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Citation: Hamed, R.; Abu Nahia, B.J.;
Alkilani, A.Z.; Al-Adhami, Y.;
Obaidat, R. Recent Advances in
Microneedling-Assisted Cosmetic
Applications. Cosmetics 2024,11, 51.
https://doi.org/10.3390/
cosmetics11020051
Academic Editor: Vasil Georgiev
Received: 14 February 2024
Revised: 23 March 2024
Accepted: 26 March 2024
Published: 2 April 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
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4.0/).
cosmetics
Review
Recent Advances in Microneedling-Assisted Cosmetic Applications
Rania Hamed 1, * , Baraah Jehad Abu Nahia 1, Ahlam Zaid Alkilani 2, Yasmeen Al-Adhami 1and Rana Obaidat 3
1Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan;
baraahjihad@gmail.com (B.J.A.N.); yasmeen.aladhami@yahoo.com (Y.A.-A.)
2Department of Pharmacy, Faculty of Pharmacy, Zarqa University, Zarqa 13110, Jordan; ahlamk@zu.edu.jo
3
Department of Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, The University of Jordan,
Amman 11941, Jordan; r.obaidat@ju.edu.jo
*Correspondence: rania.hamed@zuj.edu.jo; Tel.: +962-6-429-1511 (ext. 299) or +962-79-773-9590;
Fax: +962-6-429-143
Abstract: Microneedling, also known as percutaneous collagen induction, using microneedling
devices and fabricated microneedle patches, has been widely employed in cosmetic applications
for acne scar treatment, skin care, hair loss, melasma, skin rejuvenation, and skin cancer. The
micro-channels formed by microneedling through the stratum corneum facilitate the delivery of
cosmetic agents and stimulate collagen and elastin production by inducing the wound-healing
cascade, keeping the skin shiny and wrinkle-free. Several cosmetic agents, such as ascorbic acid,
hyaluronic acid, retinoids, niacinamide, and peptides, have been delivered by microneedling. This
review aims to highlight the use of microneedling devices and fabricated microneedle patches
in facilitating the delivery of cosmetic agents through the skin layers. Moreover, the differences
between the microneedling devices, commonly used alone or in combinational treatments with topical
formulations, are explored. Furthermore, the safety of microneedling in terms of skin irritation, pain
sensation, skin or systemic infection, and chemical and biological materials used in the fabrication of
microneedles is discussed.
Keywords: microneedling devices; fabricated microneedle patches; cosmetic agents; skin care; hair
loss; melasma; skin rejuvenation
1. Introduction
Healthy skin has positive psychological and social impacts on individuals [
1
]. It has
been shown that there is a direct link between skin conditions and psychology, where
individuals with skin conditions are more likely to suffer from depression, social isolation,
loneliness, and a lower quality of life [
2
]. Several strategies have been employed to improve
skin conditions, such as topical medical preparations, chemical peeling, and ablative and
non-ablative laser photo-rejuvenations. These above strategies have been widely used
in treating skin wrinkles, aging, acne scars, and hyperpigmentation [
3
]. Moreover, the
recent advances in cosmetic applications have opened doors to treat more complex skin
conditions such as vitiligo, hair loss, melasma, and skin cancer [4].
Various topical/transdermal delivery platforms, such as nanoparticles, liposomes,
dendrimers, gels, creams, lotions, patches, nanoemulsions, and microemulsions, have been
widely used to deliver cosmetic agents to the skin [
5
,
6
]. However, these delivery platforms
often cannot cross the major barrier of the skin, the stratum corneum (SC), hindering the
penetration of the chemical molecules through the skin layers [
7
–
9
]. Additionally, this
barrier limits the penetration of the hydrophilic and high-molecular-weight molecules
(>500 Da) through the intact skin [
10
–
12
]. This will ultimately increase the frequency of
application of the delivery platforms onto the skin so that a sufficient amount of cosmetic
agents can penetrate the skin layers (epidermis and dermis), leading to poor patient
compliance [1].
Cosmetics 2024,11, 51. https://doi.org/10.3390/cosmetics11020051 https://www.mdpi.com/journal/cosmetics
Cosmetics 2024,11, 51 2 of 29
Recently, the microneedling technique, also known as percutaneous collagen induction
(PCI), using microneedling devices such as Dermaroller and Dermapen, and fabricated
microneedle patches (MNs), such as solid, hollow, dissolved, coated, and hydrogel MNs,
have been widely employed in the cosmetics field [
13
]. Microneedling is characterized by
its minimal invasiveness, painlessness, and self-administration, which can result in good
patient compliance, in addition to reduced hazardous waste sharps [
14
]. These advantages
suggest that there will be a broad market for microneedling applications in the cosmetics
field.
Microneedling or PCI was introduced in 1990 to treat scars [
15
], and it then became
more widely explored for the delivery of drugs after 1990 [
14
]. Recently, microneedling
has been employed to enhance the delivery of active ingredients used in cosmetics, such
as ascorbic acid (AA), retinoids, melanin, proteins, and peptides [
1
]. When applying
microneedling devices and fabricated MNs, micro-sized needles can pass through the
SC, creating micro-channels of aqueous transport pathways that enhance the transport of
molecules through the skin at therapeutically relevant doses [
16
,
17
]. This will eventually
increase the absorption of cosmetic agents compared with topical administration and
effectively reduce the quantity delivered [
1
]. It is worth noting that the disruption of
the molecular architecture of the SC by microneedling is reversible, resulting in less pain
or bleeding compared with hypodermic needles, particularly for short microneedles of
<600
µ
m in length [
18
,
19
]. It has been shown that the microneedle’s length dramatically
correlates with pain and bleeding [
20
]. For instance, microneedles of 500–1500
µ
m in
length would result in a sevenfold increase in pain score for human subjects [
21
]. This
is because pain receptors innervate the epidermis and dermis; thus, the penetration of
longer microneedles would excite more receptors [
21
]. Additionally, microneedles of
1000–1500 µm
in length have been reported to puncture tiny blood capillaries, leaving
blood spots on the skin surface [
22
,
23
]. It should also be noted that the thickness of the skin
vastly varies within the human body, a factor that needs to be considered when applying
microneedles to specific areas of the body [24].
The use of microneedling in cosmetic applications has previously been reviewed by
McCrudden et al. [
13
] and Iriarte et al. [
25
]. McCrudden et al. [
13
] explored the chronology
of using Dermaroller
®
and Dermapen
®
, developed based on Fernandes’s PCI innovation,
and Dermastamp
®
in inducing collagen and treating acne, burn scars, and photo-aging.
The design of the microneedling devices and some commercially available devices were
reported in this review. In addition, the safety, regulatory considerations, and public
perception relating to the use of these devices were addressed. This was followed by a
review article by Iriarte et al. [
25
] that discussed the use of microneedling in combination
with topical medications for treating various dermatological conditions, including scars,
alopecia, pigmentary disorders, verruca, and actinic keratosis. The frequency and interval
between treatments for optimal effects were also evaluated. A very recent review by
Huang et al. [
1
] focused on describing the preparation methods, polymers, loading drugs,
mechanical and penetrative properties, and types of fabricated MNs used in a wide range
of cosmetic applications, such as whitening, moisturizing, wrinkle removal, fat reduction,
scar removal, alopecia treatment, and acne treatment. Different drug loading methods,
like simple physical mixing of active ingredients and matrix materials, drug carriers such
as liposomes, polymeric micelles, nanoparticles, nanogels, and nanocapsules, and drug
coupling through covalent bonds between drug molecules and polymer materials, were
also discussed.
Therefore, this paper reviews the most recent update on the extensive use of mi-
croneedling in various cosmetic applications, including skin anti-aging, scar removal, skin
whitening, skin moisturizing, skin rejuvenation, hair loss, melasma, vitiligo, and skin
cancer. In addition, this review highlights the expansion of using microneedling as adju-
vant therapy for various indications in dermatology. Moreover, this review focuses on the
difference between microneedling devices used alone or in combinational treatments with
topical formulations. Furthermore, it summarizes the types of fabricated MNs, polymers
Cosmetics 2024,11, 51 3 of 29
used in fabrication, approaches used to deliver cosmetic agents across the skin, clinical
outcomes of the cosmetic-agent-loaded MNs, and their safety when applied to the skin.
2. Microneedling Devices
Microneedling using microneedling devices such as Dermaroller and Dermapen
(Figure 1)
in cosmetic applications is gaining prominence, particularly for improving the
skin’s appearance and treating blemishes and scars [
25
–
29
]. The use of these devices has
continuously evolved since their origin in the early twentieth century. Recently, dermatolo-
gists introduced microneedling in anti-aging and rejuvenation therapy to achieve smooth
and young-looking skin [
28
]. These devices puncture the skin with micron-sized needles
in a non-pathogenic manner, causing the underlying cells to produce more collagen and
elastin, the crucial dermal components [
28
,
30
,
31
]. In addition, these devices have been used
to enhance the delivery of cosmetic agents [31–33].
Cosmetics 2024, 11, x FOR PEER REVIEW 3 of 29
therapy for various indications in dermatology. Moreover, this review focuses on the dif-
ference between microneedling devices used alone or in combinational treatments with
topical formulations. Furthermore, it summarizes the types of fabricated MNs, polymers
used in fabrication, approaches used to deliver cosmetic agents across the skin, clinical
outcomes of the cosmetic-agent-loaded MNs, and their safety when applied to the skin.
2. Microneedling Devices
Microneedling using microneedling devices such as Dermaroller and Dermapen
(Figure 1) in cosmetic applications is gaining prominence, particularly for improving the
skin’s appearance and treating blemishes and scars [25–29]. The use of these devices has
continuously evolved since their origin in the early twentieth century. Recently, derma-
tologists introduced microneedling in anti-aging and rejuvenation therapy to achieve
smooth and young-looking skin [28]. These devices puncture the skin with micron-sized
needles in a non-pathogenic manner, causing the underlying cells to produce more colla-
gen and elastin, the crucial dermal components [28,30,31]. In addition, these devices have
been used to enhance the delivery of cosmetic agents [31–33].
Dermaroller® is a simple handheld microneedling device with fine needles of 200–
3000 µm in length and an effective diameter of 0.1 mm [28]. The needles of the Dermarol-
ler® are fabricated from silicon or stainless steel by reactive ion etching [28]. The silicon
and stainless steel needles are known to be tough and durable [28,34]. Dermarollers® are
commonly used for acne scar treatment [13,29], skin care [28], burn scars [35], pigmentary
disorders [36], and PCI [37]. In addition, they can be used in facial rejuvenation, stretch
marks, and hair loss [37,38]. However, because of the length of the needles, this treatment
is not optimal, as it may cause skin bleeding [27].
Figure 1. Representative images of (A) Dermaroller and (B) Dermapen when applied to the skin.
