pharmaceuticals
Review
Microneedle-Based Natural Polysaccharide for Drug Delivery
Systems (DDS): Progress and Challenges
Fouad Damiri 1, * , Nagavendra Kommineni 2 , Samuel Ogbeide Ebhodaghe 3 , Raviteja Bulusu 4 ,
Vaskuri G. S. Sainaga Jyothi 5 , Amany A. Sayed 6 , Aeshah A. Awaji 7 , Mousa O. Germoush 8 ,
Hamdan S. Al-malky 9 , Mohammed Z. Nasrullah 10 , Md. Habibur Rahman 11, * ,
Mohamed M. Abdel-Daim 12,13, * and Mohammed Berrada 1






Citation: Damiri, F.; Kommineni, N.;
Ebhodaghe, S.O.; Bulusu, R.; Jyothi,
V.G.S.S.; Sayed, A.A.; Awaji, A.A.;
Germoush, M.O.; Al-malky, H.S.;
Nasrullah, M.Z.; et al.
Microneedle-Based Natural
Polysaccharide for Drug Delivery
Systems (DDS): Progress and
Challenges. Pharmaceuticals 2022, 15,
190. https://doi.org/10.3390/
ph15020190
Academic Editors: Zoilo Gonzalez,
Juan Dominguez-Robles,
Ana Ferrandez-Montero and
Yoshihiro Tokudome
Received: 22 December 2021
Accepted: 28 January 2022
Published: 3 February 2022
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Pharmaceuticals 2022, 15, 190. https://doi.org/10.3390/ph15020190
1 Laboratory of Biomolecules and Organic Synthesis (BIOSYNTHO), Department of Chemistry,
Faculty of Sciences Ben M’Sick, University Hassan II of Casablanca, Casablanca 20000, Morocco;
berrada_moh@hotmail.com
2 Center for Biomedical Research, Population Council, New York, NY 10065, USA; nagavendra.kommineni@gmail.com
3 Department of Chemical Engineering, University of Benin, Benin City 1154, Nigeria;
samuel.ebhodaghe@eng.uniben.edu
4 Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA;
bulusuraviteja@gmail.com
5 Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research,
Hyderabad 500037, India; satyajuothi949@gmail.com
6
Zoology Department, Faculty of Science, Cairo University, Giza 12613, Egypt; amanyasayed@sci.cu.edu.eg
7 Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk,
Tabuk 71491, Saudi Arabia; aawaji@ut.edu.sa
8 Biology Department, College of Science, Jouf University, P.O. Box 2014, Sakaka 72388, Saudi Arabia;
mogermoush@ju.edu.sa
9 Regional Drug Information Center, Ministry of Health, Jeddah 21589, Saudi Arabia; hamdan27@hotmail.com
10 Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University,
Jeddah 21589, Saudi Arabia; mnasrullah@kau.edu.sa
11 Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
12 Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231,
Jeddah 21442, Saudi Arabia
13 Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
* Correspondence: fouad.damiri@outlook.fr (F.D.); pharmacisthabib@gmail.com (M.H.R.);
abdeldaim.m@vet.suez.edu.eg (M.M.A.-D.)
Abstract: In this focused progress review, the most widely accepted methods of transdermal drug delivery
are hypodermic needles, transdermal patches and topical creams. However, microneedles (MNs) (or
microneedle arrays) are low-invasive 3D biomedical constructs that bypass the skin barrier and produce
systemic and localized pharmacological effects. In the past, biomaterials such as carbohydrates, due to
their physicochemical properties, have been extensively used to manufacture microneedles (MNs). Due
to their wide range of functional groups, carbohydrates enable the design and development of tunable
properties and functionalities. In recent years, numerous microneedle products have emerged on the
market, although much research needs to be undertaken to overcome the various challenges before the
successful introduction of microneedles into the market. As a result, carbohydrate-based microarrays have
a high potential to achieve a future step in sensing, drug delivery, and biologics restitution. In this review,
a comprehensive overview of carbohydrates such as hyaluronic acid, chitin, chitosan, chondroitin sulfate,
cellulose and starch is discussed systematically. It also discusses the various drug delivery strategies and
mechanical properties of biomaterial-based MNs, the progress made so far in the clinical translation of
carbohydrate-based MNs, and the promotional opportunities for their commercialization. In conclusion,
the article summarizes the future perspectives of carbohydrate-based MNs, which are considered as the
new class of topical drug delivery systems.
Keywords: microneedles; sustained and controlled release; transdermal drug delivery; natural
polysaccharide
https://www.mdpi.com/journal/pharmaceuticals
Pharmaceuticals 2022, 15, 190 2 of 26

1. Introduction
Polysaccharides are a class of biopolymers that influences the biological functions
of living organisms, including structural support, energy storage, lubrication, and cell
signal transduction [1,2]. Following recent discoveries on the novel role of biopolymers
in medicine and pharmacy [3], the use of natural polysaccharides for pharmaceutical
applications is now commonplace [4]. As a result, natural polysaccharides are impor-
tant biomaterials that enhance the quality of healthcare services provided globally. This
is because polysaccharide-based pectin [5] inhibits cancer cells, and the extracts from
Grateloupialongifolia, Gracilarialemaneiformis, and others also inhibit the growth and
activities of these cells [6,7]. Therefore, the use of polysaccharides for pharmaceutical appli-
cations addresses prevalent disease conditions such as cancer, which has caused 8.2 million
deaths in recent years [8,9].
More recently, research has been increasingly reported on the use of microneedles
(MN) for several pharmaceutical applications. This is due to their merit and potential. First,
when used for transdermal drug delivery, they are capable of penetrating directly through
the skin to the deeper layers of the dermis. This implies that they are able to deliver drug
molecules across the skin [10,11] and maintain the local drug concentration for a long time at
minimal invasive drug delivery [12]. Subsequently, MN array (MNA)-based drug delivery
can ensure the local availability of therapeutics in chronic wound microenvironments,
which is due to their potential in addressing physiochemical barriers usually present in
the wounds [13]. More so, the MNA has been reported to be able to treat the complex
pathophysiological nature of chronic wounds, particularly in microenvironments that
require flexible delivery systems [14–16]. Finally, MNA can be used for the production
of neocartilage tissue constructs for tissue engineering applications. Considering these
merits, MNAs can be utilized for the printing of tissues [17], taking into account the role
of the building blocks of cellular micro-spheroids. In bioprinting, MNA possesses the
inherent capability of ensuring a sustained micro-spheroids orientation as well as proximity
in culture. This is because the MNA often acts as a transient scaffold system for the
application [18]. Therefore, microneedles (MNs) accelerate inflammatory inhibition, tissue
formation, and several other applications when integrated with other biopolymers such as
chitosan. In addition to tissue engineering and chronic wound healing, there is a need to
review other pharmaceutical applications of MN-based natural polysaccharides, as most
recent review articles on MNs have focused on their drug delivery potential.
Furthermore, MN is currently presented as a smart approach in enhancing transdermal
drug delivery capabilities [19]. This review presents an overview of MN in their different
forms, for instance, solid, hydrogel-forming, and hollow-types, with their potential and
opportunities for extended application. The characteristics, advantages and applications
of these MN types are also provided [20]. Although the use of MN for transdermal drug
delivery has been signaled extensively, the role of technological advances in improving the
research has been investigated. For example, Jung and Jin [21] presented a critical perspec-
tive on the use of digital technology in their review on current trends in MN for transdermal
drug delivery. Building on the work of Waghule et al. [19], they provided an overview of
the design, fabrication materials and methods for manufacturing MN. Up to now, research
has been examining specific materials for fabricating MN [22]. Extending the scope of
these reviews, Guillot et al. [23] reviewed strategies, pharmaceutical formulations, safety
considerations, and applications of molecules in transdermal deliveries. Similarly, present
studies have extended the research on different MNs types to include the components of
critical therapeutic substances through the skin [24]. Therefore, advancing the review on
several of these substances, including polysaccharides biomaterials, a more recent study
has utilized the PRISMA guidelines to review the same for medical applications [25,26].
This shows that the goal of achieving clinical translation from the bench is in progress.
For this reason, we are providing an updated review on microneedle-based natural
polysaccharides for pharmaceutical applications. Furthermore, MN characteristics and
Pharmaceuticals 2022, 15, 190 3 of 26

geometry, more comprehensive fabrication processes and future perspectives are presented
in this review.

2. Microneedle and Materials

2.1. Microneedle Systems
The microneedle delivery system follows the diffusion mechanism to deliver the drug
through a topical route by disrupting the surface layer of the skin temporarily. An array of
hundreds of microneedles is arranged on a tiny patch, which aids in delivering enough
drug that produces a therapeutic effect [19,21]. The dimensions of the needle must be
optimized and confined to a limit as that of the thickness of the skin’s epidermis. If the
needles are too long and thick, they can damage the nerves in the dermis region and cause
pain and discomfort [27]. The thickness of the skin epidermis is 50 to 100 µm in general
and specific areas of palms and soles are up to 1500 µm. Usually, these microneedles
have a sharp tip with a length of 150–1500 µm, a width of 50–250 µm and tip thickness of
1–25 µm [19]. Microneedle tips can be of different shapes, for instance, pointed, pentagonal,
cylindrical, triangular, octagonal and many more [24]. There are various microneedle
designs depending on the fabrication method, delivery method, type of microneedle
and drugs that are to be delivered. Different microneedles are prepared using different
materials depending on the fabrication technique that was employed for the preparation of
the microneedle. Next, we discuss a few properties of the materials.

2.1.1. Silicon
Silicon has a crystalline structure and exhibits an anisotropic nature. The first ever
microneedle prepared using silicon material was reported in 1990. The main benefit of the
material is its flexibility in processing and production in the desired shapes and sizes [15].
This material provides a considerable mechanical strength that facilitates the disruption
of the skin and delivers the drug at the site [28]. Successfully accomplished solid silicon
microneedles have an average height of 158 m, a base width of 110.5 m, an aspect ratio
of 1.43, a tip angle of 19.4◦ , and a tip diameter of 0.40 m. The mechanical stability of the
constructed microneedles was evaluated by the Vickers hardness test and met the standards
(solid silicon microneedles for drug delivery applications).

2.1.2. Metals
Metals have had a great impact on the medical field for decades. The important
metals that are used for microneedle production are stainless steel, titanium, palladium,
nickel and palladium–cobalt alloys [14]. These materials have acceptable mechanical and
biocompatibility properties. Metals are preferred over silicon-based microneedles because
of their tough nature [19]. They developed a metal-based microneedle for a dry drug. The
tip radius, height, and diameter at the middle section of the microneedle were 20, 467.8
and 268 µm, respectively, and the force required to break the skin to perform its action was
tested on rabbit skin and confirmed to be 0.4 N [29].

2.1.3. Ceramic
Ceramics have been used to produce microneedles primarily through a micro-mold
technique. By using this technique, we can reduce the cost of the scale-up process. Alumina
(Al2 O3 ) is the main metal oxide that is used as it exhibits chemical resistance, forms
stable oxides owing to its high energetic bonds between Al and O atoms and also remains
unaffected by any environmental changes and corrosion. Other than this metal, Gypsum
and Brushite are considered as they have been using these as drug-delivering means to
bones [30]. S. Bystrova et al. introduced a micro-molding method to engineer a ceramic
microneedle and achieved satisfactory mechanical performance [31].
Pharmaceuticals 2022, 15, 190 4 of 26

2.1.4. Silica Glass

Glass microneedles can be produced instantly with desired shapes and sizes. This glass
metal allows ease while imaging fluid flow and fabricating microneedles, which are physiologi-
cally inert [15]. Though silica glass is used as an alternative to prepare microneedles, the usage
is confined to laboratory purposes [32] and is not viable for commercialization.

2.1.5. Carbohydrate
Using the templates of silicon and metal microneedle templates, carbohydrate mi-
croneedles are prepared by molding with the hot melt method [33]. These are good
alternatives toother microneedle materials because they are cost-effective, and importantly,
they are safe for human health [34]. Maltose is the common sugar used to prepare micronee-
dles [34]. Although they have some advantages, they also present a range of disadvantages.
In some studies, they mentioned the inherent problems underlining processing to stor-
age [33]. Ezgi P. Yalcintas et al. performed apoptosis and cell viability investigations on
different carbohydrates (HA, CMC, trehalose, glucose, and maltodextrin) by constructing
dissolving microneedles and confirmed that except for the high concentration of glucose,
the rest of the carbohydrates are safe in engineering microneedles [35].

