition of data.
Hye Sung Han, Ji Yeon Hong, Sun Young Choi, and Beom Joon Kim
contributed to interpretation of data. All of the authors were in-
volved in the drafting of the manuscript and in the critical revision
of the manuscript for important intellectual content, and have given
final approval of the version to be published.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from
the corresponding author upon reasonable request.
ORCID
Hye Sung Han  https://orcid.org/0000-0002-3556-0740
Ji Yeon Hong  https://orcid.org/0000-0002-5632-8449
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