Two mechanisms have been proposed for microneedling [39]: The first mechanism
suggests that microneedling leads to the release of growth factors that stimulate the for-
mation of collagen and elastin in the papillary dermis. Briefly, the needles penetrate the
SC and create small holes (micropunctures) without damaging the epidermis. These mi-
cro-injuries lead to minimal superficial bleeding, inducing the wound-healing cascade
and activating platelets and neutrophils to release growth factors (transforming growth
factor (TGF)-alpha, TGF-beta, and platelet-derived growth factor) and stimulate the pro-
duction of collagen and elastin in the papillary layer of the dermis. This ultimately results
in the deposition of collagen by fibroblasts [25,39,40]. Moreover, micropores created by
Figure 1. Representative images of (A) Dermaroller and (B) Dermapen when applied to the skin.
Dermaroller
®
is a simple handheld microneedling device with fine needles of
200–3000 µm
in length and an effective diameter of 0.1 mm [
28
]. The needles of the Dermaroller
®
are
fabricated from silicon or stainless steel by reactive ion etching [
28
]. The silicon and stainless
steel needles are known to be tough and durable [
28
,
34
]. Dermarollers
®
are commonly used
for acne scar treatment [
13
,
29
], skin care [
28
], burn scars [
35
], pigmentary disorders [
36
],
and PCI [
37
]. In addition, they can be used in facial rejuvenation, stretch marks, and hair
loss [
37
,
38
]. However, because of the length of the needles, this treatment is not optimal, as
it may cause skin bleeding [27].
Two mechanisms have been proposed for microneedling [
39
]: The first mechanism
suggests that microneedling leads to the release of growth factors that stimulate the forma-
tion of collagen and elastin in the papillary dermis. Briefly, the needles penetrate the SC and
create small holes (micropunctures) without damaging the epidermis. These micro-injuries
lead to minimal superficial bleeding, inducing the wound-healing cascade and activating
platelets and neutrophils to release growth factors (transforming growth factor (TGF)-alpha,
TGF-beta, and platelet-derived growth factor) and stimulate the production of collagen
and elastin in the papillary layer of the dermis. This ultimately results in the deposition of
collagen by fibroblasts [
25
,
39
,
40
]. Moreover, micropores created by microneedling enhance
the permeation of skin care formulations, thus boosting their efficacy [
28
]. The second
mechanism suggests that microneedling generates a demarcation current rather than phys-
ical wounds when microneedles penetrate the skin. This current triggers a cascade of
growth factors that facilitate the healing process. This mechanism is based on the concept of
bioelectricity, where epidermal injury alters the electric potential within cells to a negative
electric potential of
−
70 mV, compared to the epidermis, which has a positive potential. It
Cosmetics 2024,11, 51 4 of 29
is anticipated that the change in the potential stimulates the migration and proliferation of
fibroblasts to the site of injury, leading to collagen deposition at the injury site [39,41].
Another microneedling device used in cosmetic applications is Dermapen
®
[
38
].
Dermapen
®
is a handheld pen-like device with disposable needles used to treat acne,
burn scars, and photo-aging [
13
]. The needle’s length can be adjusted to drive the needle
up and down the treatment site [
25
,
28
]. It has a battery that can be recharged. Nine to
twelve needles are stacked in rows on the needle tip.
Moreover, Dermapen
®
has two operating modes: high speed (700 cycles per minute)
and low speed (412 cycles per minute) [
25
]. Dermapen
®
has benefits over Dermaroller
®,
as
it provides disposable needles, uniform application of pressure on the skin, and minimum
risk of tips breaking in the skin [
28
,
42
]. In addition, it can treat delicate regions around the
eyes, lips, and nose without damaging the skin [
28
]. Table 1presents a general comparison
between Dermaroller®and Dermapen®, without referring to any commercial brands.
Table 1. Comparison between Dermaroller and Dermapen.
Specifications Dermaroller Dermapen
Needle length 200–3000 µm [28] Adjustable in length from 250 to 2500 µm [38]
Needles depth
Adjustable needle penetration depth in automated
Dermarollers only [28]
Adjustable needle penetration depth during
use [28,37]
Disposable needles Disposable head in automated rollers only [28] Disposable needles [28]
Applications
In cosmetics and transdermal applications, where
the skin is pretreated with the Dermaroller,
followed by the use of the transdermal
formulation [28]
Primarily in cosmetics [13]
Uniform pressure on the
skin
Depending on the user, no way to control how
much pressure is on the skin, except for automated
Dermarollers [28]
Uniform pressure [28]
Advantages
Easy-to-use, home-usable Dermaroller, applied
across the skin vertically, horizontally, and
diagonally [43,44]
An inexpensive office maneuver, risk-free
procedure as the needles are hidden in a guide,
less painful, used to treat facial wrinkles due to
aging and smoking, penetrates the skin at a
perpendicular angle, is suitable for delicate and
specific areas, and does not require pressure on
the skin as in the case of Dermaroller [
43
,
45
,
46
]
Disadvantages
Controlling the pressure has to come with practice
and experience (except for automated devices);
difficult to treat small areas or localized scars [43]
The disadvantages of Dermaroller are
overcome by Dermapen [44]
Side effects
Bleeding, swelling, bruising, redness, temporary
erythema, pain, burning sensation, edema, itching,
and peeling (these typically go after a few days or
weeks), along with a risk of tips breaking in the
skin [27,39]
Redness and swelling that disappears within
2–3 days [43]
Microneedling setup Accessible for home use at low cost or by skin professionals in clinics [25,47,48]
Recovery of the skin
barrier function
Several hours to 72 h of device usage, based on age, skin elasticity, skin application site, needle length,
number of applications, and application pressure [44,49]
Recently, a miniature version of Dermaroller
®
(Dermastamp
®
, Figure 2) has been fabricated
to reach the small, confined areas that are difficult to reach with Dermaroller
®
[
13
,
40
,
50
,
51
].
The Dermastamp
®
(Teoxy Beauty, Wuhan, China) is a non-oscillating device composed of
microneedle arrays with 42 needles per stamp of 1000
µ
m in length, 0.12 mm in diameter, a
21–25
µ
m tip radius, and curved conical geometry, arranged at the base of the stamp [
52
].
In addition, the Dermastamp
®
is commercially available, with adjustable needle length
ranges from 200–3000
µ
m and a diameter of 0.12 mm [
53
]. It is inserted into the skin in
Cosmetics 2024,11, 51 5 of 29
a vertical position. A recent study by Sabri et al. [
37
] evaluated the mechanical insertion
of an oscillating Dermapen
®
(ZJChao, China) and a non-oscillating Dermastamp
®
(Teoxy
Beauty, Wuhan, China), used to overcome the physiological barrier of the SC and, hence,
enhance the delivery of molecules into and across the skin. The needles of Dermastamp
®
were 1000
µ
m in length, and those of Dermapen
®
were adjustable to the same length of
1000
µ
m. This study showed that greater force was required to puncture the skin with
Dermastamp
®
compared to Dermapen
®
. In addition, Dermapen
®
was more effective in
generating micro-channels across the skin, as it can penetrate deeper skin layers due to
its oscillating microneedle system. Nevertheless, the ex vivo permeation study revealed
that both microneedle systems exhibited similar permeation profiles for the model drug
imiquimod across the skin after 24 h, since both systems breached the SC, epidermis, and
most likely the superficial dermis [
37
]. Finally, a patented gold-plated micro-injection
system known as AquaGold
®
Fine Touch (Aquavit Pharmaceuticals, NY, USA) was used
to induce collagen and elastin and deliver cosmetic products deep into the skin layers,
such as retinol, vitamin C, antioxidants, anti-aging serums, vitamins, growth factors, fillers
(Botox and hyaluronic acid (HA)), plasma-rich protein, and toxins. The device contains
thin, hollow, 24-karat gold needles of 600
µ
m in length and 130
µ
m in width that create
tiny punctures in the skin and deposit products beneath the skin’s surface. This improves
the skin’s quality and texture, reduces the appearance of fine lines, shrinks the pores, and
boosts hydration [48,54].
Cosmetics 2024, 11, x FOR PEER REVIEW 5 of 29
go after a few days or weeks), along with a
risk of tips breaking in the skin [27,39]
Microneedling setup Accessible for home use at low cost or by skin professionals in clinics [25,47,48]
Recovery of the skin bar-
rier function
Several hours to 72 h of device usage, based on age, skin elasticity, skin application site,
needle length, number of applications, and application pressure [44,49]
Recently, a miniature version of Dermaroller® (Dermastamp®, Figure 2) has been fab-
ricated to reach the small, confined areas that are difficult to reach with Dermaroller®
[13,40,50,51]. The Dermastamp® (Teoxy Beauty, Wuhan, China) is a non-oscillating device
composed of microneedle arrays with 42 needles per stamp of 1000 µm in length, 0.12 mm
in diameter, a 21–25 µm tip radius, and curved conical geometry, arranged at the base of
the stamp [52]. In addition, the Dermastamp® is commercially available, with adjustable
needle length ranges from 200–3000 µm and a diameter of 0.12 mm [53]. It is inserted into
the skin in a vertical position. A recent study by Sabri et al. [37] evaluated the mechanical
insertion of an oscillating Dermapen® (ZJChao, China) and a non-oscillating Dermas-
tamp® (Teoxy Beauty, Wuhan, China), used to overcome the physiological barrier of the
SC and, hence, enhance the delivery of molecules into and across the skin. The needles of
Dermastamp® were 1000 µm in length, and those of Dermapen® were adjustable to the
same length of 1000 µm. This study showed that greater force was required to puncture
the skin with Dermastamp® compared to Dermapen®. In addition, Dermapen® was more
effective in generating micro-channels across the skin, as it can penetrate deeper skin lay-
ers due to its oscillating microneedle system. Nevertheless, the ex vivo permeation study
revealed that both microneedle systems exhibited similar permeation profiles for the
model drug imiquimod across the skin after 24 h, since both systems breached the SC,
epidermis, and most likely the superficial dermis [37]. Finally, a patented gold-plated mi-
cro-injection system known as AquaGold® Fine Touch (Aquavit Pharmaceuticals, NY,
USA) was used to induce collagen and elastin and deliver cosmetic products deep into the
skin layers, such as retinol, vitamin C, antioxidants, anti-aging serums, vitamins, growth
factors, fillers (Botox and hyaluronic acid (HA)), plasma-rich protein, and toxins. The de-
vice contains thin, hollow, 24-karat gold needles of 600 µm in length and 130 µm in width
that create tiny punctures in the skin and deposit products beneath the skin’s surface. This
improves the skin’s quality and texture, reduces the appearance of fine lines, shrinks the
pores, and boosts hydration [48,54].
Figure 2. Representative images of (A) Dermastamp and (B) Dermastamp when applied to the
skin.