2.1.6. Polymers
Polymers are under the spotlight because they exhibit better biocompatibility, biodegradabil-
ity, minimal toxicity, and cost-effective materials for microneedle production. Usually, they
are weaker than the above-mentioned materials but exhibit excellent toughness compared
to ceramics and glass [36]. Polysaccharides are also used to prepare macromolecular dis-
solving microneedle systems. Xiaoyun Hong et al. and others reported that carboxymethyl
cellulose, amylopectin, dextrin, hydroxypropyl cellulose, alginate and hyaluronic acid are
commonly used materials to prepare macromolecular microneedles [36]. PVA was used in
dissolving microneedles that increased the permeation of doxorubicin [37]. PEG- PMVE
was used in hydrogel microneedle preparation to evaluate the antimicrobial activity [38].
Ethylene glycol was used in the preparation of a hydrogel-forming microneedle using
a molding technique and achieved the sustained release of metformin HCl [39]. Ryan
F. Donnelly et al. used the Gantrez polymer in optimizing and designing a polymeric
microneedle using a laser-based technique [40].

2.2. Characteristics and Geometry of Microneedles

The geometry and characteristic properties of microneedles are very crucial during
the design and preparation. The geometry of a microneedle, including its length and width,
density of the array, shape of the needle, design of the needle, nature of fabricating material
and fabrication process, is to be considered while preparing microneedles. Apart from that,
the microneedle must have adequate strength to penetrate the skin and deliver the drug
molecule or biomolecules into the skin. Penetration of microneedles across the skin must
be ensured to avoid touching the nerves making it a painless application. Permeation of
microneedles is affected by the length, shape, array density and width of the needle and
its fabricated material [41]. However, the elastic nature of human skin can also resist the
penetration of the microneedle into the skin, leading to twisting or breakage of the needle
during its application, especially in the case of short and blunt needles [42]. The typical
length of a microneedle varies from 150 to 1500 µm with a 50–250 µm width and diameter
of 1–25 µm [43].
The microneedle design varies based on the process of fabrication, where they are
categorized as in-plane and out-of-plane microneedles. In the case of in-plane micronee-
dles, the longitudinal axis of the shaft is parallel to the surface of the substrate, whereas
microneedles with out-of-plane have the longitudinal axis perpendicular to the surface of
the substrate. The in-plane design of microneedles allows regulated tailoring of the needle
length, which is considered as its major advantage. However, it encounters difficulty in the
process of its preparation. Out-of-plane microneedles facilitate a gentle fabrication process
Pharmaceuticals 2022, 15, 190 5 of 26

with a high-density array of microneedles. Nevertheless, out-of-plane design may hamper

the control of the needle length and aspect ratio, resulting in shorter height and a lower
aspect ratio [44,45]. The tip of the needle also has various shapes where the most widely
used shapes are pyramidal, cylindrical, conical, rectangular, octagonal, and quadrangular.
The shape of the needle tip affects the penetrating potential of the needle, where the tip
with pyramidal shape has better mechanical properties compared to the conical-shaped
needles. This is due to the high cross-sectional area of the pyramidal-shaped needle having
the same base width [46]. The penetration of microneedle is also affected by its shape
where sharper and narrower tips require low application force and needle tips with large
diameter require larger application force on the needle to penetrate into the skin [47].
Moreover, the length of the tip and the inter-tip spacing also affect the penetrating
potential of the microneedle where needles with longer length, wider width and a high
density array will result in greater penetration into the skin [48]. A study was performed to
assess the effect of the radius of the tip on the penetration depth. Chitosan microneedles
with a 10-µm tip radius resulted in deeper penetration into the skin compared to the needle
with a 5 µm radius [49]. An amalgamation of all these characteristic features is to be
controlled to achieve the overall success of microneedle penetration and delivery of drugs
and biomolecules into and across the skin (Figure 1).

Figure 1. Characteristic features to be considered during the preparation of microneedles.

2.3. Fabrication Techniques

These techniques are of different types. The choice of techniques depends on the type
of drug that is incorporated in the microneedle, dose, desirable pharmacokinetics and
pharmacodynamics, targets and design or material.

2.3.1. Laser Cutting

This technique is used to manufacture metal or polymer-based microneedles. Out of
all, the most used metal is stainlesssteel [42,50,51]. This laser machine is connected to a
computer-based software called Computer-Aided Design (CAD), which assists in designing
the microneedle size and orientation [21]. The 2D shape of the microneedle is created using
a laser to cut a metallic sheet. This created 2D design is used to create a 3D design by
bending the angle to 90◦ . The created needles or ridges on the flat metallic surface are
cleaned through electropolishing [52,53].

2.3.2. Laser Ablation

This is another laser-mediated technique that is also used to manufacture metal or
polymer-based microneedles. Unlike the laser cutting method, it creates and engraves
Pharmaceuticals 2022, 15, 190 6 of 26

the plate into 3D microneedle plates [21,54]. For instance, when the CO2 laser beam
is irradiated on the substrate, it absorbs heat energy and undergoes either evaporation
or sublimation. By using this process, we can extract an inverse mold by generating a
microneedle pattern [21].

2.3.3. Photolithography
This technique is used extensively to produce hollow or solid microneedles. Based on
the microneedle structure, an inverse mold method is employed to manufacture the silicon
or dissolve hydrogel microneedles. The process for manufacturing silicon microneedles
is a thin sacrificial layer deposited on the pre-treated silicon on which a photoresist, a
photosensitive polymer, is coated using a spin coating technique [21]. Then, the subsequent
process of developing tips utilizes different types of etching processes, e.g., dry etching and
wet etching.

2.3.4. Etching
When the microneedle is prepared by using photolithography, etching remains the
most crucial step as it defines the shape of the microneedle tip. The size of the microneedle
base and the gap between the microneedles are determined before the etching process [55].
It is classified into two types, wet and dry etching, which results in isotropic or anisotropic
etching depending on the method employed.

2.3.5. Dry Etching

This method is used primarily to manufacture solid or hollow microneedles by two
methods—physical and chemical methods [10,21,56]. The physical method includes ion
milling and sputtering, whereas the chemical method includes high-pressure plasma
etching. In dry etching, by using high-energy and unidirectional electrodes, an inert gas
becomesionized, and these energized ions strike the silicon substrate to create an anisotropic
effect. In the physical manufacturing process, if the substrate or sacrificial layer is protected
using oxide film or photoresist, then that part is barely etched, and on the other hand, the
part without the photoresist layer is etched.
In the chemical process, the gas plasma becomes chemically active and reacts with
the surface of the substrate and converts it into a volatile substance, thereby producing an
isotropic etching effect [16]. However, a combination of the above-mentioned methods can
be employed to control the isotropic and anisotropic etching. Watchful optimization can
deliver a precise microneedle tip [57].

2.3.6. Wet Etching

This process is used to fabricate metal and silicon microneedles by using a chemical
etchant and produces a pattern of events on the substrate [58]. For instance, this method is
employed in producing a silicon wafer in which a potassium hydroxide solution is used
as a chemical etchant [57]. The shape of the microneedle tip can be modified by altering
the etching rate, and it depends upon the direction of silicon crystals. The etching rate is
significantly faster than dry etching, and this process also follows isotropic etching similar
to dry etching. The main limitation of this process is its poor accuracy for fine fabrication.

2.3.7. Three-Dimensional Printing

Three-dimensional printing has expanded its wings to various fields, which includes
the manufacturing of microneedles. This technology helps in producing not only simple
microneedle structures but also complicated structures without compromising accuracy.
There are a few different high precision techniques [59,60].

2.3.8. Micro-Stereolithography
This method was introduced in the late 1980s [60,61]. Since then, it has been used
in various fields, primarily in biomedical and tissue engineering. By using this technol-
Pharmaceuticals 2022, 15, 190 7 of 26

ogy, currently, researchers are manufacturing tissue scaffolds, nerve guidance conduits
and cardiovascular stents [62]. This procedure is reliable and capable of producing high
complex microneedles with great precision. These 3D objects are generated by controlled
solidification of liquid resin using photopolymerization (UV radiation). This solidification
helps the resin to adhere to the support platform, and the built layer is recoated with liquid
resin. Thus, this process is also called a layer-by-layer fabrication process [63].

2.3.9. Continuous Liquid Phase Production

This process also comes under the layer-by-layer approach. Continuous liquid phase
production is a traditional system that fabricates an object by photopolymerization of resin
using a digital light process. The working principle of continuous liquid interface produc-
tion is similar to that of digital light. Through this system, we could be able to produce a
microneedle within 10 min by eliminating the rate-limiting steps that conventional methods
face during development [64]. Some papers have reported the usage of biocompatible
polymers in the production of microneedles [65].

2.3.10. Two-Photon Polymerization

This method is a complete additive manufacturing process that can be used to pro-
duce microneedles of approximately 100 nm [66]. Unlike the continuous liquid interface
production technique, this system employs a near-infrared wave-length laser instead of UV
radiation. This laser initiates polymerization of the resin by multiphoton absorption. It can
produce extensive and complex 3D designs [67,68].

2.4. Mechanical Properties of Natural Microneedles

In numerous microneedle studies, the mechanical strength of the microneedle patch
has been examined by compressing the entire patch against a flat surface, and then the
rupture force of individual microneedles has been calculated by taking the total rupture
force and dividing by the number of needles. This strategy is inadequate because it does
not identify possible variations in mechanical properties between microneedles across the
patch [69]. The mechanical properties obtained are also limited to the breaking strength of
the overall patch. In other studies of microneedles, their mechanical properties were not
measured directly but were reflected by their efficiency of penetration into the skin. The
small holes in the skin generated by microneedle penetration were normally stained and vi-
sualized to calculate the skin penetration efficiency. However, this method does not provide
any quantitative results on the mechanical properties of the microneedles. Atomic force
microscopy (AFM) was also used to measure the mechanical properties of microneedles,
and the depth or force of penetration is limited to a nanoscale measurement [69].
Yuquan Chi et al. developed the fabrication of three types of HA-MNs with different
molecular weights (10, 74 and 290 kDa), which incorporate rhodamine B as a model drug.
We evaluate the influence of HA molecular weight on the mechanical properties of HA-
MNs and the transdermal delivery of rhodamine B in vitro and in vivo. The mechanical
strength of all types of HA-MNs exceeds the minimum force required for skin penetration,
with the highest values of compressive force found at 10 k HA-MN. Interestingly, 74 k HA-
MN, which has medium mechanical strength, exhibits the highest efficacy in transdermal
delivery of rhodamine B in transdermal pigskin and Franz cell model [70].

2.5. Advantages of Natural Microneedles

Recently, natural microneedles for transdermal drug delivery have received increasing
attention as they can provide painless, minimally invasive drug delivery [71].
It was in the early 19th century that methods of enhancing skin transport for transder-
mal delivery received enormous interest to conduct extensive research. As is well known,
transdermal drug delivery through the skin faces a major challenge due to the strong barrier
of the intact stratum corneum. Transdermal delivery has many significant advantages over
intramuscular injection, subcutaneous injection and intradermal injection. Therefore, the
 N, which has ical medium
strength of mechanical ical
all types icalstrength
ofstrength
strength, ofof
Recently,
HA-MNs Recently, allall
exhibitstypestypes
74k-HA-MN,
transdermal
natural
exceeds naturalofthe
the ofHA-MNs
HA-MNs
highest which
microneedlesdelivery
minimum
microneedles exceeds
exceeds
efficacy
has medium
transdermal
of
for
force the
in
rhodamine
for theminimum
transdermal
required
transdermal minimum
mechanical
delivery B in
for drug force
ical
force
transdermal
skin
drug of required
strength
rhodamine
delivery
pene- required
strength,
delivery offor
B all
pigskin
have
have for
exhibits
in skin andpene-
types
skin the
transdermal
received
received pene-
of
Franz HA-MNs
highest
increas-
increas-cell
pigskin exceed
efficacy
model and [70i
al delivery of rhodamine
tration, with the B inhighest tration,
tration,
transdermal ing withwith
ingattention
values the
pigskin
of the
attentionthe highest
highest
transdermal
compressive and
as asthey values
Franz
they values
canforce
can cell of
delivery
provide ofcompressive
model
found
provide compressive
ofat [70].
rhodamine
painless,
10k HA-MN.
painless, force
force
minimally
minimally found
B in found at
transdermal
invasive
Interestingly, 10k
tration,
at
invasive 10k HA-MN.
HA-MN.
with
drug pigskin the Interestingly,
delivery Interestingly,
highest
and[71]. Franz values
[71]. cell model [70].of compress
Pharmaceuticals 2022, 15, x FOR PEER HA-MNs
REVIEW and which
74k-HA-MN,
74k-HA-MN, which transdermal
has has medium
medium delivery mechanical of
mechanical rhodamine strength,
strength, B in vitro
exhibits
exhibits and
74k-HA-MN, the indrug
the vivo.
highest
highest
delivery
The
which mechan-
efficacy
efficacy
has 8 of 28
intrans-
medium
in mechani
74k-HA-MN, whichical hasstrength
medium ItItwas was inin 2.5.
mechanicalthe the Advantages
early
HA-MNs early 19th
strength,
19th
and of
Pharmaceuticals
century
theNatural
2.5.
exhibits
century Advantages
that
transdermal Microneedles
2022,
that the 15,
methods x FOR
highest
methods of
delivery Natural
PEER
ofof efficacy REVIEW
enhancing
enhancing Microneedles
of rhodamine in skin skintransport
Btransport
inskin
vitropene- for
andfor intrans-
vivo. The me
ages
,x of Natural
Pharmaceuticals
FOR PEER REVIEW Microneedles
2022, 15, x FOR PEERtransdermal transdermal
REVIEW of
deliveryall
delivery types
2.5. of of
Advantages
of rhodamineHA-MNs
rhodamine of exceeds
Natural
B in
B in the
Microneedles
transdermal
transdermal minimum pigskinpigskin force
and
transdermal
and
8 of required
Franz28 cell
Franz for
cell model
deliverymodel [70].
of
8 [70].rhodamine
of 28 B in tran
transdermal delivery dermal
of rhodamine delivery
Bhighest received
in transdermal enormous interest to conduct extensive research. As isiswell
tration, dermal
with the delivery ical received
strength
Recently,
values ofpigskin
enormous
of all types
natural
compressive and Franz
interest
offorce
microneedles
Recently, HA-MNs cell
to model
conduct
natural
found for exceeds
transdermal[70].
at microneedles
10k extensive
the minimum
HA-MN. drug research.
for delivery force
transdermal
Interestingly, As required
have well
drugfor
received skin
delivery
incr
tly, natural microneedles 2022, for transdermal known,
known, drug delivery
transdermal
transdermal Recently,
tration, havedrugdrug received
with natural
delivery
delivery
asthe increas-
microneedles
highest through
through values the the for
skin
ofthey transdermal
skin faces
compressive faces a amajor drug
major delivery
challenge
challenge have
due due to received
to thethe increa
Pharmaceuticals 15, 190
74k-HA-MN,
2.5.
2.5.Advantages
Advantages which
ofthe
ing
Natural
of has
Natural
attention
medium
Microneedles
Microneedles
they
mechanical ing
canattention
providestrength, as
painless, exhibitscan minimally
2.5. deliverytheforce
provide
Advantages highest found
painless,
invasive atminimally
efficacy
ofmany
Natural
drug10kin HA-MN.
delivery8
Microneedles
invasive
of 26 Interest
[71]. dru
n as they can provide painless, HA-MNs
minimally and
invasive ing transdermal
drug
attention delivery
15,as delivery
they[71]. of
cancorneum. rhodamine
provide painless, Bthat
in vitrominimally and inof vivo.
invasive The drug mechan- delivery [71]. for
, x FOR PEER2.5. Advantages of Natural Microneedles
strong barrier of the intact
strong Pharmaceuticals
barrier of 2022,
the
74k-HA-MN,
It intact
was xstratum
in FORstratum
the PEER
which early REVIEW
corneum.
has
19th
It wasmedium
century Transdermal
in Transdermal
the mechanical
early methods
HA-MNs19th delivery
strength,
century
and hashas
enhancing
that
the many
exhibits
methods
transdermal significant
significant
skin the highest
transport
of enhancing
delivery effica
of tra
rhs
REVIEW transdermal delivery of rhodamine B in transdermal pigskin and Franz cell model [70]. 8 of 28 8 of 28
in the earlyHA-MNs 19th century
Recently, and the natural ical
thattransdermal
methods
HA-MNs Recently,
strength
Recently,
of
advantages and
advantages
microneedles natural
ofnatural
enhancing
delivery
the all
for transdermal
over of
over
dermal microneedles
types
Itskin
was
rhodamine ofdelivery
microneedles
intramuscular
intramuscular
transdermal
transdermal HA-MNs
transport
in the
delivery
drug for
early
Bdelivery
in for transdermal
exceeds
vitro
of transdermal
19th
trans-
injection,
received
dermal
delivery rhodamine
injection,ofand the
century drug
minimum
insubcutaneous
rhodamine
enormous
delivery
have vivo.
subcutaneous Bdrug
that
received inThe
B delivery
methods
vitro
in
received
interest force
delivery
mechan- and
injection have
injection
transdermal
increas-
ical to required
Recently,
inhave
of
enormous
strength vivo.
conduct received
enhancing
andand
of for
received
natural
The increas-
skin skin
mechan-
intradermal
pigskinintradermal
interest
extensive
all types and pene-
increas-
microneedles
transport
ofFranz
to injec-
injec-
research.
conduct
HA-MNs cell formodel tran
extensiv
As
exceed is [w
ivery received ing enormous
ical attention
strength of interest
as all
they ing
typesing
ical
can attention
tration,
toattention
tion.
tion.
provide with
conduct
strength
of HA-MNs as
of
Therefore,the
Therefore,they
as
painless, highest
they
extensive
all dermal
exceeds
types can
the
known, can
the ofprovide
values
provide
delivery
research.
the
minimally HA-MNs
microneedle minimum
microneedle
transdermal painless,
of compressive
painless,
received
As
invasive exceeds
isis is
force minimally
well
considered minimally
enormous
considered
known,
drug drug the force
requiredminimum
delivery anan
transdermal
delivery invasive
found
invasive
interest
for
effective
through skin
effective
[71]. atdrug
ing
force
drug 10k
drug
to
pene-
and
tration, and
the delivery
HA-MN.
attention
conduct
required delivery
painless
painless
delivery
skin
with as
for
faces
the [71].
Interestingly,
they[71].
extensive
skin
device,
device,
through can
apatients,
highest majorpene-
easy provide
research.
easy
the totouse
challenge
valuesskin use painless,
faces
of Asdue aismajo
compress we
to m
,x Pharmaceuticals
FOR PEER REVIEW 2022, 15, x FOR PEER2.5.
Pharmaceuticals REVIEW
2022, microneedle
Advantages
15, x FOR of
PEER Naturalis considered
REVIEW Microneedles an effective and painless device, 8 skin
ofeasy to use
28 transport for of 28 promis-
8trans- 8 o
nsdermal drug delivery through theIt
74k-HA-MN, was
It was
skin in in
facesthe which
the early
known,early
a promising
major 19th
has 19th century
medium
transdermal
challenge century that
mechanical
due that
drug methods
to10k methods
the
delivery of
strength, of enhancing
through exhibits
enhancing the It the
skin
was highest
transport
in
faces the for
efficacy
earlyfor
atransdermal
major 19th
trans- in
challenge century that m
sier and
tration, It withinthe
was thehighest tration,
early values
for
19th with
for
ing
Recently,centuryof
patients,
for the
patients, compressive
the highest
natural
promising
that strong
delivery2.5. values
methods
microneedles
force
of for
Advantages
barrier for of
the
of found
thecompressive
of delivery
enhancing
macromolecules for
at
delivery
of
the Natural
strong
intact
HA-MNs
transdermal
of of
skinHA-MN.
in force
macromolecules
the found
macromolecules
Microneedles
barrier
stratum transport
and field
drug
Interestingly,
ofcorneum.
the
the of at 10k
intact
for
transdermal in
transdermal
delivery
in HA-MN.
the thefield
Transdermal
trans-
74k-HA-MN, stratum
have
field of Interestingly,
oftransdermal
corneum.
which
delivery
drug
received
delivery
of
delivery. has drug
Transdermal
rhodamine
increas-
has
medium
However, drug
many Bdue to th
insignific
delive
mechanivitro
of the
thetransdermal
HA-MNs
intact stratum
74k-HA-MN,
dermal
and
delivery
delivery
the transdermal
corneum.
which ofhasrhodamine
dermal
transdermal
dermal
Transdermal
74k-HA-MN,
received medium
delivery.
delivery.
enormous
delivery
delivery
delivery Bdelivery
whichinreceived
vitro
mechanical
However,
However,
ofhas
received
delivery
strong rhodamine
advantages
interest ofand
barrier
has
medium
Jian in
enormous
rhodamine
strength,
Jian
vivo.
enormous
many
Yang
to conduct of
Yang
over
Bthe inTheB vitro
mechanical
et in mechan-
interest
significant
intact
exhibits
et al.al.
intramuscular
and
discussed
advantages
extensive
ical
to
transdermal
interest stratum
the
discussed
in
to vivo.
conduct
strength,
strength
conduct
highestrecent
over
research. recent
injection,
offor
The
pigskin
corneum. exhibits mechan-
extensive
efficacy
advances and
extensive
dermalTransdermal
advances
intramuscular
all As types the
subcutaneous
is
transdermalwell
of28in research.
Franz
delivery
highest
of of
HA-MNs
cell
research.
microneedles As
model
received
deliveryAs
efficacy
microneedles
injection,injection
delivery exceeds
is well
[70].
is
subcutaneous
of well
has
andin
forenormous
for
rhodamine
the many
bio-
bio-
intradermal intere
significan
injection
B in tran in
ing Jian Yang et al. discussed
Recently, recent
natural advances
microneedles of microneedles
for for biomedical
drug delivery8applications: 28 minimum
28have received forc
in
ofattention asinjection
they can provide painless, minimally invasive drug delivery [71].
,gth
x
Pharmaceuticals
FOR PEER
PharmaceuticalsREVIEW
of intramuscular
all types
ical 2022,
of 15,
2022,
strength x FOR
15,
HA-MNs x of
FOR PEER
allPEER REVIEW
exceeds
types REVIEWofthe HA-MNs
minimum exceeds force the
required Pharmaceuticals
minimum for skin
force 2022,
pene- 15,
required x FOR PEER skin 8pene-
REVIEW of 8of of
over transdermal
known, transdermal injection,
delivery known,
known,
subcutaneous
transdermal
drug medicaltransdermal
rhodamine
medicaltransdermal
delivery delivery advantages
Bthrough
intion.
applications:
applications: drugdrug
and
transdermal
of the delivery
rhodamine
drug
Therefore, delivery
intradermal
over
drug
skin delivery Bthrough
delivery
the
faces through
intramuscular
pigskin in a injec-
transdermal
and and
microneedle
tion. major the the
Franz
beyond skin
beyond
Therefore, skin
injection,
challenge cell
is faces
pigskin faces
[72].model
[72].
considered
the asubcutaneous
amajor
known,
and
microneedle
due major
[70].
to Franz
anthe challenge
transdermal
challenge
cell
effective
is injection
model
considered
anddue due to
drug
and
[70].
painless tothe
an the
delivery
intradermal
effective
device, through
and
easy inje
pain
to
with It drug
was in delivery
the early and
ing 19th beyond
attention century [72].
as they
that tration,
can
methods with
provide of the highest
painless,
enhancing values
minimally
skin of
transport compressive
invasive for drug
trans- force
delivery found [71].at 10
fore,the the highest
tration,
HA-MNs
microneedle valueswithis of
and thecompressive
the
consideredhighest 2.5.
strong
strong
transdermal
HA-MNs anvaluesforce
Advantages
barrier
barrier
and
effective offound
deliverycompressive
of
the of
andof
the the
tion.
for
at
Natural
transdermal
HA-MNs
of 10k
intact
intact
rhodamine
painless
Therefore,
patients,
HA-MN.
force
Microneedles
stratum
stratum
and found
delivery
device, B
the
the
promising
Interestingly,
corneum.
in atto
corneum.
transdermal
easy vitro
of
microneedle
for
10k
rhodamine
and
use
patients,
for
HA-MN.
Transdermal
the Transdermal
in isdelivery
vivo.
delivery B
considered
promising
Interestingly,
inThe delivery
vitro
of delivery
strong
ofmechan-
rhodamine
and
an
macromolecules
for has
barrier
in has
effective
the vivo.many
delivery Bmany
of
in
The
and significant
the
vitro
in
of significant
intact
mechan-
painless
the and
macromolecules
field stratum
in vivo.
device, corneum
The
easy mech
to us
MN, which2.5.
strong
74k-HA-MN,
barrier
hasAdvantages
medium
of the intact
dermal stratum
delivery corneum.
received Transdermal
It was
enormous in the delivery
74k-HA-MN,
early 19th
interest has
toHA-MNs many
century
conduct which that 2.5.
significant
extensive has Advantages
methods medium
research.
of
of enhancing Natural
mechanical
As ispene- skin transport forfid
well
of transdermal
Microneedles
strength, in the
exhibi
, promising ical
for strength
the
advantages delivery ofwhich
over
mechanical
all
of of types
Naturalhas
advantages
ical
2.5. medium
advantages
strength
of
macromolecules strength,
HA-MNs
Advantages
intramuscular Microneedles
3.Types
3.Types
Recently,
3. Typesoverover
ofof mechanical
all
of
of
injection,in
of exhibits
intramuscular
for intramuscular
exceeds
types
theical
Natural strength
of
patients,
Microneedles field
Microneedles
naturalMicroneedles
delivery.
the
thestrength,
HA-MNs
of
subcutaneous
highest
minimuminjection,
ofinjection,
transdermal
promising
Microneedles
microneedles However,
exhibits
efficacy
allinjection
exceeds
types
for force
for drug
delivery.
Jian of
the
transdermal
Yang
transdermal
the
subcutaneous
the in
subcutaneous
required
delivery
and
highest
minimum
However,
et al. for
drug
intradermal of efficacy
injection
injection
exceeds
skin advantages
force pene-
macromolecules
delivery
discussed
delivery Jian of Yang
injec-and
the inand
required
have
recent
rhodamine etintradermal
minimum intradermal
over
al. for
in
received
advances skin
the force
discussed
Bduein field injec-
intramuscular injec-
required
increas-
of
transdermal of injection,
transdermal
recent
microneedles for skin
advances
pigskin dru
for an
su
pe
o
mal delivery transdermal
of rhodamine delivery
B in known,
transdermal
of transdermal
rhodamine pigskinB in dermal
drug
transdermal
and Franz delivery
delivery cell
pigskin through
model received
and the
[70]. Franz enormous
skin cell facesmodel interest
a major
[70]. to
Recently, conduct
challenge natural extensivemicroneedles
to the research. forAs tran is
However, Jian HA-MNs
tration,
Yang with
et
Recently, andal. the
the transdermal
discussed
natural HA-MNs
HA-MNs
tion.
highest tion.
tration,
ing Therefore,
recent
attention
microneedles
Recently, and
delivery
Therefore,
valueswith and
of
There thethe
advances
asthe
the
natural