Figure 2. Representative images of (A) Dermastamp and (B) Dermastamp when applied to the skin.
2.1. Microneedling in Cosmetic Applications
2.1.1. Treatment of Acne Scars
Microneedling is a technique used to improve cutaneous scarring by increasing the
production of collagen and elastin in the dermis, collagen remodeling, and increasing the
thickness of the epidermis and dermis [
27
]. The most frequently used alpha-hydroxy acid
peel is the glycolic acid (GA) peel. Sharad [
55
] compared the effectiveness of a combination
of microneedling using Dermaroller
®
MF8 and 35% GA peel for treating acne scars in skin
types III–V versus microneedling alone. Microneedling was performed six times a week
for six weeks, followed by a 35% GA peel three weeks later. The superficial or moderately
deep scars were improved significantly. In addition, the skin’s texture was improved,
and the post-acne pigmentation was reduced. Saadawi et al. [
56
] compared the efficacy
of using a combination of microneedling using Dermapen
®
(Bomtech Electronics, Seoul,
Republic of Korea) and GA peel versus each alone. Thirty participants with acne scars
were included in this study. The participants were divided into three groups at random,
each with ten patients. Six sessions were given to each patient at two-week intervals.
The results showed that combining microneedling with GA peel was more effective in
treating acne scars compared with monotherapy. In another study [
57
], microneedling
using Dermaroller
®
with a topical application of platelet-rich plasma (PRP) was found
Cosmetics 2024,11, 51 6 of 29
to be effective in accelerating the wound healing of atrophic acne scars by enhancing
nucleogenesis and inducing remodeling of acne scars. In this study [
57
], the authors found
that a combination of microneedling and chemical peeling using 15% trichloroacetic acid
(TCA) improved severe atrophic acne scars.
Furthermore, Costa and Costa [
58
] found that microneedling improved varicella scars
in dark-skinned teenagers. Recently, Ali et al. [
59
] used microneedling using Dermapen
®
(Derma Stamp Electric Pen, Beijing, China) and Jessner’s peeling solution—a mixture of
salicylic acid, resorcinol, and lactic acid in 95% ethanol—for the treatment of acne scars.
The results showed that the combined technique of microneedling and Jessner’s solution
was considered to be the best clinical treatment for atrophic acne scars, with the smallest
number of sessions compared to each technique alone.
Additionally, microneedling using a Dermastamp
®
with stainless steel needles of
2.1 mm
in length was used to treat hypertrophic burn scars. Five patients underwent
8–12 microneedling
sessions every two weeks. During the treatment, the scar was pressed
by the Dermastamp 3–4 times, producing 200–300 holes in the scar area. The results
demonstrated a clinical improvement in the burn scars when evaluating the Vancouver Scar
Scale score and the scar depth. The scar improvement was attributed to the microneedling
of the scars using Dermastamp
®,
which induces the rearrangement of collagen fibers on
scar tissue and thins the height of the scar [60].
Moreover, microneedling is a widely used procedure for improving the final appear-
ance of surgical scars [
61
]. Microneedling creates controlled micro-injuries to the skin,
which stimulate the natural wound-healing response of the body. The healing process leads
to the production of new collagen and elastin, resulting in the remodeling of scar tissues,
which ultimately improves the texture, color, and overall appearance of the scars [
53
].
Several studies have demonstrated the effectiveness of microneedling in treating various
types of scars, including surgical scars [62–64].
2.1.2. Treatment of Vitiligo
Vitiligo is a chronic skin disorder characterized by depigmented white patches caused
by the destruction of melanocytes, and it affects both sexes equally. These patches are
known to resist conventional therapies such as topical creams of corticosteroids and
calcineurin inhibitors, systemic corticosteroids, immunosuppressants, biologic medica-
tions, and ultraviolet light and laser therapy, in addition to combinations of these treat-
ments [
65
,
66
]. Microneedling has shown its efficacy in treating vitiligo either as a monother-
apy or as a combination therapy with topical treatment [
45
,
65
,
67
–
69
]. Microneedling can
potentially stimulate melanocytes and skin re-pigmentation by creating micro-injuries,
which lead to the release of the growth factors in the bulge area and the epidermis [
70
].
Bailey et al. [
71
] reported that microneedling facilitated re-pigmentation in vitiligo by
increasing the penetration of topical therapies into the dermis, inducing neocollagenesis,
and activating melanocytes. Thus, microneedling was an effective and well-tolerated ad-
juvant to topical therapy for vitiligo, as evidenced by increasing the rate of treatment to
>25%. Studies have shown the efficacy of microneedling in treating vitiligo, particularly
when combined with topical treatments [
46
,
72
–
74
]. For instance, a topical tacrolimus oint-
ment (0.1%) combined with microneedling, performed with an electric Dermapen
®
(My
M Micro Needle Therapy, Shanghai, China) with different needle ranging in size from
1500 to
2000 µm,
was more efficient in treating patients with vitiligo than microneedling
alone [
46
]. Additionally, twenty-seven patients with localized stable vitiligo were subjected
to six sessions of microneedling with Dermapen
®
(Dr. Pen Derma Pen Ultima M5
®
) at
2-week intervals. Afterwards, a solution of 5-fluorouracil (5-FU, 5%) was applied once daily
for two weeks over the affected areas. The results showed that the combination therapy
(microneedling + 5-FU) yielded a better response (by 3.8 times) compared to microneedling
alone [
72
]. Another study compared the efficacy of microneedling using Dermapen
®
(My
M Micro Needle Therapy, Shanghai, China) with 5-FU solution (50 mg/mL) versus mi-
croneedling with topical tacrolimus ointment (0.03%) in the treatment of vitiligo. Excellent
Cosmetics 2024,11, 51 7 of 29
re-pigmentation and a higher clinical response were found in patients subjected to 5-FU
with microneedling (48% vs. 16%, 5-FU vs. tacrolimus) [
73
]. Moreover, the efficacy of a
combination of microneedling with Dermapen
®
(My M Micro Needle Therapy, Shanghai,
China) and a topical combination of calcipotriol (0.05 mg/g) and betamethasone (0.5 mg)
was compared with the efficacy of microneedling and topical tacrolimus ointment (0.03%).
The results showed that microneedling with topical calcipotriol and betamethasone was
superior to microneedling with topical tacrolimus (60% vs. 32%) in treating vitiligo [74].
2.1.3. Treatment of Hair Loss
Microneedling can be used for androgenic alopecia and alopecia areata [
75
]. In treating
hair loss, scalp rollers with titanium needles are thought to be suitable for androgenic alope-
cia, where hair growth starts after 8–10 sessions [
28
]. Microneedling using Dermaroller
®
with a needle length of 1500
µ
m activates the stem cells in the hair bulge area under wound-
healing conditions, which results in a new hair cycle and new hair growth. In addition,
it facilitates the penetration of first-line medications [
76
]. The success of microneedling
in stimulating hair growth has been reported in severe male and female alopecia [
76
],
particularly in patients who cannot use systemic treatment [
77
]. Generally, there is no stan-
dard procedure for microneedling in hair loss. Typically, a needle length of
500–2500 µm
is used, and the procedure involves multiple, repeated, and sequential movements of
the Dermaroller
®
until pinpoint bleeding is visible [
77
]. Faghihi et al. [
78
] showed that
a combination of microneedling, performed with an electrical pen-shaped device (Auto
MTS, Republic of Korea) with adjustable penetration depth from 100 to 2000
µ
m, and
minoxidil (5% lotion) has a better therapeutic effect in treating androgenic alopecia in terms
of hair count, thickness, and growth than using the topical minoxidil lotion alone. This
was because microneedling induced the release of platelet-derived growth factor via the
activation of platelets and stimulated the overexpression of hair-growth-related genes [
78
].
Additionally, it is believed that microneedling stimulates the deposition of collagen, en-
hances the release of growth factors, and facilitates the penetration of medications such as
minoxidil and topical steroids [79].
Recently, preclinical studies demonstrated the clear benefits of integrating MNs with
therapeutic exosomes for hair regeneration. Yang et al. [
80
] prepared detachable MNs using
a water-soluble HA base, integrated with therapeutic exosomes and a small-molecular
drug (UK5099) for hair regeneration. The matrix of MNs was fabricated using the natural
hair protein keratin. The hair follicle stem cells were loaded into exosomes, UK5099 was
loaded into poly(lactic-co-glycolic acid) nanoparticles, and then both systems delivery
were encapsulated into keratin-hydrogel-based MNs. The results showed that this system
promoted pigmentation and hair regrowth in treated mice within 6 days by activating the
telogen-to-antigen transition and acting as a depot inside the skin for sustaining the release
of therapeutics. The MNs–exosomal system was clinically more effective when compared
to the subcutaneous injection of exosomes and topical administration of UK5099. Moreover,
MNs integrated with therapeutic exosomes were used to activate the dermal papilla cells,
which play a key role in hair regeneration [
81
]. MNs were fabricated with HA and swellable
PVA needles and loaded with chitosan lactate and exosome-encapsulated dermal papilla
cells (DPCs). Chitosan lactate released L-lactate, promoting cell growth by activating
lactate dehydrogenase, whereas exosomes sustained the release of DPC, stimulating cell
proliferation by activating the Wnt/
β
-catenin signaling pathway, which plays a role in
regenerating the hair follicles [
82
]. Therefore, this transdermally combined system of MNs
and exosomes was able to promote hair regeneration by regulating hair follicle cycling,
providing great potential for clinical application. Finally, a new hair growth technology
inspired by seed germination (plowing, breeding, and lighting) was employed to promote
hair regeneration [
83
]. MN patches were loaded with exosomes of stem cells (human
amniotic mesenchymal stem cells (hAMSCs)) and hair-derived nanoparticles. The results
showed that the MNs were able to penetrate the cuticle (plowing), facilitating the delivery
of hAMSC exosomes into the dermis and stimulating the hair follicles’ stem cells (breeding).
Cosmetics 2024,11, 51 8 of 29
Moreover, the yellow-light irradiation alleviated the inflammation of hair follicles (lighting),
further prompting hair regeneration. This strategy demonstrated effective hair growth
within 7 days with minimum inflammation, offering a broad clinical application.
2.1.4. Treatment of Melasma
Melasma is a type of acquired hyperpigmentation disorder that affects the photo-
exposed parts of the face and significantly influences the quality of life of those who suffer
from it [
84
,
85
]. Microneedling plays a role in the treatment of melasma by facilitating the de-
livery of topical therapies to the epidermis and dermis [
85
–
87
]. For instance, Lima et al. [
87
]
evaluated the effectiveness of microneedling performed with a Dermaroller
®
(Dr. Roller
®
Mooham Enterprise, Gyeonggi-do, Republic of Korea) with a needle length of 1500
µ
m,
with a combination of depigmentation therapy and sunscreen in treating 22 patients with re-
calcitrant melasma that was unresponsive to topical lightening and sunscreen. Although it
was suggested that the lightening of the skin was attainable due to modifications in the skin
after a moderate injury caused by the Dermaroller, the exact mechanism of skin lightening
via microneedling remained unclear. Over a 4-month treatment, Farshi et al. [
88
] compared
the efficacy of microneedling performed with needles with meso-depigmentation solution
(mesoneedling) to the standard microneedling performed with needles only. In this pilot
study, 20 patients received microneedling on one side of their face and mesoneedling on the
other side. The needles had a 1500
µ
m length and 0.25 mm diameter. The therapy involved
rolling in all four directions four times (right–left and horizontal–vertical). The method was
used to treat melasma areas. For four months, the treatment was repeated every month.
The results showed that 2–4 sessions of mesoneedling were considerably more effective
in treating melasma than microneedling alone [
88
]. Meymandi et al. [
89
] compared the
effectiveness of microneedling combined with 4% tranexamic acid to 4% hydroquinone
in treating melasma. In this study, 60 melasma patients were randomly assigned to one
of the two groups: group A (microneedling + topical 4% tranexamic acid, monthly) or
group B (topical 4% hydroquinone, nightly). The utilized microneedling device (Amiea
Med, MT Derm GmbH) contained six fine needles of 1500
µ
m in length and 0.25 mm in
width that could pierce the skin from 0.1 to 1.3 mm. The results showed that the efficacy of
microneedling + topical 4% tranexamic acid in the treatment of melasma was comparable
to that of 4% hydroquinone [89].
Microneedling shows promise in treating melasma (hyperpigmentation) and vitiligo
(hypopigmentation) to varying degrees with different mechanisms [
25
,
87
]. The skin’s
reaction to microneedling differs between melasma and vitiligo due to their distinct patho-
physiology [
90
]. In melasma, microneedling may help by stimulating collagen production
and facilitating the penetration of topical medications, potentially leading to improvement
in hyperpigmented spots [
86
,
87
]. Additionally, microneedling may induce controlled in-
jury, triggering a healing response that could lead to melanocyte activation and pigment
dispersion [
84
]. Meanwhile, in vitiligo, microneedling may not directly address the under-
lying cause of depigmentation, but it could potentially aid in promoting melanocytes’ and
keratinocytes’ proliferation and their migration to the hypopigmented areas, potentially
aiding re-pigmentation [
91
,
92
]. As for the intelligence of wound-healing cells in modulat-
ing melanocytes, research suggests that fibroblasts, keratinocytes, and immune cells play
critical roles in regulating melanocytes’ function and distribution. These cells release factors
such as cytokines, growth factors, and extracellular matrix components, which influence
melanocytes’ behavior in response to stimuli, including wound-healing processes [93].
2.1.5. Skin Rejuvenation
Subsurface resurfacing and laser toning are two concepts used to describe minimally
invasive skin rejuvenation techniques [
94
]. These modalities are designed to improve
wrinkles, skin laxity, and skin texture. Recently, microneedling has gained popularity in skin
rejuvenation due to its efficacy, safety, and long-lasting and natural results [
94
,
95
]. For facial
rejuvenation, El-Domyati et al. [
94
] investigated the use and effectiveness of microneedling
Cosmetics 2024,11, 51 9 of 29
combined with PRP or 15% trichloroacetic acid (TCA) peeling. The Dermaroller
®
(ADROLL,
TD, Spain) was made of 600 stainless steel needles of 1000
µ
m in length. Twenty-four
photo-aging volunteers were randomized into three equal groups based on the technique
conducted on each side of the face (microneedling alone or in combination with PRP or 15%
TCA peeling). The volunteers received six sessions of treatment, with one session every
two weeks. When microneedling and PRP or microneedling and TCA were combined, the
results were significantly better than microneedling alone, since there was a significant
increase in the thickness of the epidermis, particularly following TCA treatment. In the
three groups studied, there were organized collagen bundles with newly generated collagen
formation. However, the use of microneedling in conjunction with PRP appeared to be more
beneficial for facial rejuvenation than microneedling in conjunction with TCA. In another
study [
29
], ten patients with Fitzpatrick skin types III and IV and Glogau wrinkle classes II
to III received six skin microneedling sessions separated by two weeks. Microneedling was
carried out with a Dermaroller
®
(Directive MDD, Germany) that had 192 needles arranged
in eight rows, with a needle length of 1500
µ
m and diameter of 0.25 mm. The Dermaroller
®
passed six times in eight directions (vertical, up and down, horizontal, right and left, and
in both diagonal directions). The results showed that microneedling improved the photo-
aged skin significantly. However, to preserve the progress made, multiple sessions were
frequently required.
Microneedling was combined with radiofrequency (RF) energy to stimulate the pro-
duction of collagen [
96
]. Radiofrequency microneedling (RFM) is used to treat various
skin conditions, such as acne scars, acne vulgaris, and skin rejuvenation [
97
]. The RFM
devices are composed of an energy system with a 50 W output and a disposable tip with
49 insulated gold-plated needles. The depth of the needles can be adjusted from 0.5 to
3.5 mm [
98
]. The RF energy heats the skin to 65–70
◦
C, without thermally damaging the
epidermis [
97
,
99
]. The insulated needles penetrate the epidermis with minimal heating
while effectively delivering the desired energy to predetermined depths [
99
]. The nee-
dles’ adjustable depth allows for distinct electrothermal coagulation in different dermis
layers [
98
]. Several studies have shown that fractional radiofrequency is safe and effec-
tive for treating moderate and severe acne scars in different skin types [
98
,
100
,
101
]. Kim
et al. [
102
] reported the findings of a pilot study on the effect of an antioxidant topical
formulation containing L-ascorbic acid, vitamin E, and ferulic acid on facial photo-aging
after microneedling treatment with radiofrequency (FMRF). In this study, all patients were
treated using a pulse-type fractional microneedle FMRF device (SylfirmTM, Seongnam,
Republic of Korea) with 25 non-insulated microneedles in 5
×
5 arrays. The patients were
instructed to apply four to five drops of the topical formulation to one side of the face
immediately after FMRF treatment. The results showed that the laser-assisted delivery of
the antioxidant formulation following FMRF was a safe and effective adjuvant approach
for the treatment of photo-damaged skin.
2.1.6. Treatment of Skin Cancer
Microneedling has been combined with anticancer drugs to treat squamous- and
basal-cell skin carcinoma and melanoma [
103
–
106
]. Ahmed et al. [
105
] found that mi-
croneedling by pretreating the skin with a Dermaroller
®
(SQY
®
, Guangdong, China) con-
taining
40 needles
of 500
µ
m in length and 50
µ
m in diameter enhanced the penetration of
doxorubicin and celecoxib to tumor tissues by ~2-fold compared to passive delivery. Both
drugs were encapsulated into liposomes and loaded into gels to be delivered topically, with
and without microneedling. Almayahy and co-workers [
106
] reported that microneedling
using Dermapen
®
(ZJchao, China) enhanced the penetration of imiquimod, a drug used to
treat basal-cell carcinoma and characterized by its limited permeation into the skin. Porcine
skin was initially pierced with the stainless steel Dermapen
®
, and the commercial product
Aldara
®
cream containing imiquimod was applied onto the skin. In another study [
103
],
microneedling using a Dermapen
®
(ZJchao, China) was also used to promote the intra-
dermal delivery of imiquimod. A 5% w/wimiquimod cream was applied to the skin
Cosmetics 2024,11, 51 10 of 29
after pretreatment with either an oscillating Dermapen or a non-oscillating Dermastamp
to overcome the limitations of drug permeation. The results of this study highlighted
the significant increase in the intradermal permeation of imiquimod when the oscillating
Dermapen was used compared to the limited dermal permeation of imiquimod with the
non-oscillating Dermastamp. This approach would ultimately improve the treatment of
basal-cell carcinoma, particularly in patients who do not prefer surgery. Naguib et al. [
104
]
used microneedling (Dermaroller
®
, Cynergy, LLC, NV, USA) to effectively deliver a topical
5-FU cream into the target tissues to treat basal-cell carcinoma. The results showed that the
pretreatment of the skin with microneedling increased the flux of 5-FU by up to 4.5-fold,
improving its clinical efficacy. Therefore, the above studies confirmed that microneedling
could effectively deliver the therapeutic agents to the target tissues, thus enhancing the
tumor inhibition effect [
107
,
108
]. Table 2summarizes the microneedling devices approved
by the Food and Drug Administration (FDA) for cosmetic applications.
Table 2. FDA-approved microneedling devices for cosmetic applications.
Microneedling
Product Company Name Description of the Device Uses
Dermaroller®[109]White Lotus, Germany
A cylindrical roller with solid
microneedles of 200–2500 µm
in length
Improve skin texture and treat scars
and hyperpigmentation
Dermaroller®[110]DermaSpark, Vancouver,
Canada Solid or metal microneedles
Induce the production of collagen
and elastin and enhance the
penetration of cosmetic agents
Promote skin repair and reduce the
appearance of wrinkles, scars, and
stretch marks
Dermaroller
®
Genosys
[110]
Hansderma, Downey, CA,
USA
Different needle lengths of
250–2000 µm
Induce the production of collagen
and elastin
Treat wrinkles and acne scars
Dermaroller®C-8
[111]
Dermaroller Series by
Anastassakis K.
The needles’ length is 130 µm,
with 24 circular arrays of
8 needles each (total
192 needles)
Enhance the penetration of topical
agents
Dermaroller®CIT-8
[111]
Dermaroller Series by
Anastassakis K. The needle’s length of 500 µmInduce the production of collagen
and remodel the skin
Dermaroller®MF-8
[111]
Dermaroller Series by
Anastassakis K.
The needle’s length of
1500 µmTreat scars
Dermaroller®MS-4
[111]
Dermaroller Series by
Anastassakis K.
A small cylinder of 1 cm in
length and 2 cm in diameter
with four circular arrays of
1500 µm needle length
Treat scars
Dermaroller®C-8HE
[53]
Dermaroller Series by
Anastassakis K. Has a 200 µm needle length Used in hair-bearing surfaces like the
scalp
Dermapen®[13]MDerma FDS (USA) Made up of 12 microneedles Induce the production of collagen
and elastin
Dermapen®[112]Dermapenworld, Sydney,
Austria
A 33-gauge gamma-sterilized
stainless steel needles
Treat various skin conditions such as
acne, stretch marks, and hair loss
Enhance drug absorption
Exceed
Microneedling
®
device
[112]
MT. Derm GmbH, Berlin,
Germany
Needle length can be adjusted
between 0.0 and 1500 µm.