for
are transdermal
the
compressive of
delivery.
they rhodamine
transdermal
microneedle
highest microneedle
tration,
of
can
transdermal
medical values with
force
microneedles
microneedles
numerous However,
provide delivery
is
of
applications:
types theB
delivery
found
drug in
considered
is
compressivevitro
highest
Jian
painless,
for
of of
considered
at
for
deliveryofrhodamine
10k and
rhodamine
Yang
transdermal
medical
drug
microneedles an
values
bio- in
an
HA-MN.
force
minimally
haveet
delivery vivo.
effective
effective
of
al.
applications: B
found in
B The
invitro
and
compressive
received
drug
that and mechan-
vitro
HA-MNs
Interestingly,
discussed
invasive
and at
delivery
have beyond10k
drug and
been and
painless
tion. painless
drug
increas- in
Therefore,
HA-MN.
recentforce
have vivo.
in andvivo.
device,
device,
found
advances
delivery
delivery
[72].
classifiedreceivedThe
the The
theeasy mechan-
transdermal
easy
Interestingly,
and at
[71]. mechan-
10k
of to
microneedle
increas-
beyond
depending use
to use
HA-MN.
microneedles
[72].
upon delivery
is considere
Interestin
for of rh
bio
tion. Therefore, the microneedle strong barrier is of
There
There considered
are
the numerous
areintact numerous
known, an effective
stratum types
types
transdermal and
of
corneum. painless
ofmicroneedles
microneedles
drug device,
delivery
Transdermal that
that easy
have
have
through ingto
delivery beenuse
been the
attention classified
has classified
skinmany asfaces
they depending
depending
acan
significantmajor provide upon
upon
challenge painless, duem
plications: drug ical attention
ing strength
74k-HA-MN,delivery of
asandall
which
they types
ical
forical
for strength
74k-HA-MN,
inghas
beyond
can of
patients, HA-MNs
strength
patients,
medium
[72].
It
attention
provide
the was of
in
as
fabrication of
promisingall
promising
which exceeds
all types
mechanical
the
painless,
they types for
74k-HA-MN,
medical has
early
can
and of
for the
ofHA-MNs
the
medium
19th
minimally the minimum
HA-MNs
delivery
strength,
applications:
provide
their delivery
century
desired which exceeds
mechanical
painless,
invasive of force
exceeds
exhibits
drug
that has the
required
macromolecules
of medium
methods
minimally
drug
application, the the
macromolecules minimum
strength,
delivery minimum
highest
delivery of
includingand for in
mechanicalskin
exhibitsforce
in ical
the
for
efficacy
beyond
enhancing
invasive [71]. thepene-
forcefield
drug
solid, required
strength
the required
patients,
field of of
strength,
in
[72].
skin highest offor
transdermal
transport
delivery
coated, all
for
transdermal
promising skin
exhibits forpene-
types
skin
efficacy
[71].
dissolving, drug
for pene-
of
drug
thein
trans- HA-MNs
the
hollow, delivery
highest exceed
of ma
efficac
ntages of Natural for
2.5. patients,
Advantages
Microneedles promising
of Natural for
advantages the
the
Microneedlesfabrication
delivery
fabrication
over of and
macromolecules
and
strong
intramuscular their
theirbarrier desired
desired
injection,of in
the 2.5.
the intact Advantages
application,
field
application,
subcutaneous of
stratum including
transdermal
including of Natural
corneum.
injection solid,
drug
solid, ItMicroneedles
and coated,
coated,
Transdermal
was in the
intradermal dissolving,
dissolving,
delivery
early 19th
injec- hollow,
hollow,
has
century many thatsigni m
tration,
transdermal
It waswithindelivery
the
thehighest tration,
delivery.
early dermal values
tration,
delivery.
transdermal
of 19th
It
and with
rhodamine
was
and with ofthe
However,
However,
delivery
century
in compressive
the
delivery
the Bhighest
hydrogel-forming highest
in
that
hydrogel-forming Jian
received
3.Types
early Jian
transdermalvalues
transdermal
of
methods
19thYang force
values
Yang
rhodamine ofenormousof
et found
etofcompressive
al.
delivery
Microneedles
century
MN.MN. of al.
pigskin
enhancing
Each
Each in
that at
Bcompressive
discussed
discussed10k
transdermal
type
typeand
of
interest
3.Types HA-MN.
force
rhodamine
methods
of Franz
skin
of to
of force
recent
recent found
cell
pigskin
conduct
Microneedles
transport
microneedle
microneedleof BInterestingly,
found
advancesin at
advances
model
enhancing 10k
tration,
at
transdermal
for
has and
extensive 10k
delivery.of
[70]. HA-MN.
of
Franz
trans-
itsskin own
own HA-MN.
with
microneedles
microneedles
However,
cell the
pigskin
research.
transport
benefits
benefits Interestingly,
Interestingly,
highest
model for for
Jian
and
As
and
and for
[70].
is
trans- values
bio-
Yang
bio- cell
Franz
well
limitation
limitation etofforcompress
al.
modeldiscuss [70
delivery. However, Jian Yangand et al. discussed
hydrogel-forming advantages recentMN. advances
overEach type
intramuscular of microneedles
microneedle
Recently, injection,
natural for
has
dermal bio-
its
microneedlesown
subcutaneous delivery benefits and
injection
received
for transdermal limitation
and
enormous intradermal intere
ently, natural
Microneedles microneedles
dermal Recently,
74k-HA-MN, delivery natural
whichfor tion.
74k-HA-MN,
has
medical
medical
known,
received
dermal
Therefore,
transdermal
microneedles
medium
74k-HA-MN,
for
drug
applications:
applications:
transdermal
enormous
delivery
delivery
delivery
the
which for
of
microneedle
delivery
mechanical
which transdermal
3.Types
received
interest
of the has has
drugdrug
drug
drug oftohave
medium
strength,
medium is
atMicroneedles
delivery
delivery
delivery
enormous
conduct
the
considered
received
drug and
target delivery
mechanical
exhibits
mechanical
and
through increas-
beyond
interest
extensivebeyond
site.
an
tohave
the
the
However,
effective
strength,
[72].[72].
skin
research.
conduct received
highest
strength, faces
some
and
exhibits
efficacy
exhibits painless
increas-
74k-HA-MN,
medical
extensive
As aresearchers
ismajor the
well in
the device,
highest
highestwhich
applications:
challenge
research. classified
easy
efficacy
As due is
to use
efficacy
has
drug well in
microneedles in drug
medium
delivery
tomicronee-
the mechanidelive
and bey
medical applications: for drug for
patients, delivery
promising and ofthebeyond
the
tion.drug
for drug
There the at
Therefore,atthe
[72].
are
deliverythe target
target
numerousthe of site.
ing site.
microneedle
ThereHowever,
types However,
attention
macromolecules are is
of microneedles
numerous
as some
some
considered
they
in researchers
known,
the can researchers
types
field an
that
provideofeffective classified
classified
oftransdermal
havemicroneedles
transdermal been
painless, and micronee-
painless
classified
drug that
minimally
drug delivery device,
have
depending been easy
through
invasive claud
tionnumerous
are as theytransdermal
ing
can
2.5.
known, attention
provide
Advantages
types as
painless,
ofthey
delivery
of microneedles
transdermal can
Naturalofminimally
known,
drug provide
transdermal
rhodamine
transdermal
2.5. Advantages
strong Microneedles
that
dles barrier
based have
delivery
transdermal
based painless,
invasive
delivery
on B
delivery
of of
been inthe
Natural
through
the
on 2.5.
the minimally
drug
transdermal
of ofrhodamine
classified
There
drug
fabricationthe
fabrication delivery
rhodamine
Advantages
intact Microneedles
stratum
are
delivery depending
skin invasive
pigskin
numerous
methodfaces
method [71].
ofBthrough
inin
B
Natural
corneum. drug
transdermal
and
upon
a[73]. types
major
[73]. Franz
transdermal
the
As delivery
Microneedles
Transdermal
of cell
pigskin
microneedles
challenge
skin
the
As faces [71].
model
pigskin
characteristics
the dueaof
characteristicsand [70].
transdermal
and
delivery
major Franz
that
todesired
theFranz
of has
have cell
challenge cell
many
microneedles
of model
delivery
been model
microneedles due [70].
of [70].
significant
classified
to
vary rhodamine
the
vary bydepending
type,
by B in upo tran
delivery. dles based
However, on the
for
Jian fabrication
patients,
Yang et al.and method
promising their
the
discussed [73].
for
fabrication
desired
It the
wasAs
recent the
delivery
in characteristics
application,
andthe
advances their
early macromolecules
strong including
19th barrierof
century
of microneedles microneedles
application,
solid,
of thein
that the
coated,
intact field vary
including
methods
for bio- of by
transdermal
dissolving,
stratum of solid,
corneum
enhancing holl
coa
asioninand thetheir
early 19th
It
desired
strong
3.Types was century
Recently,
barrier
of in the
application,
of
Microneedles that
natural
the 3.Types
early methods
strong 19th
3.Types
advantages
microneedles
Recently,
including
intact of
barrier
stratum
an Microneedles
century
of ofMicroneedles
enhancing
over
natural
solid,
of
appropriate that
forthe
corneum.
the methods
intramuscular
transdermal
coated, skin
microneedles
Recently,
fabrication
intact transport
ofand
dissolving,
Transdermal
stratum
microneedle enhancing
druginjection,
natural
fortheir
corneum.
design formicroneedles
delivery
hollow,
delivery trans-
transdermal skin
subcutaneous
desired have
Transdermal
should has transport
received
drug
application,
be many for
selected for
delivery3.Types
injection
transdermal
significant
delivery trans-
increas-
including
based haveand
hasof
onon Microneedles
intradermal
received
drug
solid,
many
drug deliveryincreas-
coated,
significant
dose, theinjec-
have
dissolving,
onset received
of its incr
hollow
type,
type, an anappropriate
appropriate
and delivery. microneedle
microneedle
hydrogel-forming However, design
design
and Jian
MN.
dermal should
should
Yang
hydrogel-forming
Eachdelivery et be
type be
al.selected
selected
discussed
of based
microneedle
MN.
advantages
received based recent
Each
enormous on
typedrug
has
over drug
advances
its
of dose,
dose,
microneedle
own
intramuscular
interest the
ofthe onset
onset
microneedles
benefits
to has
and
injection,
conduct limita
own
exten fo
su
delivery 2.5.
received
dermal Advantages
enormous
delivery of medical
Natural
2.5.
2.5.
received
interest Advantages
to applications:
Microneedles
Advantages
enormous
conduct of Natural
of Natural
interest drug
extensive todelivery
Microneedles
Microneedles
research.
conduct and beyond
extensive
As is well [72].
research. As 2.5.is Advantages
well of Natural Microneedles
gel-formingadvantages ing
MN. attention
Each
There are as
type
over they
of ingtion.
can
intramuscular
numerous There
microneedle
advantagesof There
attention
provide
action,
ofaction,
types are
Therefore, are
as
has
over
action,
of numerous
painless,
they
its
delivery
injection, the
numerous
and ing
own microneedle
can
intramuscular
delivery
delivery
microneedles formedical types
minimally
attention
period, types
provide
hydrogel-forming
benefits
subcutaneous
period,
period,
delivery that of of
as
deliverymicroneedles
is
injection,considered
microneedles
painless,
andinvasive
they
theinjection
delivery
delivery
applications:
ofhave drug
been can
limitation
MN. minimally
drug
efficiency, provide
Each
subcutaneous
efficiency,
forknown, drug
delivery
at the and
efficiency,
classified that
an that
delivery have
effective
type
packaging, have
painless,
invasive
intradermal
delivery
target packaging,
of the
depending of been
[71].and
been
injection
packaging, and
site.
drug classified
painless
cuttingclassified
minimally
microneedledrug There
injec-
beyond
However,
tion. atupon and
cutting
cutting
the delivery
waste, depending
device,
are
has depending
intradermal
waste,
[72].
target
Therefore, somewaste, numerous
invasive[71].
its
and
site. andeasy
ownpatch
and
researchers
the However,upon
drug to
upon
benefits
injec-
patch
microneedle use
types
wear
patch delivery
wear of
and
time
wear
classified
some is microneed
[71].
limitatio
research
micron
considere
transdermal drug delivery through the skin faces a m
yransdermal
of the drug known,
the
drug It delivery
was
atfabrication
tion. the transdermal
Recently,
target
Therefore, in the
site.through
natural
the
and the
early drug
for
the
However,
microneedle
tion.
their
the
time delivery
microneedles
Recently,
fabrication
patients,
19th
It time
desired
skin
Recently,
fabrication
was century
some
(Tables
Therefore, in
(Tables
(Tables
faces
1andthrough
natural
for
natural
promising
the and
that
researchers
andfor
isapplication,
considered
the adelivery
1their
earlyand
dles 2).major
transdermal
their
methods
1 microneedle
and 19th
It
2).the
microneedles
microneedles
desired
for
based was
an
2).
challenge
the
desiredskin
century
classified
including ofonof
in
effective drug
the
is faces
the for
application,
delivery drug due
application,
enhancing
the that
earlyaofat
delivery
for
micronee-
consideredand majorto
transdermal
transdermal
methods
fabrication
solid, dles 19th
the the
skin
painless an
based
coated,
strong
havechallenge
including
macromolecules
including
century
target ofreceived
drug
transport
effective
method
ondevice,
dissolving,
barrier
drug solid,
enhancing
site.
the of thatdue
delivery
solid,
easyin
forthe
However,
and
fabrication
[73].
the
to
increas-
delivery
coated,
the
methods
trans-
skin
painless
As to
hollow,
for
the
have
Recently,
field
coated,
use
the
patients,
intact
have
fabrication received
transport
somedevice,
method received
dissolving,
of natural
transdermal
dissolving,and
enhancing
characteristics
stratum promising for
researchers
easy
[73].
corneum.
increas-
Asincreas-
microneedles
hollow,
their hollow,
trans-
to drug
desired
skin
of
for use
the transport
classified
microneedles
the characteristics
delivery
Transdermal
forfor
application
microneof
tran
vary
deliv tro
ma
arrier of the strong
intact barrier
stratum of corneum.
the 3.Types
intact of
Transdermal
stratum Microneedles
corneum. delivery Transdermal
has many significant
delivery has many significant
on the fabrication ing
dermal
for attention
delivery
method
patients, as they
[73].
promising ing
can
anding
As
for attention
provide
theattention
hydrogel-forming
delivery.
and
received
dermal enormous
patients,
for the as
painless,
However,
hydrogel-forming
delivery
characteristics
delivery
promisingthey
as they
received
interest
dlesof can
dermal
type, minimally
can
MN.
Jian
based
of provide
MN. provide
Yang
to Each
enormous
macromolecules
for
3.Types the Each
delivery
conduct
microneedles
on theet
delivery
of
an appropriate painless,
invasive
typepainless,
al.
type
Microneedles of of
received
interest
extensive
fabrication
in vary
the minimally
drug minimally
microneedle
discussed microneedle
by to
macromolecules
type, field
microneedle delivery
recent
enormous
anbenefits research.
conduct
methodof
appropriate invasive
has
transdermal
design has
[73].[71].
invasive
its
advances its
interest ing
own
and
extensive
As
in As
the drug
isowndrug
the
microneedle
should attention
well
fieldto delivery
benefits
of delivery
microneedles
hydrogel-forming
benefits
research.
conduct
characteristics
of as
and
transdermal
be selecteddesign [71].
they
and [71].
extensive
As
based can
limitation
is
of
should for
limitation
MN. provide
wellbio- Each
research.
microneedles
drugon bedrug selectedpainless,
type As of
vary mi
is mbw
and hydrogel-forming MN. There Each are type
numerous of microneedle
types of has its
microneedles own
advantages that have over and been limitation
delivery.
intramuscular
classified However,
injection,
depending Jian Yang
subcutaneous
upon etdose, based
the on
al. discuss
injectio
ges over intramuscular
propriate microneedleadvantages
known,
delivery.It was over
ininjection,
transdermal
design
However, intramuscular
the early for subcutaneous
known,
drug
should 19th
delivery.
Jian It
delivery
medical
for was
It
be
Table
Yang century
was
Table
delivery
delivery ininjection,
of
transdermal
Tableselected in
1. the the
1.Thedecision
However,
et al. injection
that
early
Thedecision
the
applications:
of the drug
through
type,
basedearly
drug
known,
discussed
1.Thedecision subcutaneous
methods
drug
Jian 19th
anat
drug
on at
the
matrix
Yangand
19th
matrix
the the
delivery intradermal
century
of
century
target
delivery
transdermal
skin
appropriate
drug
recent
matrix for
et for
targetenhancing
dose,
for faces
the
al. theinjection
that
site.
and
throughthat
thedesign
site.
design
advances
the a
discussed
designHowever,
drug
major
microneedle
onset injec-
methods
beyond
of skin
methods
However,
the
ofof and
of suitable
delivery intradermal
transport
of
challenge
skin
suitable
recent of
some
[72].
design
microneedles
suitable enhancing
some enhancing
facesthrough
advances dueafor
microneedles
researchers
researchers
should
microneedles
microneedles for
major
for toinjec-
trans-
skin
the
of Itskin
delivery
the
be
on
bio- was
ontransport
transport
the
challenge
skin
selected
the
microneedles
on the in
classified the
following
classified
of
facesthe
following for
early
micronee-
drug
due
based
following a major
for trans-
to
on 19th
trans-
performances
micronee- atthe the
drug
performances
bio-
performances century
target
challengedose, that
site.
due
the Ho
ons m
to
for delivery of the drug at the targetand site. ofHowever,
action, There delivery
some
are period,
numerousoftion.
action,
researchers delivery
delivery
classified
Therefore,
types efficiency,
the
of microneedlesperiod,
micronee-
medical
microneedle delivery
packaging, efficiency,
applications:
that is
have cutting
considered
been drug waste,
packaging,
an
classified delivery and
effective patch
cutting
and
depending and bey pw
refore,
eliverythe microneedle
tion.
dermal
period, Therefore,
delivery
delivery is ofconsidered
the the
received
dermal
dles
dlesfabrication
microneedle
dermal an effective
enormous
delivery
presenting
based
based on
presenting
presenting is
delivery considered
onthe as
theas
as and
low their
received
interest
received
efficacy
fabrication
low desired
painless an
efficacy
fabrication
low efficacy to effective
enormous
conduct
enormous
(),
method ),application,
(device,
moderate
method
(), moderate
moderate and
easy
interest
extensive
[73].
[73]. painless
interest to
efficacy
As As including
use
to
the
efficacy
efficacy to
the (device,
research.
conduct(N
conduct solid,
),),efficiency,
),and
(characteristicsand
characteristics
and easy
extensive
As
high
high coated,
dles
high to of use
isefficacy
extensive
dermal well
efficacy
based
of
efficacy dissolving,
research.
delivery
research.
()
microneedles
( ()). [21].
microneedles
on Reprinted
the
[21]. As hollow,
received
As isvary
vary
fabrication is well
from well
by enormous
ref.
by [21].
method intere
[73]. A
strong
medical
dles based barrier on efficiency,
thethe
applications: strong
intact
medical
drug
fabrication
and
packaging,
barrier
stratum
delivery
applications:
method
hydrogel-forming
of cutting
andof
corneum.
the action,
strong
time
[73]. intact
beyond
drug
the Aswaste,
MN.
Transdermal
barrier
(Tablesstratum
thedelivery
[72].
fabrication
Each
and1 of
and
characteristics
type
patch
period,
corneum.
the
and
and 2). wear
delivery
intact
beyond
time
ofathefor
their
delivery
Transdermal
(Tables
of
microneedle
stratum
has
[72].
microneedles
patients,
desired 1many and corneum.
promising significant
2).
application,
has its
delivery
vary
own
packaging,
forTransdermal
by has
the
including
benefits
many
delivery cutting
and
significant
delivery
solid,of waste,
macromolecules
limitation
has andmany
coated, dissolving, ho
patch signifi
in wea
the
nts,
s 1 andpromising
2). for
known,patients,
for the
advantages delivery
promising
transdermal
over of macromolecules
type, for
3.Types
known,
drug
known,
type,
intramuscular
advantages anthe
an delivery
ofover
delivery Microneedles
transdermal
transdermal
appropriate
appropriate
injection, in
throughof the
macromolecules
drug field
drug the
microneedle
intramuscular
time microneedle
advantages
subcutaneous
(Tables of
delivery
skin
delivery
1 transdermal
over faces
design
design
injection,
and in
through
through major
should
injection
intramuscular
2). field
drug
shouldthe
subcutaneousthe
and be of
challenge
skin
be transdermal
skin
selected faces
selected
intradermal
injection, faces duea known,
based
injection amajor
type,
based to drug
major the
onan
subcutaneous
injec-and challenge
on transdermal
challenge
drug
appropriate
drug dose,
intradermaldose, due due
the
injection the to
drug to
onset
microneedlethe
onset
injec-and the
delivery through
design
intradermal shoin
type,MicroneedleType
an appropriatefor
MicroneedleType microneedle
MicroneedleType design should
and betarget
selected
hydrogel-forming based
delivery.MN. on drug EachHowever, dose,
type of3.Types
the Jian onset Yang
microneedle
Dissolving of Microneedles
et al. hasdiscussed
its Hydrogel
own benefits recent advances and limi
However, delivery.Jian Therefore,
strong
tion.
3.Types Yang ofHowever,
barrier et al.ofthe
Microneedlesdiscussed
Jian
strong
of of
tion. delivery
themicroneedle
intact
strong Yang
action,
3.Types action,recent
barrier
stratum
Therefore,
of et
barrierof
deliveryal.
delivery
is the
advances
of
considered
the
Microneedles drug
discussed
corneum.
ofthe the intact
period,
Solidperiod,
microneedle
tion. atof
intact therecent
microneedles
Transdermal
stratum
stratum
delivery
Microneedle
Therefore,
an delivery
effective
is site.
advances
corneum.
efficiency, However,
for
delivery
corneum.
efficiency,
considered
the Coated
and
microneedle of
painlessbio-
an microneedles
Transdermal
has
Transdermal
packaging, some
packaging,
Microneedleeffective many
Dissolving
device,
is researchers
considered
Dissolving cutting
and
easy for
significant
delivery
delivery
strong
cutting
of bio-
action,
Mi-
painless
to anwaste,
use
Mi- classified
has
barrier
has
waste, many
effective many
and
delivery
device, ofand
and micronee-
significant
the
patch significant
patch
easy intact
period, wear
painless
to wear
use stratum
delivery
device, corneum
efficienc
easy to
DecisionParameter
of action, delivery period, There
delivery
Solid are
Microneedle numerous
Table
efficiency, for types
1.Thedecision
packaging,
delivery
Coated of of microneedles
the matrix
Table
cutting
Microneedle medical
drug for
at waste,
the that
1.Thedecision
the design
applications:
target have
and of been
matrix
patch
site. suitable classified
for
wear
Microneedle
drug
However,Therethe
microneedles
design
delivery depending
some
Hydrogel
are of
and suitable
on the
Microneedle
beyond
researchers
numerous Microneedleupon
following
microneedles
types [72].
classified
of performa
microneed on
micr th
applications: medical
drug delivery
applications: and dles
beyond
drug basedSolid
deliveryon
[72]. Microneedle
the and fabrication
beyond Coated
method
[72]. Microneedle
[73]. As the characteristics of Hydrogel
microneedles Microneedle
vary by
decision matrix for for
advantages the
patients,
There
time (Tables 1Drug
design
over
promising
are of
numerous
anddose
suitable
intramuscular
advantages
2).
advantages
time
fortime
the microneedles
(Tables
(Tables
patients,
for the
fabrication
There
types over
are
ofinjection,
1
deliveryover
and
1
promising andTable
and
microneedles
numerous on the
intramuscular
presenting1.Thedecision
intramuscular
2).
of 2).
for their following
subcutaneous
macromolecules
patients,
for the
desired
types that delivery
as oflow
have performances
injection,matrix
injection
injection,
promising inof
efficacy
application,
microneedles
been the for the
subcutaneous
macromolecules
for
presenting field
(), and
subcutaneous
the
Low
classified design
of intradermal
delivery
moderate
as
including
that transdermal
low
have
depending of suitable
injection
injection
in
croneedleof
croneedle
efficacy
efficacy
solid,
been advantages
time
the  microneedles
injec-
macromolecules
field
drug
(),
( and
Low
coated,
classified
upon ), and
(Tablesof
and
moderateintradermal
intradermal
over
1 and
transdermal
high
dissolving,
depending inon the
intramuscular
2).
the
efficacy
efficacy  following
injec-
field
drug
( injec-
()
hollow,
upon ), of
[21].
and performanc
injection,
transdermal
high efficacy su
d(
DecisionParameter
s low efficacy DecisionParameter
(),Therefore,
moderate efficacy type,(Therefore,
an appropriate
),Therefore,
and high efficacy
presentingdles
microneedle
() based
[21].
as
High low on designtheNfabrication
efficacy should
(),
(If be
moderate
several method
selected
patches efficacy N[73]. the
based
(If  As on
),bio-
(painless
several andthe
fabrication
drug characteristics
high
patches andthe
dose,
efficacy their
()onset of
desired
[21].
High
microneedlesapplication va
tion.
delivery. However, the
the fabrication andMicroneedleType microneedle
tion.
tion.
delivery.
Jian
and
their Yang is
However,
et
hydrogel-forming
the fabrication
desired application, considered
al. the the microneedle
discussed microneedle
delivery.
Jian
andMicroneedleType
their an
Yang
MN. effective
recent
desired
including is
However,
Eachet considered
is
al.advances
type and
considered
discussed
application, Jian
of
solid,3.Types painless
of an
Yang
microneedle
coated, an effective
recent device,
effective
microneedles
et al.advancesand
easy
and
discussed
has itstion.
for to
ownof use
painless
Therefore,
recent device,
device,
microneedles
benefits the
advances
and easyeasy
for to
microneedle
of
limitation use
to
bio-use
microneedles is considere for
of Microneedles 3.Types of Microneedles ofTable
action, delivery type,
period, an appropriate
delivery efficiency,
 LowLow areincluding
microneedle
used) dissolving,
of
packaging,
solid,and
Microneedles
design
 Low Low
cutting
hollow,
coated,
should used)
waste,
dissolving,
be
arehydrogel-forming selected
and patch
hollow,
based MN.
wear onEach drug dose,
type ofthe mi
for Table 1.Thedecision
1.Thedecision matrix
matrix for for the the design
design of
ofofsuitable
suitable microneedles
ofmicroneedles on
Tableon the the following
1.Thedecision
following performances
performances
matrix forthethe design of
of sui
andpatients,
medical
Table promising
applications:
hydrogel-forming
1.Thedecision for
andfor
matrix patients,
for
medical
drug
forMN.
MicroneedleType
the
patients,
delivery delivery
delivery
hydrogel-forming
for Each
the promising
promising
applications:
of
type
design and
theof of
of macromolecules
medical
drug for
beyond
drug
suitable
of
forat
microneedle
MN.
action,
the the
the
Each delivery
delivery delivery
applications:
[72]. target
microneedlestype
deliveryhas and in
site.
its
of the
macromolecules
of
beyond
drug
on field
macromolecules
However,
microneedle
own
period, the delivery
[72].
benefits
following
delivery
transdermal
somehas and
and in inthe
for
beyondthe
researchers
itslimitation
own
performances
efficiency,
for
field
drug
patients,
field of
[72].
Dissolving
benefits
delivery
oftransdermal
transdermal
promising
classified
packaging, of and
the Mi- drug
for
micronee-
limitation
cutting
drug at
drug
Dissolving
waste,
the
delivery
target and Mi-patch
site.
ma
Ho
Drug
Drug dose
dose time
presenting(Tables
presenting asasal.
1
low and
High
lowHigh 2).
efficacy Solid
efficacy (), (),  
Microneedle (If
moderate (If
moderate several
several Solid
efficacy Coated
patches
efficacy 
patches
( There
( ), 
Microneedle
and
), and are
depending
Microneedle
(If
high(If numerous
several
highseveral
efficacy Coated
efficacy patches types
patches
presenting () () [21].
[21].
as of
Microneedle
lowmicroneedles
 Jian
efficacy HighHigh Hydrogel
(), that
moderate have been
Micronee
efficacy c
re are numerous
oneedle presenting
delivery.
for There
types
Onset
delivery
Coated asare
of
ofHowever,
low
action
of
Microneedle
microneedles
numerous
efficacy
for atDissolving
delivery.
Jian types
Yang
delivery.
dles (),
(Pharmacokinetics/
the drug delivery
the that
based of
moderate have
However,
et
However,
target
ofon the Mi-
microneedles
the been
discussed
efficacy
site.
drug
Solid
Jian classified
Jianat(Yang
fabrication
However,
time
Slow
 the
Hydrogel ),that
recent
Yang
Microneedle
(Tables
release
and et
targethave
depending
et
method
some
by
al.
highadvances
al. been
discussed
Microneedle
1 and
discussed
[73].
efficacy
site.
researchers classified
However,
Coated
2).
the
upon
of
As() recent
microneedles
therecent
[21].
classified
Microneedle
fabrication some advances
advances
characteristics researchers
and
forupon
delivery.
micronee-
dles
their
Dependent
Dissolving
ofbio-
of
of
based
microneedles
microneedles
desired
However,
microneedles
croneedle
classified
on on
the
Mi-micronee-
the
application,
for
Slow
forbio-
vary
Hydrogel
fabrication
Yang
bio-by et al. discuss
croneedle
including
release method
by Microneed [73].
solid, A
co
cation andMicroneedleType
their
the fabrication
desired DecisionParameter
pharmacodynamics)
application,
andfabrication
their desired DecisionParameter
croneedle
including application, are are used)
used) are areused) used) croneedle
medical
3.Types applications:
of Microneedles medical
drug
medical
3.Types delivery thesolid,
applications:
applications:
ofmethod
Microneedles and 3.Typescoated,
beyond
drugdrug including dissolving,
delivery
[72].
delivery
of Microneedles solid,
and and hollow,
coated,
beyond
beyond dissolving,
[72].[72]. hollow,
medical applications: drug bydelivery and bey
type, an appropriate microneedle design Rapid shoulddissolution be selected based onappropriate
drug dose,vary the onset
dles based
MicroneedleType on the
DecisionParameter dles
Table based on
1.Thedecision fabrication
[73].
matrix As the
diffusion
for method
the characteristics
design[73]. and Asof
of MicroneedleType
suitable themicroneedles
characteristics
hydrogel-forming
microneedles onvary ofan
formulation
type, MN.
the bymicroneedles
Each
following type of
performances
diffusion
microneedle
microneedle design
has itssho ow
dleType
rogel-forming Onset
OnsetandofMN.
ofaction
action (Pharmaco-
hydrogel-forming
Each (Pharmaco-
type of microneedle
MN. Each 
type
has its
of microneedle
own benefits has
and itslimitation
own 
Dissolving
benefits Low
Dissolving and 
Mi- 
Mi-
limitation  Low Low   Low
type,There are numerous
anappropriate
Low of
type,
Solid
Solid action,
There
presenting types
microneedle
anMicroneedledelivery
are
of
appropriate
Microneedle
 as low
Low microneedles
numerous
design efficacy period,
N There
microneedle
should
Coated
Table types
Coated
(),
Several delivery
that are
Dissolving
be of have
selected
design
Microneedle
moderate
hours Microneedle
1.Thedecision efficiency,
microneedles
numerous been
Mi-
based
should
matrix
efficacy classified
(types
 on
for
), packaging,
that
bedrug
andthe
Low of have
depending
selectedmicroneedles
dose,
design
high been cutting
based
the
of
efficacy Solid
of classified
upon
onset
suitable on waste,
that
Hydrogel
()
action, drug
Hydrogel have
Microneedle
 and
depending
dose,
microneedles
[21].delivery
Low been patch
the
Microneedle
Microneedleon
period, onset
Coated wear
classified
upon the depending
Microneedle
following
delivery perform
efficienc u
ery of the Solid
3.Types
kinetics/
drug
for
kinetics/ Microneedle
delivery
at the of Microneedles
pharmacodynam-
target
of
pharmacodynam- the Drug
site. Coated
3.Types
drug Slow
3.Types
However,
at Slow
dose the of Microneedle
release
ofrelease
Microneedles
target by
Microneedles
some site.by
Drug diffu-
diffu-
researchers dose
However,  High classified
some for