Improve the appearance of facial acne
scars in Fitzpatrick skin types I, II, III,
and IV in adults
Cosmetics 2024,11, 51 11 of 29
While microneedling has proven its efficacy in treating skin cancer, there are concerns
regarding the potential spread of cancer cells if microneedling is performed over a skin
lesion affected by cancer. Nevertheless, to the best of our knowledge, there are currently
no published studies that definitively confirm the spread of existing skin cancer through
microneedling.
3. Fabricated Microneedle Patches
Different materials have been used to fabricate microneedle patches (MNs) [
113
,
114
].
Previously, MNs were made of stainless steel, silicon, ceramic, and glass. However, these
MNs lack biocompatibility and biodegradability. MNs have now become more popular
and exhibit better breakage resistance due to their sufficient mechanical strength [
115
]. In
addition, the use of biodegradable and biocompatible materials becomes desirable for the
fabrication of microneedles [116].
Silicon, metals, ceramics, and polymeric materials are employed in the fabrication of
MNs [
117
]. The first introduced MNs were made of silicon. Multiple shapes and types of
MNs could be made from silicon owing to its flexible nature, which makes it a preferable
material. However, a variety of drawbacks limit the usage of silicon in MN fabrication,
including high cost, time-consuming and complex procedures, and high skin fracture
potential, which may lead to skin infections. For handling such concerns, a compatible,
biodegradable, nano-structured, porous silicon has been developed for the MNs’ tips.
Thus, even if the tip is fractured and persists within the skin, it will be degraded in a few
weeks. The manufacturing of silicon MNs with nano- and porous features significantly
affects the skin’s permeability and results in improved drug delivery [
109
]. Metals, mainly
stainless steel and titanium, exhibit decent mechanical characteristics; hence, they are
prevalent in the production of MNs [
23
]. Before titanium, stainless steel was the first
metal used in the manufacturing of MNs. It has been utilized over a few decades due to
its biocompatibility under expanded clinical use and patient compliance [
109
]. Metallic
materials are more rigid and difficult to fracture relative to silicon [
114
]. Although metal
MNs are capable of penetrating skin, their application may lead to an allergic response [
114
].
Porous titanium MNs, which are relatively novel developments, have been investigated
for various biomedical transdermal delivery systems, including the loading and delivery
of macromolecule compounds like insulin [
118
]. Ceramic materials, such as alumina,
calcium sulfate dihydrate, and calcium phosphate dihydrate, have been employed in the
manufacturing of MNs owing to their valuable chemical characteristics, reliable resistance
to compression, and biocompatibility [
114
]. On the other hand, these materials tend to have
lower tensile strength, particularly alumina, which is fragile and readily broken within
the patient’s body [
119
]. Currently, alumina is frequently utilized to fabricate micro- or
nano-scale porous MNs for delivering fluids [
119
]. Polymers have gained a lot of interest
in MNs’ fabrication due to their biocompatibility, biodegradability, cost-effectiveness, and
distinct mechanical properties, such as their capacity to resist higher bending stresses
without breaking down [
120
]. However, they are weaker than metals and silicon [
121
].
A variety of polymers, including poly (methyl methacrylate) (PMMA), polylactic acid
(PLA), poly (carbonate), polystyrene, and SU-8 photoresist, have been utilized to fabricate
MNs [114,122].
There are five types of MNs: solid, hollow, dissolvable, coated, and hydrogel [
121
]
(Figure 3). Each type of MN has its own attributes, benefits, drawbacks, uses, and materials.
Solid MNs, also known as “poke and patch”, have attracted attention in transdermal
delivery because of their capability to improve skin penetration by making holes in the
skin over the SC [
121
]. Solid MNs can be made from various materials, such as silicon [
123
],
metals [
124
], and polymers [
125
]. Additionally, solid MNs have several advantages, includ-
ing low cost, a broad range of mass production technologies, and appropriate mechanical
strength [
126
]. In this type of MN, the cosmetic agent is not encapsulated within the MNs.
However, it is applied via semi-solid formulations onto skin pretreated with solid MNs to
transport the active cosmetic molecules into the dermis through the pores [
127
]. Despite
Cosmetics 2024,11, 51 12 of 29
their numerous advantages, the use of solid MNs is not patient-friendly, as it requires a
two-step application [
128
]. In addition, removing broken metal or silicon MNs from the
skin is considered to be another major drawback for this type of MN [119].
Cosmetics 2024, 11, x FOR PEER REVIEW 12 of 29
medical transdermal delivery systems, including the loading and delivery of macromole-
cule compounds like insulin [118]. Ceramic materials, such as alumina, calcium sulfate
dihydrate, and calcium phosphate dihydrate, have been employed in the manufacturing
of MNs owing to their valuable chemical characteristics, reliable resistance to compression,
and biocompatibility [114]. On the other hand, these materials tend to have lower tensile
strength, particularly alumina, which is fragile and readily broken within the patient’s
body [119]. Currently, alumina is frequently utilized to fabricate micro- or nano-scale po-
rous MNs for delivering fluids [119]. Polymers have gained a lot of interest in MNs’ fab-
rication due to their biocompatibility, biodegradability, cost-effectiveness, and distinct
mechanical properties, such as their capacity to resist higher bending stresses without
breaking down [120]. However, they are weaker than metals and silicon [121]. A variety
of polymers, including poly (methyl methacrylate) (PMMA), polylactic acid (PLA), poly
(carbonate), polystyrene, and SU-8 photoresist, have been utilized to fabricate MNs
[114,122].
There are five types of MNs: solid, hollow, dissolvable, coated, and hydrogel [121]
(Figure 3). Each type of MN has its own aributes, benefits, drawbacks, uses, and materi-
als.
Figure 3. Types of microneedles (solid, hollow, dissolvable, coated, and hydrogel MNs).
Solid MNs, also known as “poke and patch”, have aracted aention in transdermal
delivery because of their capability to improve skin penetration by making holes in the
skin over the SC [121]. Solid MNs can be made from various materials, such as silicon
[123], metals [124], and polymers [125]. Additionally, solid MNs have several advantages,
including low cost, a broad range of mass production technologies, and appropriate me-
chanical strength [126]. In this type of MN, the cosmetic agent is not encapsulated within
the MNs. However, it is applied via semi-solid formulations onto skin pretreated with
solid MNs to transport the active cosmetic molecules into the dermis through the pores
[127]. Despite their numerous advantages, the use of solid MNs is not patient-friendly, as
it requires a two-step application [128]. In addition, removing broken metal or silicon MNs
from the skin is considered to be another major drawback for this type of MN [119].
Figure 3. Types of microneedles (solid, hollow, dissolvable, coated, and hydrogel MNs).
Vibrating solid MNs are designed by connecting solid MNs with a motor-driven vibra-
tor at different vibrational frequencies [
129
]. The results showed that solid MNs were more
effective when vibrating at higher frequencies. This is because a higher vibration frequency
creates more pores, which act as transdermal pathways, enhancing the permeability of
drugs across the skin [
129
]. This type of MN has been used to enhance the transdermal
delivery of ascorbic acid (AA) through the skin. Optimal conditions for the
in vitro
and
in vivo
transdermal delivery of AA were chosen based on vibrating the MNs at three levels
of intensity, application time, and application power. A pharmacokinetics study of AA
gel in rats found that the AUC
0–∞
and C
max
increased by 1.35- and 1.44-fold, respectively,
compared with those of AA gel obtained without using the vibrating solid MNs [130].
Hollow MNs, also known as “poke and flow”, contain a conical cavity internally
fabricated with a biocompatible polymer using injection molding [
121
,
131
]. When the
hollow MNs are applied to the skin, they provide a pressure-driven flow of the liquid
formulations. The delivery rate can be modulated to rapid bolus injection, slow infusion, or
other delivery rates [
127
]. On the other hand, hollow MNs usually require high-precision
and high-cost manufacturing technologies [
113
]. In addition, after insertion, the tips
of MNs press against the surrounding dense dermal tissue, obstructing the flow of the
cosmetic agent solution and resulting in an inaccurate dose [
132
,
133
]. Although various
researchers have studied hollow MNs for transdermal vaccination routes [
134
] and insulin
delivery [
135
], as they can be used like tiny hypodermic needles for injection [
136
], studies
have shown that they are not primarily used in cosmetic applications.
Contrarily, studies have shown that dissolvable MNs offer great potential in the cosmet-
ics field [
137
], making them the most commonly used MNs for delivering active cosmetic
agents. In the dissolved MNs, also known as “poke and release”, the cosmetic agent can be
encapsulated within a dissolved or biodegradable matrix that is completely dissolved when
Cosmetics 2024,11, 51 13 of 29
introduced into the skin, without producing any biohazardous waste [
121
,
138
]. These
MNs can deliver and release molecules immediately for short-term applications [
139
],
or over prolonged/sustained periods [
140
], based on the degradation rates of the poly-
mers [
121
]. The dissolvable MNs have several advantages, such as high loading efficiency
and the absence of the requirement for the disposal of sharps, as well as the risk of MNs’
reuse [
125
,
140
]. Cosmetic agents delivered to the skin using dissolvable MNs are discussed
in more detail in the following section.
Coated MNs, also known as “coat and patch”, are used to deliver ionic, polar, and
water-soluble molecules like proteins and peptides [
121
,
122
]. This strategy is a one-step
procedure that provides rapid delivery with a lower loading efficiency, making it ideal
for delivering highly potent compounds [
122
,
141
]. In this type of MN, a formulation
composed of polymer(s) and the loading compound is deposited on the tips of the MNs by
dip-coating, casting deposition, spray-drying, and inkjet printing [
121
]. Metal or silicone
MNs are commonly used as the base structure to ensure sufficient mechanical strength to
pierce the skin. Additionally, studies have shown that drugs coated on MNs in a solid phase
can be stable for a long time [
142
]. The delivery of high-molecular-weight compounds from
coated MNs has proven attractive [122].
Finally, hydrogel MNs are made from super-swelling polymers [
143
]. The hydrophilic
structure of the polymers allows them to absorb a considerable amount of water into
their three-dimensional polymeric network, which regulates the release of the loading
compounds. Due to the presence of interstitial fluid, these polymers swell when applied
to the skin [
144
]. The rate of release of loading compounds can be controlled based on
the degree of crosslinking of the hydrogel network, allowing for slow release over several
days [
121
,
144
]. This may result in patient discomfort due to the long patch-wearing
time [
141
]. In general, polymers used in the fabrication of MNs should be biocompatible,
non-immunogenic, and mechanically strong enough to be inserted into the skin [
109
,
121
].
Aung et al. [
145
] fabricated dissolved MNs and hydrogel MNs to deliver the hydrophilic
cosmetic agent alpha-arbutin (
α
-arbutin), commonly used for skin lightening. MNs were
made from polyacrylic acid-co-maleic acid (PAMA) and polyvinyl alcohol (PVA) (1:4).