researchers
micronee- delivery

(IfHydrogel
several
Highcroneedle ofpatches
Dependent
Dependent
croneedle
classified the drug
Microneedle  on
3.Types
micronee-  onat
(If the
(Ifthe
the
several target
Slow
several
of Slow site.
release
patches release
patches
Microneedles However,
 byby
(If diffu-
diffu-
severalsome
 High resear
patches
the
of fabrication
 action, delivery andperiodthetime
their
period,
of dose
action, (Tables
fabrication
desired
delivery
delivery 1 and
application,
and
efficiency, 2).
their
the
period,
(agents fabrication
desired
including
that
presenting delivery
packaging,
keep
Rapid asapplication,
croneedle
Rapid thelowandsolid, their
efficiency,
cutting
efficacy
dissolution
dissolution coated,
desired
including
waste,
(), dissolving,
packaging,
moderate application,
and solid,
patch
cutting
efficacy
Severalhollow,
coated,
wear 
including
waste,),dissolving,
((Tables
(Ifminutes and toand solid,
1high patch hollow,
coated,
efficacy wear
As() dissolving,
[21]. holl
rdDecisionParameter
gh DecisionParameter
on the fabrication
dles (Ifbased
several
MicroneedleType
Thereics)
ics)on1patches
Delivery
method
are the Drug
numerous

fabrication
[73]. As (Ifthe
There
types
several
There method
are sion
ofare
patches
sion
characteristics [73].
microneedles
numerous pores
numerous
ofHigh
As
open the
types
DecisionParameter

microneedles
longer
that
types
High
characteristics
of are
have
of microneedles
been

microneedles
dles(Ifof
vary
Several
based
several
classifiedbyare
microneedles
minutes
thatthat
on
used)patches
have
depending
have
the
formulation
formulation
weeks
been been
(depending
time
fabrication
vary
classified
upon byseveral
areare
classified
There
method
used)on
and
patches
used)
depending
are depending
numerous
2).
[73].
N Several
sionsionupon upon
the
types
hours
are 
characteristics
of
High
used)
microneed
and
timehydrogel-forming
(Tables and and
2).
time MN.hydrogel-forming
(Tables Each 1 type
and of
2).and microneedle
MN.
hydrogel-forming
Each
 Low type
Lowhas its
of microneedle
ownMN.
type, benefits
Each
Dissolving
an 
appropriate type
has
Low and
Low its
oflimitation
Mi- microneedle
ownmicroneedlebenefits has
and its
limitation
own
design should be benefits selected
Low and limita
base
areappropriate
used) MicroneedleType are used)
Low additionally
needed)
 Low are used)
drug the are
formulation) used) Microneedle application
 micro
appropriatethe type,
microneedle
for an
fabrication
delivery Onsetofdesign
theof drug
and microneedle
should
action
forTable
Solid
their
thethe  be
(Pharmaco-
fabrication
delivery
the selected
Onset
Several
1.Thedecision
Microneedle
fabrication
atdesired target design
Several the of
ofapplication,
and and
site.
drug based
action
hours should
matrix
hours
their
for Coated
their
However, on
desired be
(Pharmaco-
for
including
delivery
at desired
the drug
theselected dose,
design
Microneedle
ofapplication,
target
some the solid,
application,
site. based
the
of
researchers
drug onset
suitable
coated,
However,
at on
including
the microneedles
dissolving,
including
classified
targetsome dose,
solid, 
solid,
site. the

researchers on onset
hollow,
thecoated,
micronee-
However, theDissolving
Hydrogel
coated,
fabricationfollowing
dissolving,
dissolving,
classified
some and performances
hollow,
their
researchers
micronee-
Mi- hollow,desiredclassified
Drug
, DecisionParameter
delivery period, Drug
of dose
dose
action, Onset
delivery
High
deliveryofefficiency,
action
period,  
(Pharmaco-
(If High
High
several
delivery 
packaging, patches
efficiency,
cutting 
Solid
 (If several
(If several
Microneedle
(If
waste, several
packaging, 
and patches
patches
Drug
patches
patch of
cutting  
action,
Coated
wear (If
dose
 (If
(waste,

several
several
delivery
croneedle
Microneedle

and patches
Highpatch
Table
patches
period, wear  
1.Thedecision
High
delivery
   HighHigh matrix
efficiency,  for
(If the
several
packaging,
Hydrogel
design
 on of
patches sui
cuttin
Micron
and
Table
dles based kinetics/
hydrogel-forming
1.Thedecision
on the andpresenting
pharmacodynam-
and
matrix
Table MN.
fabrication
dles (agents
for as
kinetics/
hydrogel-forming
(agents Each
1.Thedecision
based the
method
on low
type
that
hydrogel-forming that
design
the Slow
efficacy
keepof
keep
of
matrix
fabrication
[73].dles release
pharmacodynam-
the
suitable
As (),
microneedle
MN.
the MN.for
based the Each
theEach by
moderate
microneedles
method design diffu-
type
has
type
characteristics
on the  Slow
efficacy
its
of
of of
suitable
on
fabrication
[73]. As release
microneedle
own the
ofthe ),
benefits
microneedle 
followingby
and
Several
Several
microneedles
microneedles
method diffu-
characteristicshigh
hasand
has itsefficacy
minutes
minutes
limitation
itsown
and
performances
[73]. onvaryown
As the
presenting Dependent
of the()
byto
benefits [21].
tocharacteristics
hydrogel-forming
benefits
following
microneedles
as lowand on
and the
limitation
efficacylimitation
performances
vary MN.
ofDependent
Slow
by
(), Each release
microneedles
moderate type bythe dif
ofvary
efficacy mi
by diffu- Delivery
Delivery
Delivery period
efficiencyperiod
(Expensive Dependent
drugs require onSlow the
Some release
Slow
drug are are
by
remains used)
used)
diffu-
release by time
diffu- Rapid (Tables dissolution
are are 1
used) and
used) 2). Rapid
Dependent croneedle
dissolutionon Several
the
Several hours
Slow hours are
release used) by diffu
bles 1 and 2). time
presenting
for delivery kinetics/
(Tables as 1
low
of and
the pharmacodynam-
DecisionParameter
2).
efficacy
presenting
drug
for (),
delivery
ics)
for at the are
moderate
delivery as used)
low
target
of of the efficacy
efficacy
site.
the drug (),
(
However,
drugics) at 
atthesion
),
the are
Several
and
moderate
target
some
targetused)
high
Several minutes
efficacy
efficacy
site. minutes
researchers
site. However, (()
However, sion
), weeks
[21].
and weeks
classifiedhigh
somesome (depending
efficacy
(depending
researchers
micronee-
researchers
for ()
delivery formulation
on
[21].
on
classified
classified
of the micronee-
Some
drug drug
micronee- at formulation
remains
the target sion site. Ho
type,
Rapid an appropriate
dissolution type,
high delivery efficiency)
MicroneedleType pores
microneedle
an
pores open
appropriate
open longer
design longer type, are
microneedle
should arean
in the patch or 
appropriate
be selected
Low design based
microneedle
should
Rapid on bedrug 
selected
dissolution design
dose,
Low based
the
should onseton be
drugselected dose, based
the onseton drug dose, the o
n OnsetOnset ofofaction
action (Pharmaco-
(Pharmaco-
 ics) 
formulation sion Onsetsion
 of MicroneedleType
action (Pharmaco- 
Dissolving  Mi- formulation
Low   Low  in the patch sion
harmaco- dles based
of action,
Drug on
dose delivery Slow the fabrication
dles
dles
period,
ofSolid based
action,based method
delivery
additionally on on
delivery
additionally
High 
the the of
fabrication
[73].
efficiency,
period,
needed)
needed) As
fabrication
action, the
(Ifdelivery
Several
formulation method
packaging, 
method
delivery
several hours patches
characteristics [73].
efficiency, 
[73].
cutting
period, As
Table of
As the
Several microneedles
the
Dependent
waste,
delivery
packaging,
(If the
characteristics
the
hours
several
1.Thedecision and formulation)
characteristicsformulation)
efficiency,
patch
cutting
patches vary
dles
matrix of
wear by
based
of microneedles
waste,
packaging,
for 
microneedles
onand

therelease the
designHighpatch
cutting
ofbyvary
fabrication
vary
wear
suitable by by 
method
waste, and patchonw [73]. A
ldleType
kinetics/
kinetics/
hedecision
hours MicroneedleType
pharmacodynam-
pharmacodynam-
matrix
Table
Slow for
1.Thedecision
release the design
by diffu- of Slow
matrix
Drug
release
suitable for
dose
Microneedle
release
the by by
microneedles
design diffu-
diffu-
of Coated
suitable
on the
Several following Microneedle
kinetics/
microneedles
Dependent hours
High pharmacodynam-
performances
on on
the the Dependent
following
Slow
(If several release on on the
Slow
performances
by
patches the
Soliddiffu- 
Hydrogel
Slow
releaseSlow 
Microneedle
(If by
several
Microneedle
diffu-
release by
patches diffu-microneedles
diffu-
Coated Microneedle
 High
type,
odynam- time (Tables 1 and 2). an appropriate type,
microneedle
type, an 1
appropriate
an appropriate  2).
design microneedle
should
microneedle
Rapid Dissolving
Rapid be selected
design
dissolution design
dissolution Mi-
based
should
should onDissolving
bedrug
be croneedle
selected
asselecteddose, Mi-based
the
type,
based onsetonan
Several drug
onmoderate
appropriate
drug
minutesdose,
dose, the the onset
microneedle
to onset
Several design
minutes tosho
 (
time (Tables and time
(agents (Tables
that 1 and
keep the2).
(agents thatare keep the Rapid dissolution
),are used) used)
Rapid presenting low efficacy (), N Swollen
efficacy hydrogel
), and high efficac
gkeepasDecisionParameter
low Delivery
the Solid
efficacy
Delivery ics)
ics) Microneedle
efficiency
presenting
(), moderate
as low
Sharp
efficiency
 (Expen-
waste Solid
efficacy
efficacy
generation
(Expen-
Delivery (
Coated
(),
period
Several sion dissolution
Microneedle
Microneedle
sion
),moderate
and high
minutes efficacy
efficacy
Delivery
(agents to (
Coated ()
period
that Microneedle
[21].
and
keep high
DecisionParameter
the efficacy ics) Hydrogel
() formulation
formulation
[21].
 Microneedle SeveralHydrogelsionminutes Microneedle
sionsion to Several hours
of action, sion delivery period,
of ofaction,
Some
Somedelivery
action, delivery
delivery
drug
drug efficiency,
remains period,
remains period,in in formulation
delivery
packaging,
delivery
croneedle efficiency,
cutting
efficiency, waste,
Several are
packaging,
packaging,
croneedle used)
and
minutes sion patch
cutting
cutting
Noof wear
action,
sharp
weeks waste,
Several waste,
waste are and
delivery
(depending
minutesused)
and patch
patch
period, wear
microneedle
onweeks wear delivery
tip
(depending efficienc
Onsetsive
ronger of action
DecisionParameter (Pharmaco- Delivery  period  pores open longer
 Several  Low are

pores
hours

open longer  Low are Some
Some drug drug remains  Several
remains inLow hourson
in performa
dleType
sive
are drugs
drugs
Table
time
 Severalrequire
require
(Tables
Several minutes
1.Thedecision 1
Onset
high
hours
high
and de-
2).
of de-
matrix
Table
time 
weeks
time
actionSeveral
Several
for
1.Thedecision
(Tables
the the
(Tables
the hours
(depending
(Pharmaco-
patch
patch 1 hours
designand
1
or orpores
and of
2).
formula- MicroneedleType
matrixon
Table
2).
formula-
N open
suitable
Separate for longer
1.Thedecision
the
packaging 
microneedles
design
 are of
matrix onSeveral
suitable the
for minutes
following
the
microneedles
design performances
of weeksthe
suitable
on
time Several(depending
following hours
microneedles
(Tables
the 1
formulation)and on
performances
on
2). the the 
following
formulation)  Mi-
kinetics/ pharmacodynam- Slow release  by diffu- additionally  needed) additionally Dependent
Several needed)
 onpatchesthe Slow release  efficacyby diffu- Dissolving
yicroneedle
needed) Drug
livery
livery
presenting dose
efficiency)
efficiency)
askinetics/
low (agents
efficacy
Packaging (agentsthe
presenting
(), that High
Dissolving
that
moderate
as Low
keepkeep
formulation)
low the Mi-
the
efficacy
efficacy
for Rapid
presenting
additionally (),
( 
microneedles
Slow (If
),
release 
Dissolving
and
moderate
as 
several
Low
low
needed) Low
dissolution
high
andby patches
Mi-
efficacy
efficacy
efficacy
diffu- DrugSolid 
(),
( Several
()
dose), (If
[21].
and
moderate 
Microneedleseveral
highLow
minutes
minutesefficacy
efficacy toCoated
(agents to
the
( 
() ),
 that
[21].
and
High
Dependent Microneedle
formulation)keep
high the
High
thethepatch
on thepatch
 ()
(If [21].
several
Slow releasepatches by d
Solid
Coated
(agents
Delivery
Delivery Microneedle
thatMicroneedle
period keep the Coated pharmacodynam-sion tion tion
Microneedle Several 
Hydrogel minutesMicroneedle to 
Hydrogel
formulation Microneedle Severalsion hours croneedle
iod Drug ics)
Tabledose period
High
Delivery pores
1.Thedecision  open
efficiency
pores
matrix
Table
Table 
(If
foropen croneedle
several
High
(Expen-
Delivery patches
DecisionParameter
longer
1.Thedecision
the longer
design
1.Thedecision are are
of
matrix 
efficiency 
formulation
suitable
matrix (If
Several

for (If
for theare
croneedle
several
several
(Expen-
Several
microneedles
the
sion used)
minutes
design
design
Delivery
patches
minutes patches
of suitable
of on 
weeks
the
suitable
period
Rapid
(If
weeks several
following dissolution
are
microneedles used)
Several
(depending
(depending
microneedles High
patcheshours
pores
performances
on
Tableon
on on
the open
the following Several
longer
1.Thedecision
following
formulation High are
hours
performances
performances
matrix Several
for the
are design
used) sion
minutes of sui
rdleType pores open
MicroneedleType longerefficiency
Delivery are  Several
ics)
MicroneedleType
Several(Expen- minutes
hours Some weeks drug remains (depending
 in on
Some drug remains  in SwollenSwollenhydrogel hydrogel
emainsOnsetin Sharp
of
Sharp waste
action
presentingwaste generation
(Pharmaco-
as generation
sivelow drugsefficacyrequire
presenting
(),
presenting
additionally
additionally are
high
sive
moderate
as used)
aslow 
de-
low
needed) 
drugs
needed)efficacy
efficacy
Some require
efficacy (),
drug ( 
(), ),are
highare
and
moderate used)
moderate
remains
Dissolving used)
de-
high in 
efficacy
efficacy
efficacy
Mi- (()
( ),
the are
[21].
and
),
the 
and high
formulation)
Dissolving 
used)
high
formulation) efficacy
efficacy
Mi- presenting
additionally () () [21].
[21].