Both types of MN were sharp, stable for 3 months at 25
◦
C, and showed high mechanical
strength, allowing for their successful insertion into porcine skin. Needles of dissolved
MNs were completely dissolved after 45 min, and those of hydrogel MNs swelled after
4 h. The
in vitro
permeation and
in vivo
studies demonstrated significant enhancement
of
α
-arbutin-loaded dissolved and hydrogel MNs when compared to
α
-arbutin gel and
α
-arbutin commercial cream. The benefits, risks, and limitations of the fabricated MNs are
summarized in Table 3. In addition, fabricated MNs approved by the FDA for cosmetic
applications are summarized in Table 4.
Table 3. Benefits, risks, and limitations of fabricated MNs.
Types of MNs Benefits Risks Limitations
Solid
Suitable for the delivery of cosmetic
agents into the lower skin layers, as
microneedles create channels due to
their sharp needles [114]
It might cause damage to
the skin [114]
Allow slow diffusion through the
skin [146]
Micropores remain open for a limited
time,
stopping the delivery of cosmetic
agents [147]
Two-step application [128]
Cosmetics 2024,11, 51 14 of 29
Table 3. Cont.
Types of
MNs Benefits Risks Limitations
Hollow
Have an empty shape that is filled with
a large amount of cosmetic agents [
114
]
Ability to control the release over time
[114]
Might cause leakage
and clogging [114]
Deposit the cosmetic agent directly into
the epidermis or the upper dermis layer
[109]
Increasing the microneedle bore in an
attempt to increase the flow rate may
decrease the microneedles’ strength
and sharpness, making insertion into
the skin more difficult [109,148]
Weaker than solid MNs [148]
Dissolvable
Biocompatible [114]
One-step application, as microneedles
can pierce the skin and are kept
inserted until complete dissolution
[147]
Tuning the delivery rate by controlling
the dissolution rate of the polymer used
in the microneedles’ formulation
[147,149]
Avoiding the generation of sharps
waste, minimizing the cost of waste
management, and reducing
needle-stick injuries [147,149]
Potential accumulation of
polymer within the skin
upon repeated application
of microneedles [149]
Limited loading capacity and limited
ability to perforate the SC [147]
Long-term safety for repeated use has
not been established in humans [149]
Requires technical expertise to
manufacture [114]
Takes time to dissolve [114]
Coated
Fast delivery to the skin [114]
Tuning the delivery rate by altering the
polymer(s) architecture and the
thickness of the film [149]
Potential accumulation of
polymer within the skin
upon repeated application
of microneedles [149]
Relatively low loading capacity on the
surface of the microneedles [147,150]
The coating’s thickness can decrease
the sharpness of the microneedles,
impacting their ability to perforate the
skin [147]
The shape of the microneedles must be
designed to ensure delivery and
overcome the insertion forces into the
skin [150]
Biohazardous sharps waste after use
[149]
Lack of safety data [149]
Hydrogel
Tuning the delivery
rate by controlling the
the density of crosslinking [149,151]
Delivering cosmetic agents in a
molecular weight range of 0.17–67 kDa
through the hydrogel matrix [149]
Removal of swollen microneedles after
use
reduces the risk of intradermal material
accumulation [149]
The release profile is characterized by
an initial burst release followed by a
steady rate of release [151]
Cytotoxicity due to the
accumulation of unreacted
polymers during
crosslinking [151]
Restricted to agents that are stable to
crosslinking conditions such as heat
and UV exposure [149]
Restricted to polymeric
materials capable of crosslinking under
mild
conditions such as freeze/thaw [149]
Biohazardous waste
after use [149]
Table 4. FDA-approved fabricated MNs for cosmetic applications.
Fabricated MNs Company Name Type Uses
MicroHyala®[109–111]CosMED Pharmaceutical,
Kyoto city, Japan Dissolvable MNs Intradermal delivery of HA
for skin aging
Cosmetics 2024,11, 51 15 of 29
Table 4. Cont.
Fabricated MNs Company Name Type Uses
LiteClear®[109,152]
Nanomed Skincare, Delaware,
USA Solid MNs made of silicon
Treat acne and skin blemishes
Used to pretreat the skin
before topical application
3M®Hollow
Microstructured Transdermal
System [111]
3M, Minnesota, USA
Hollow MNs (1 cm2array
with a needle length of
1500 µm)
Intradermal delivery
3M®Solid
Microstructured Transdermal
System [111]
3M, Minnesota, USA
Solid MNs (1 cm2array with
needle lengths of 250, 500, and
700 µm)
Intradermal delivery
4. Cosmetic-Agent-Loaded Dissolvable Microneedles
Our literature search revealed that dissolvable MNs are most commonly used when de-
livering cosmetic agents through the skin. Cosmetic agents such as ascorbic acid (AA) [
153
],
HA [
154
], retinoids [
155
], glutathione [
156
], acetyl hexapeptide-3 (AHP-3) [
157
,
158
], and
other agents that are frequently used in various skin conditions and loaded into dissolvable
MNs are discussed in detail below.
4.1. Ascorbic Acid (AA)
AA is an antioxidant agent with an anti-wrinkle effect [
159
], characterized by its
limited skin permeation due to high aqueous solubility (333 mg/mL) and low log P
(
−
1.85) [
160
]. AA-loaded dissolvable MNs showed a significant improvement in skin with
wrinkles, offering a potential anti-wrinkle cosmetic application. Moreover, clinical results
showed that these MNs were more convenient, safer, and did not induce skin irritation
or sensitization [
159
]. Kim et al. [
161
] developed HA-dissolvable MNs to deliver mag-
nesium ascorbyl phosphate (MAP) transdermally through porcine ear skin. The length
of the needles was ~400
µ
m. The MNs were able to form 95–100 micro-channels after
2 min
of treatment with ~125
µ
m depths, as determined by confocal microscopy. It was
found that the application of HA-dissolvable MNs enhanced the delivery of MAP into the
skin by twofold compared to the passive topical delivery of MAP (solution with no MNs)
(96.8 ±3.9 µg/cm2
vs. 44.9
±
16.3
µ
g/cm
2
). Another study by Park et al. [
162
] showed that
the biocompatible dissolvable carboxymethyl cellulose (CMC) MNs significantly enhanced
the antioxidant activity of AA after crossing the skin: about a sixfold increase compared to
the same amount of AA applied topically onto the skin without MNs. Additionally, amy-
lopectin was used in combination with CMC to finely tune the dissolution and mechanical
properties of MNs.
4.2. Hyaluronic Acid (HA)
HA is commonly used as a polymer matrix to fabricate MNs for cosmetic applica-
tions [
32
,
159
,
161
,
163
–
166
]. HA exhibited high compatibility, viscoelastic properties, and
skin-moisturizing effects [
32
]. In addition, HA has a high volumizing effect due to its
strong water-binding potential and stimulates the fibroblasts, leading to collagen synthe-
sis [
167
]. Avcil et al. [
165
] demonstrated the usefulness of HA-dissolvable MNs loaded
with bioactives of arginine/lysine polypeptide, acetyl octapeptide-3, palmitoyl tripeptide-
5, adenosine, and seaweed extract in improving skin hydration, reducing wrinkles, and
increasing the density of the skin and the thickness of the dermis. Choi et al. [
167
] investi-
gated the efficacy of HA as an anti-wrinkle agent using HA-MNs and found that these MNs
were more effective against wrinkles after an 8-week treatment, increasing the elasticity
of the skin compared to topical applications containing HA. Additionally, the authors of
this study reported that the application of HA-MNs was not associated with skin irritation.
Moreover, a combination of HA and the herbal medicine Lonicerae flos ethanol extract
(LEE) was loaded into the MN patch to improve skin moisturization [
168
]. Owing to the
Cosmetics 2024,11, 51 16 of 29
moisturizing effect of HA, the twenty female participants, who placed the patches on their
forearms, demonstrated an increase in skin moisture content of between 29.6 and 88.5%
compared to the untreated group, suggesting the addition of HA and LEE to the moistur-
izing formulations available on the market. In another study [
169
], dissolvable HA-MNs
with a backing layer made of nanocellulose and loaded with the natural antioxidant rurin
were developed for skin applications. The HA-MNs arrays of 200
µ
m base widths, 450
µ
m
height, and 500
µ
m tip-to-tip distance showed sufficient mechanical properties to withstand
skin insertion. Due to the hydrating and regenerative properties and volumizing effect of
HA, the results showed that this novel system can potentially be used for skin cosmetic
applications [169].
4.3. Retinoids
Retinoids are a group of compounds that include vitamin A and retinoic acid deriva-
tives such as retinyl retinoate, all-trans retinoic acid (ATRA), retinal, and retinol. Retinoids
are commonly used in photo-aged skin characterized by increasing wrinkles, thickening,
inelasticity, dryness, roughness, shallowness, and pigmentary mottling of patchy and
irregular colors of the skin [
170
–
172
]. Limcharoen et al. [
173
] developed a combination
of two transdermal delivery systems using chitosan, MNs, and proretinal nanoparticles
(PRNs) to directly target retinal into the epidermis and dermis. The amount of retinal in
the dermis was investigated after applying three different forms (PRN-loaded MNs, PRN
suspension, or conventional retinal solution). Imaging techniques confirmed the forma-
tion of micro-channels in the skin after applying PRN-loaded MNs, resulting in higher
recovery of retinal in the dermis, which could benefit skin conditions such as atrophic scars
and photo-aged skin. Recently, this research group loaded PRNs into detachable MNs
made of HA and maltose at a 1:1 ratio. The arrays of MNs were embedded into the skin
tissues, resulting in diffusion of PRNs in the epidermis and dermis layers, which, in turn,
increased the epidermal thickness compared with unloaded microneedles [
172
]. In another
study [
174
], the retinoid derivative ATRA was loaded into MNs (ATRA-MNs) to treat pig-
mented lesions commonly seen on the skin of elderly people. The ATRA-MNs were made
of sodium hyaluronate as the base material. The ATRA-MNs were applied to the lesion site
once a week for four weeks, and the local (skin irritation) and systemic adverse reactions
were assessed during the study. These results showed that the ATRA-MNs were promising
for whitening pigmented lesions; in addition, they were safe in humans. Additionally, a
follow-up study [
175
] evaluated the use of the ATRA-MNs patches in treating seborrheic
keratosis, one of the most common benign skin tumors in people > 50 years of age. The
dissolvable MNs, made of sodium hyaluronate, were efficient in delivering ATRA into the
epidermis and dermis without causing serious adverse events. The activity of ATRA was
confirmed by inducing the epidermal hyperplasia and the expression of heparin-binding
epidermal growth factor-like growth factor, and by accelerating epidermal cell turnover
and stratum corneum turnover. This ultimately resulted in the seborrheic keratosis lesions
falling off the surface of the skin.
4.4. Glutathione
Glutathione is a natural anti-aging agent that protects protein thiols from oxidation by
reactive oxygen species. In addition, glutathione can be used as a skin-whitening agent in
cosmetics because it prevents melanin synthesis via tyrosinase inhibition. Nevertheless,
the poor permeability and unpleasant odor of glutathione limit its use in cosmetic applica-
tions [
176
]. To circumvent the drawbacks of the current glutathione delivery systems, Lee
et al. [
176
] proposed fast-dissolving MNs made from deodorizing biopolymers that would
improve glutathione efficacy and patient compliance. After screening different biopolymers
for odorless glutathione formulations, HA was used to fabricate glutathione-loaded MNs.
The glutathione MN arrays (10*10 MNs/cm
2
) were made by the solvent casting of aqueous
solutions containing 10% dissolved solutions with variable glutathione concentrations.
Based on the experimental findings presented in this study, the feasibility of HA-MNs as
Cosmetics 2024,11, 51 17 of 29
a potential platform for transdermal delivery of glutathione or drugs with unpleasant or
unsatisfactory organoleptic qualities has been proven.
4.5. Acetyl-Hexapeptide-3 (AHP-3)
Acetyl hexapeptide-3 (AHP-3) or acetyl hexapeptide-8 (AHP-8), also marketed as
Argireline
®
, are peptide mimetics or neurotransmitter-inhibiting peptides that are effective
anti-aging ingredients for skin [
177
,
178
]. Several MN eye patches with varying geome-
tries and curvatures were fabricated with resin using 3D printing for the delivery of the
anti-wrinkle peptide AHP-3 [
179
]. The best MN geometry was then used to fabricate
personalized MNs for anti-wrinkle therapy of 800
µ
m in height, with 100
µ
m tip diam-
eters, 800
µ
m interspacing, and 400
µ
m base diameter across all curvatures. Using the
personalized MNs, the
in vitro
skin permeation study revealed an improvement in the
transdermal delivery of AHP-3 for wrinkle treatment [
179
]. In another study [
180
], critical
parameters such as the mechanical strength, rate of polymerization, rate of swelling, 3D
printing resolution, and safety profile of the final polymer were investigated using the
two liquid monomers polyethylene glycol diacrylate (PEGDA) and vinyl pyrrolidone (VP),
in various proportions. Based on the above factors, the best resin had a weight ratio of
7:3 (VP: PEGDA) for the delivery of the anti-wrinkle AHP-3 [
180
]. A personalized MN
eye patch was produced using computer-assisted design (CAD) V 1.1.7 software and then
fabricated using a Digital Light Processing (DLP) 3D printer with the best resin, utilizing a
3D-scanned face model. The ability of the fabricated MNs to penetrate human cadaver skin
was demonstrated
in vitro
. It was found that the MNs remained intact after compression,
and that the human dermal fibroblasts were also unaffected by the final polymer. As a
result, the photopolymer-fabricated personalized MNs were considered to be a novel way
to boost the transdermal delivery of AHP-3 for effective wrinkle reduction. Furthermore,
An et al. [
181
] fabricated MN patches of mixed HA and crosslinked HA (CLHA). CLHA is
commonly used in dermal fillers. The HA/CLHA MN patches were loaded with AHP-8 or
epidermal growth factor (EGF) for wrinkle improvement. Korean females (n = 52) were
enrolled in a double-blind, randomized clinical study conducted for 29 days. Based on
treatment, the subjects were divided into three groups. The first group was treated with
MNs alone, the second group with MNs/AHP-8, and the third group with MNs/EGF. The
results revealed that the second and third groups treated with MNs/AHP-8 and MNs/EGF
showed statistically significant improvements in wrinkles compared to those treated with
MNs alone (p< 0.05). Additionally, no serious adverse events were noted for the fifty
subjects who completed this study.
4.6. Niacinamide
Niacinamide, also known as vitamin B3, is a hydrophilic compound that is well
recognized for its beneficial effects on skin aging, photo-aging, hyperpigmentation, anti-
inflammatory effects in acne, and discolored skin patches [
163
,
182
]. Park et al. [
183
]
developed niacinamide-loaded MNs using various compositions of sodium hyaluronate
and CMC. In addition, amylopectin was added to the polymer matrix to increase the
mechanical strength of the MNs. In this study [
183
], the effect of the MN composition on
the skin permeability of niacinamide and the mechanical strength and solubility of the
MNs were investigated. The results demonstrated that increasing the CMC concentration
improved the mechanical properties of the MNs, leading to a dramatic increase in the
permeability of niacinamide through the skin due to the high ability of the MNs to puncture
the SC barrier.
Additionally, the niacinamide’s skin permeability was controlled by changing the poly-
meric composition of the MNs. In a recent study, Shin et al. [
184
] developed microneedle-
like particles (MLPs), a modified approach to conventional MNs. MNs are currently only
available as patches that can cover a limited skin area. Thus, this new platform allows for
the application of MLPs over a large area of the skin surface, where needles disrupt the
skin during the rubbing process due to their sufficient mechanical strength. The results of
Cosmetics 2024,11, 51 18 of 29
this study found that, after applying MLPs to the skin, the permeability of niacinamide
increased by up to 200%. This was attributed to the fact that the MLPs were able to disrupt
the skin, as confirmed by fluorescence images of porcine skin slices, where the fluorescent
dye was able to penetrate deeper into the skin tissues.
4.7. Collagen
Collagen makes up a large proportion of the human skin, giving the skin smoothness,
hydration, density, and elasticity [
185
]. As the skin ages, its collagen content decreases,
resulting in wrinkled skin [
186
]. Dissolvable MNs were used as a platform to deliver
collagen to skin layers to replace the collagen levels lost due to natural skin aging. For
instance, Sun et al. [
187
] delivered various concentrations of type I collagen (1, 2, 4, and
8% w/w) into porcine and human skin utilizing PVP-MNs. The needles’ length was
~365
µ
m, with 135
µ
m in diameter at the base. The distribution of collagen I-labeled
rhodamine B isocyanate through the skin was evaluated using fluorescence images. The
penetration efficiency of the PVP-MNs varied based on the concentration of collagen,
where the penetration decreased concomitant with an increase in collagen concentration.
This is because increasing the collagen content resulted in poor mechanical strength of
the MNs. The results showed that PVP-MNs were effective in delivering collagen I into
the epidermis and dermis of porcine and human skin, offering a fast, safe, effective, and
simple delivery system for cosmetic applications. Aditya et al. [
188
] developed dissolvable
collagen MNs of various needle lengths (300–600
µ
m) to reach different targeted layers of
the skin. The collagen MNs were fabricated from collagen and PVP at a ratio of 7:3. Various
process parameters, such as pressure, temperature, and duration of solidification, were
optimized using the Taguchi method. The results showed that the needles’ height and time
of solidification played an important role in the MN fabrication. The histological images
revealed the ability of collagen to penetrate the skin, indicating that collagen MNs may
serve as a promising platform for delivering collagen for younger-looking skin.
Moreover, a mold-free approach was used to develop collagen MNs using a simple
photolithographic method [
189
]. This approach used a photomask consisting of embedded
micro-lenses to govern the MNs’ geometry with a shock-absorbing backing layer. The use
of simple glass scaffolds controlled the length of needles. The collagen MNs were tested for
their mechanical properties, insertion into human skin, and collagen delivery. The results
illustrated that the needles were sharp, with two different lengths of 1336 and 957
µ
m. In
addition, the MNs could resist fracture forces of up to 25 N, penetrate human skin when
inserted with the force of a thumb, and enhance the permeation of collagen through rat
skin. Thus, the mold-free approach proved that collagen could be delivered within the
dermis for cosmetic applications [
189
]. Regardless of the reported benefits of the exogenous
collagen delivered to the dermis, there is no strong evidence to support the notion that
externally applied collagen can promote collagen remodeling and dermal improvement or
reverse natural aging [190,191].
4.8. Combinations of Cosmetic Agents
Combinations of cosmetic agents were loaded into dissolvable microneedles. Park
et al. [
163
] used polydimethylsiloxane (PDMS) molds fabricated using a laser-writing
process to develop dissolvable MNs and enhance the skin permeability of the cosmetic
agents AA and niacinamide. The dissolvable MNs were prepared from sodium hyaluronate
and amylopectin. The results showed that adding amylopectin increased the mechanical
strength of the needles but decreased their dissolution rate. In addition, MNs improved the
skin permeability of AA and niacinamide compared to their application without MNs [
32
].
For wrinkle improvement, AA was combined with retinyl retinoate. The two cosmetic
agents exhibited different hydrophilicity and were loaded into dissolvable HA-MN patches.
The patches were safe and demonstrated efficacy in improving wrinkles, suggesting their
potential application in cosmetics [
32
]. A recent study by Sawutdeechaikul et al. [
164
]
developed special dissolvable MNs known as detachable dissolvable MNs (DDMNs),
Cosmetics 2024,11, 51 19 of 29
which allow the needles to detach from the base within 2 min post-administration. DDMNs
were fabricated from HA and PVA and could effectively embed AA into the epidermis and
dermis to lessen the spots of post-acne hyperpigmentation. Glutathione was co-loaded
with AA into the detachable MNs (DDMNs) to stabilize AA. The experimental studies
found that glutathione effectively stabilized AA in the DDMNs, compared to vitamin E
and coenzyme Q10, due to its redox potential. No degradation was detected for AA in
DDMNs for at least 6 months when stored at 25, 40, or 50
◦
C, corresponding to a shelf-life of
>2 years
at room temperature as estimated using the Arrhenius equation. In addition, the
co-delivery of AA and glutathione to skin tissues resulted in a reduction in melanin, which,
in turn, decreased skin hyperpigmentation. Recently, Jang et al. [
192
] studied the skin
improvement effects of HA. The anti-wrinkle agent adenosine was loaded into high- and
low-molecular-weight HA-dissolvable MN patches (Ad-HMN and Ad-LMN, respectively).
Both Ad-HMN and Ad-LMN patches were evaluated for skin wrinkling, dermal density,
elasticity, and safety. Clinical tests were performed for 12 weeks on
23 females,
where
patches were applied once every 3 days for 8 weeks to the designated crow’s feet area.
The results showed significant skin improvement without adverse skin events for both
Ad-HMN and Ad-LMN patches. Additionally, the Ad-HMN patch had a better skin effect
than the Ad-LMN patches with a similar adenosine dose. Furthermore, the lipophilic
compound horse oil was combined with the hydrophilic compound adenosine for wrinkle
improvement and skin restoration [193]. A topical formulation of horse oil was co-loaded
into adenosine-dissolvable MNs (Ad-MNs), forming a two-phase delivery system in a single
patch (HO-Ad-MNs patch). Dissolvable Ad-MNs were fabricated using HA. The efficacy
of HO-Ad-MN patches on skin elasticity, hydration, dermal density, and wrinkles was
clinically evaluated for 20 women and compared with that of Ad-MNs. The microscopic
images demonstrated the successful delivery of adenosine and horse oil into the skin
through the micro-channels created by the HO-Ad-MN patches. Additionally, the HO-Ad-
MN patches significantly improved skin restoration and wrinkles compared with Ad-MNs,
without observing adverse events [193].
4.9. Other Cosmetic Agents
Cosmetic agents such as horse oil [
194
] and adenosine [
195
,
196
] have also been loaded
into dissolvable MNs using HA as a matrix base. It is worth noting that other cosmetic
agents, such as coenzyme Q10 [
197
], peptides [
198
], green tea extract [
199
], grape seed
extract [
200
], vitamin E [
201
], and quercetin [
202
–
204
], can also be potential candidates for
fabricated MNs (particularly dissolvable MNs) for cosmetic applications.
5. Safety of Microneedling
Microneedling using Dermaroller, Dermapen, Dermastamp, and fabricated MNs has
safety issues related to transdermal delivery, such as skin irritation and pain
sensation [204,205].
The FDA has reported that the risk associated with microneedling, including skin irritation,
mild bleeding, bruising, redness, itching, rashes, and peeling, may last for a short time
(few days) or a long time (few weeks) [
28
,
206
]. In addition, the use of the devices can
sometimes be accompanied by skin infections [
207
], irritant and allergic contact dermatitis,
hyperpigmentation, abnormal scarring, and irritant and allergic granulomas [
208
]. The
FDA has addressed the safe use of these devices, such as cleaning and disinfecting the
reusable parts between patients, where reusing needle cartridges can cause or spread
infection. Furthermore, special care might be needed after microneedling, as skin might
become more sensitive to the sun and skin care products containing retinol, glycolic acid,
or alcohol [
206
]. Because microneedling is relatively similar to conventional hypodermic
injection, they are supplied as sterile products. Additionally, the fabrication of devices from
metals routinely used in a dermatological setup makes their sterilization and re-sterilization
an easy process [
13
,
28
]. To minimize the side effects of microneedling, patients with recent
sun exposure are recommended to delay the microneedling procedure until all traces of
suntan have faded to avoid post-microneedling dyspigmentation. In addition, patients
Cosmetics 2024,11, 51 20 of 29
with oral herpes labialis might be at high risk of viral reactivation post-microneedling.
Moreover, microneedling over inflammatory or active acne lesions may lead to bacterial
micro-abscesses or granulomas. Furthermore, skin preparation and hygiene before the
microneedling procedure are important, where proper skin cleansing removes makeup and
debris from the skin’s surface and reduces the risk of introducing bacteria into the deeper
skin layers, decreasing superficial skin infections [31].
For polymeric MNs, owing to the small size of MN arrays, sufficient mechanical
strength, including the strength, the geometry of tips, the aspect ratio of height-to-base
diameter, and the sharpness of needles, is required to insert the needle successfully into the
skin without breakage [
209
]. It is worth noting that after MNs are inserted into the skin, the
loading agent is delivered, and there is no way to remove the needles from the body [
210
].
The variation in the MNs’ safety depends on the types of MNs and materials used in
the fabrication [
109
]. The microbiological characterization of hydrogel-forming MNs and
the potential for microbes to pass into the skin following the penetration of MNs were
described by Donnelly et al. [
211
]. There was no evidence of microbial penetration through
swollen MNs. Investigation of human volunteers indicated that when MNs were employed
for transdermal drug delivery, skin or systemic infections were relatively uncommon [
211
].
Altogether, the chemical and biological safety of materials used in the fabrication of MNs,
generally regarded as safe (GRAS), should be considered to achieve successful and safe
administration [
18
,
204
]. MNs should possess a fracture force greater than the insertion
force required for successful microporation, where the higher the fracture force, the safer
the MN insertion [
212
]. Microporation using MNs demonstrated minimal invasiveness,
reduced pain, and less tissue trauma in human subjects, with a very low average pain score
on a 0–100 mm visual analog pain scale compared to a hypodermic needle [
20
]. The pain
sensation is inversely proportional to the MNs’ length and number [21]. Additionally, the
pain intensity depends on the tip angle and shape of the needles [
213
]. MNs may induce
bleeding, which depends on the length of the MN arrays and their penetration depth into
the skin [58].
6. Regulations Related to Microneedling Products
The licensing of microneedling products is handled individually for each application
(as product-specific approval), and not for each microneedle system (as specific MN sys-
tems) [
116
,
141
]. This approach usually delays the licensing process and commercialization
of microneedling products, as several variables should be considered during licensing,
including shape, formulation, sterilization, and packaging [
141
]. The FDA has raised
several concerns regarding fabricated MNs, particularly those used to deliver therapeutic
agents, including the stability of the formulation and the loaded therapeutic agent, content
uniformity of MNs, risk analysis, sterility, and manufacturing [
116
]. Therefore, a thorough
investigation is required to assess MNs, including cell, animal, and clinical studies. The
FDA considered microneedles loaded with a therapeutic agent as a “combination product”
composed of drug and device. The FDA regulations for combined products emphasized
the safety and effectiveness of each product component and the product as a whole [116].
The guidance for industry and FDA staff was issued on 10 November 2020 for regula-
tory considerations for microneedling products. The guidance included definitions and
classifications of microneedling products. Definitions of the stratum corneum, exfoliation,
living layers of skin, and dermabrasion were included within the context of this guid-
ance [
214
]. In addition, the guidance classified the microneedling products into (1) devices,
(2) not devices, and (3) devices for aesthetic use (class II devices). It is noteworthy that
microneedling combination products, acupuncture needles, hypodermic needles, tattoo
machine needles, and dermabrasion devices are outside the scope of this guidance [
214
].
For the first category, the microneedling product is considered to be a device when it
is intended for use in the diagnosis, treatment, or prevention of disease, or to affect the
structure or any function of the body. Therefore, to determine whether the microneedling
product is a device, the FDA considers any claim or statement that indicates penetration
Cosmetics 2024,11, 51 21 of 29
beyond the stratum corneum into living layers of skin (epidermis and dermis) to represent
a device. Other claims, such as treating scars, wrinkles, facial lines, cellulite, dermatoses,
acne, and alopecia and stimulating collagen and wound healing, also meet the definition of
a device. Additionally, the FDA may evaluate the needles’ length, arrangement, sharpness,
and degree of penetration into skin layers, all related to the product’s design and the
technological features of the microneedling products that can be determined to be devices.
Microneedling products are not considered to be devices when they do not penetrate living
skin and claim only exfoliation of the skin, improving the appearance of the skin by giving
it a smoother feel and a luminous look. However, these products may still be subject to
other Federal Food, Drug, and Cosmetic (FD&C) Act requirements or other federal agencies.
Finally, specific microneedling devices designed for aesthetic uses are classified by the FDA
as class II devices (a de novo classification process). These devices use one or more needles
to mechanically puncture the skin tissue for aesthetic use. This classification excludes
devices intended for transdermal/topical delivery of cosmetic agents.
Additionally, according to FDA guidance, for a new microneedling device enter-
ing the market, the manufacturers should demonstrate a significant equivalent of their
device to those legally available in the market. Based on the special controls described
in 21 CFR 878.4430, the health risks associated with microneedling devices should be
mitigated. These health risks include adverse tissue reaction or tissue damage, cross-
contamination and skin infection, electrical shock, nerve and blood vessel damage, scarring,
hyper/hypopigmentation, mechanical failure, and software failure. For new microneedling
devices, the FDA may request clinical data and non-clinical testing, if needed. The clinical
data should describe the following: (1) the clinical study protocol and representative sub-
jects enrolled for the intended use of the device, (2) safety data collection to support the
safe use of the device, (3) the proposed effectiveness endpoint of the new microneedling
device, and (4) a follow-up period that ensures a reasonable assessment of the short-term
and long-term performance of the device, including the safety and effectiveness of the
device [
214
]. Nevertheless, the special controls in 21 CFR 878.4430 might differ based on
the specific features of the new microneedling device, where a wireless microneedling
device would require additional controls to mitigate electrical shock hazards, which are
not essential in a roller with fixed needles [214].
7. Conclusions
Microneedling has now attracted great attention in the cosmetics field. This simple,
inexpensive, painless, and self-administered application has shown promising results in
various skin conditions, making this application widespread in the cosmeceuticals market
and opening doors for many active cosmetic agents to be delivered via the microneedling
technique. For microneedling, cosmetic agents can be delivered into the skin via topical
preparations pretreated with microneedling devices. Meanwhile, in fabricated MNs, cos-
metic agents can be loaded into the matrix of MNs. Nevertheless, due to the promising
results of microneedling in cosmetic applications, numerous cosmetic agents that have not
yet been delivered by microneedling applications can be regarded as potential candidates.
Additionally, due to the recent advances in machine technology and materials science,
microneedling, as a cosmetic application, is expected to commercially boom worldwide.
One of the limitations of the clinical application of fabricated MN patches is their ability
to cover small areas of the skin. However, attempts have been made to increase the size
of the MN patches to cover a larger area of the skin surface by developing larger MN
patches. In addition, current limitations include the complexity of the application when
using a combinational treatment of microneedling and topical preparations. Furthermore,
fabricated MNs possess a limited loading ability. To overcome the limitations of the clinical
application of fabricated MN patches, alternative materials with desirable MN attributes,
such as better mechanical properties (strength and flexibility) and biocompatibility, should
be explored. In addition, new fabrication methods for MNs that can improve the delivery
of several types of MNs for different therapeutic applications should be investigated. In
Cosmetics 2024,11, 51 22 of 29
future research, novel materials, new fabrication methods, and commercialization will be
discussed in detail to ensure medical efficiency, cost-effectiveness, and mass production of
fabricated MNs. In addition, advanced applications of MNs, including disease detection,
management, monitoring, diagnosis, and personalized medicine, will be explored. More-
over, commercially available microneedling devices, particularly those used at home, need
strict regulatory control over manufacturing. For example, it is necessary to strengthen
the supervision of devices in terms of the materials used in manufacturing, mechanical
properties, insertion force, dosing and release accuracy, and needle depth.
Author Contributions: R.H., B.J.A.N., A.Z.A., Y.A.-A. and R.O. contributed to the conception, design,
and interpretation of the relevant literature in this review article; R.H., B.J.A.N., A.Z.A. and R.O.
wrote the review article; R.H. and A.Z.A. revised the review article. All authors have read and agreed
to the published version of the manuscript.
Funding: The APC was funded by the Deanship of Scientific Research and Innovation at Al-
Zaytoonah University of Jordan.
Conflicts of Interest: The authors declare no conflicts of interest.
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