Dissolvingas low
needed)
Low
 microneedle 
efficacy
Mi- Some
(), moderate

drug Low remains
efficacy
additionally Patch-wearing
 Lowneeded) time  Low Low the Some
patch the
Several Onset

formulation)
orMicroneedle
formula-
 hours
Low of
theactionpatch (Pharmaco-
or No
formula-Nosharp sharp waste
waste  microneedle tip tip
 drugs    release
Solid Microneedle SolidCoated Microneedle drug remains inSeveral minutes to bySome drug  remains in
harmaco- kinetics/
Onset
formula- Delivery
sive
pharmacodynam-
of action (Pharmaco-
period livery require
(agents
Slow
efficiency)highMicroneedle
that
release de-
keep by liverythe
diffu-
the
SolidCoated
Several
efficiency)
patch
Drug
Microneedle
or
dose
hours
formula-
croneedle  Coated
Several Hydrogel
minutes

Microneedle
Dependent
croneedle
High  Microneedle
 on Several
Slow the
Hydrogel
minutes
(If
releaseSlow

croneedle
several by
Several
Microneedle
patches
diffu-
Several
hours
Hydrogel
diffu-

hours
(If the
several
Micronee
patch patche
rdleType
High Delivery
Delivery  (If
MicroneedleType
MicroneedleType
efficiency
DecisionParameter efficiency 
 several
High
(Expen-
(Expen- patches
DecisionParameter
livery  
efficiency)
pores (If
open (If
several 
several
longer patches
patches
are (agents Rapid
Several tion
(If that kinetics/
dissolution
several
the 
keep
Deliverypatch
minutes High the
patchespharmacodynam-
MicroneedleType
efficiency
weeks tion (Expen-
(depending  High on Several minutes
  to
Rapid the patch
dissolution
(Expen-
odynam-
n kinetics/Some Slow release by
ics)
pharmacodynam- diffu- Slow
Delivery
Some
Some release
drug period
drug sion by
remains
remains diffu- inin tion Dependent
Dissolvingon Mi- the Dependent Slow formulation
Dissolving
Dissolvingrelease  on Mi-by thediffu-
Mi-
Some Slow
drug are release
remains
used) sion by
in diffu- are Several hou
sive
sivedrugs
drugs Solid
requiredrug
require are remains
Microneedle
high used)
high de-de- inSolid Rapid
Coated
Solid
additionally are dissolution
Microneedle
Microneedle
Microneedle
areused)
Low used)
needed) pores Rapid
Coated
Coated open  dissolution
arelonger
Microneedle
sive
Low 
Microneedle
used)
Low drugs are requireics)Hydrogel
Several
the  high

formulation)
Low minutes
Low  Microneedle
de- Solid weeks
Hydrogel
Some sion
Hydrogel
Microneedle
Some  
(depending
drugdrug
Low Microneedle
remains
Microneedle
remains onin
Coated inSwollen used)

Microneedle hydrog
high de- ics) sionSharp waste thethe patch
patch 3.1.
sion
generation
oror
Several formula-
Solid
Sharp
formula-

Onsethours Microneedles
waste
of action generation
 formulation
croneedle
Swollen
(Pharmaco-  hydrogel  Some 
formulation
croneedle
 drug
croneedle  remains
sion the patch or in  sion
formula-  Swollen  hydrogel
 DecisionParameter
r
harmaco- liverythe
DecisionParameter
livery
Drug patch
efficiency)
efficiency)
 High
dose or
 formula-
Sharp waste Drug  tion
generation
dose
(If 
several
High patches additionally
 
(If (If
several
High
several patches
needed) 
DecisionParameter
livery
patches  
efficiency)
(If(If 
several
several 
minutes
patches
High
patches   No
(Ifthe
Several sharp
severalthe

 the waste
formulation)
hours patch
High patch
patches No sharp
microneedle waste
 High tip
ncy)  Several 
hours (agents  Several
No tion
that
sharp 
A keep
hours waste
solid themicroneedle is generally Slow used Several
release to the
deliver
by  patch
diffu-the to
drugNo tion
sharp
through waste
micronized channels
ase Delivery
odynam- by diffu- efficiency
Slow release
Delivery (Expen-
tion
period by diffu- Some drug are
Dependent kinetics/
Low
remains
used) on pharmacodynam-
inthe Dependent
microneedle
Slow
are 
are release
Low
used)Low
Low
used) onby tip
thediffu- Slowareare  
release
used) Low
used)Lowby (agents
diffu-Rapid that 
are keep
Several
dissolution
used) the hours  Low on Dependent
microneedle  tipthe
sive drugs (agents Rapid
require that highDelivery
dissolution
keep de- efficiency
pores
the(agents Rapid formed
open
that (Expen-

dissolution
longer
keep in thethe are skin Several
Several
layer 
to
 minutes
minutes
increase Delivery to
the period
weeks
Several
permeability
sion 
minutes
 
(depending of theto on
drug 
Some  molecules
Swollen
Swollen
drug [21].
hydrogel
hydrogel
remains Inin this type
formulation 
ion
iod Sharp
Sharp Drug
ofwaste
Drug
waste
Delivery 
dose sion
High
generation
dose
generation
period  the 
patch 
(If 
or formula-
formulation
several
High
High patches Some  ics)
 (Ifdrug
(If
several
(If 
formulation
several
several patches
remains
Sharpsion in dose
patches
patches
Drug
waste  (If
(If  Swollen
several
generation severalsion
Several High hydrogel
patchespores open
patches
hours  longer
High 
Several High are
Highhours  Several
(IfSomeseveral minutespatches
harmaco-
Onset
eration livery
action
pores (Pharmaco-
open
efficiency) Onset
sive drugs
longer ofare
action
pores require of
(Pharmaco-
Several
additionally
open minutes
high
microneedle,
longer
 de-
needed) arethethe weeks drug
Several
patch No
 
molecule
(depending

sharp
or minutes
formula- waste is  attached
onweeks No
SeveralNo
the sharp 
sharp
(depending

 the
formulation)
to hours wastewaste
channel, on and by 
microneedlethe
microneedle
the time
patch oftip
tip termination drug

 remai
ral
odynam- hours Slow
kinetics/  Several
release
pharmacodynam- hours
by
kinetics/ diffu- Slow release
pharmacodynam- are
tion by 
used) diffu- Slow release are
Dependent are
are used)
by 
used)
used)
diffu- on the Dependent
Slow microneedle
are are used)
release used)
on by the tip
additionally
diffu-Dependent
Slow needed)
release on bythe diffu- Slow are used)
release by dif
additionally needed) livery
additionally
Rapid of the
efficiency)  therapy, the
needed)
dissolution Rapid microchannel
thetion formulation)
dissolution needs Rapid to be
the closed to avoid the unnecessary entry
formulation)
dissolution of the the patch
harmaco-
hat Delivery
Onset
Onset
keep of
the efficiency
action
of action
(agents 
(Pharmaco-(Expen-

(Pharmaco-
that
sion keep the 
Several
sion   minutes to Several
sion Onset
formulation 
minutes of (agents
to
action that
(Pharmaco-
formulation keep
  
sion the    sion

Swollen
formulation  hydrogel
Several minutes to
sion
ics)  ics) drug toxic substance Deliveryin through period the microchannel. efficiencySolid microneedles can act as a drug reservoir.
iodsive Sharp waste generation Some  
 remains Delivery
 Several
 on hours
pores open
(Expen-
Several
longer  onare hours
Some Several
drug Some minutes
remains diffu-
drug inby
remains weeks in 
(depending
 Swollen hydro
n(Expen-
Delivery
odynam-
kinetics/
kinetics/
longer Slow
drugs
are release
require
efficiency
Several
pharmacodynam-
pharmacodynam-
pores
 open
Several
Some drug remains
by
high
(Expen-
longer
hours diffu-
de-
minutes Slow
are
SharpSome
Slow

inwaste
release
weeksrelease
Several
Several
theRapid There
generation
patch
drug
by by
(depending
are
hours
or formula-
remains
dissolution
diffu-
minutes diffu-
various 
in Rapid
onweeksDependent
Several
Rapid  (depending
non–biodegradablekinetics/
hours
sive 
dissolution
dissolutiondrugs the on Dependent
pharmacodynam- Slow
No
metals
require Dependent
sharp
high release
used   waste
de- for onby the
Slow
the diffu-
the Slow
releaseSlow
fabrication release
by
microneedle
 ofsolid
release by diffu-
tip diffu-
microneedles
Rapid 
dissolution
   livery additionally Some needed)
sion the patch inNo orsharp
formula-
the waste inthe microneedle
patch formulation)t
high
llysive de-
drugs
needed) livery
(agents
the
sion
efficiency)
require
ics)
ics)that
additionally
patch
high de-the(agents the
needed)
keep
or formula- the patch
sionsion
(Figure
that
or
formulation)
tion  2).the(agentsSeveral
keep
formula-
the
that formulation
formulation)
minutes
keep ics)
the toefficiency) Several drug
formulation
formulation
minutes remains to Several Some sion drug sion
minutes remains
sion to
iod
 Delivery period longer Delivery period   Several
the patch hours 
tion Several
the hours
patch on micronized  Several hours
ncy) livery 
efficiency)
pores Several
open tion hoursare pores Several
Several
Several
open tion These
hours
hours
minutes
Delivery
longer MNs
arepores are
weeks
Several
efficiency
open fabricated  are
(depending
minutes
(Expen-
longer with the onweeks pointed
Several (depending 
minutes 
tips
atin the on end,
weeksSeveral which hours
(depending
Swollen facilitateshydrogel
(Expen- keep 
 de-surface Some drug remains
g remains SharpSomeinwaste
(agents generation
drugthatremains
keep thein
(agents
(agents pore
that
that 
creation
keep the the onrequire
the Several
epidermal  
minutes to Several
of Several
the minutes
skin minutes
[74]. toto
In
(agents general, this
 microneedle perme- 

iodhigh de- additionally
Delivery
Delivery period
period needed)
 additionally sive  drugs
needed)
 additionally the
Some formulation)
high Sharp
needed)
 Delivery

drug waste
remains
the patch
the
generation
No
Some
in
period 
formulation)
sharp
Swollen
or drug  remains
Several
formula- waste
hydrogel
hours that
the
in Swollen

keep
microneedle
formulation)
Several
Several
the
hydrogel
hours
hours tip
or formula-
eration Sharp waste the patch
pores open 
orlonger
generation
 formula- are
pores
pores Several
openopen
ates
longer
the
longer drug
minutes are are molecule
livery efficiency)weeks
Several
Several
 
through
(depending
minutes
minutes the passive
onweeks
weeks diffusion
(depending
(depending mechanism.
pores on on open To date,
longer various
are materials
Several minutes
ncy) (Expen-
Delivery efficiency (Expen-
Delivery efficiency (Expen- No sharp the patch waste Notion sharp
microneedle
the  waste tip
patch microneedle biodegradabletip 
ion Some tion
drug remains
additionally needed) Some
in have
drug remains
additionally
additionally been
needed)
needed) applied
Some
in to
the the
drug remains in fabrication
formulation) of solid
the the microneedles,
formulation)
formulation) including
additionally needed) and
high
sive de-
drugs require  high
sive de- drugs require high  de-   Some  drug  remains Some
in 
drug remains Some
in drug  remain
 the patch  or formula-
 the patchnon-biodegradable,

orformula-
 Sharpthe waste patch such
orSwollen
generation assilicon,
formula- hydrogeland polymers, Swollen
 including
hydrogelmethyl  vinyl ether and maleic
eration
(Expen-
Delivery
Delivery
ncy) livery efficiency
efficiency
efficiency) (Expen-
(Expen- livery efficiency) anhydride (PMVE/MA), Delivery
polycarbonate, efficiency (Expen-
the patch  
the patch  No sharp
the patch waste
Some drug tion remains Some
inSome drug No
drug
tion sharp
remains
remains waste
inin No
tion sharp
microneedle waste tip polymethylmethacrylate
microneedle Some tip drug remains (PMMA), in maltose, stain-
high
sive
sivede-
drugs
drugs require
require high
high de-de- less 
steel, titanium, and sive   drugs
nickel, etc.require Some
Conventionally, high drug  de- micropumps and microreactors 
remains Some
in Some drugdrug remains
remains in in are
the patch or formula- thethe patch
patch oror formula-
formula-   Swollen  patch the patch
hydrogel or formula-
 Swollen the hydrogel Swollen hydrog
ncy)
eration livery
livery efficiency)
efficiency)
Sharp waste generation      livery efficiency)  the the patch
patch
tionSharp waste generation tiontion No sharp waste sharp waste tip Notion
Nomicroneedle sharp waste tip
microneedle microneedle tip
  Swollen  hydrogel Swollen
Swollen hydrogel
hydrogel
eration Sharp
Sharp waste
waste 
generation
generation  Sharp
 waste generation  
No sharp waste No No sharpsharp
microneedle wastewaste tip microneedle
microneedle tiptip
Pharmaceuticals 2022, 15, 190 9 of 26

being used for the fabrication. Drug delivery through solid microneedles is influenced by
various factors, including MN insertion force, tip sharpness and MN density. However,
the fabrication of solid microneedles can be achieved by microfabrication technology, i.e.,
micro-machining or micro-electromechanical systems (MEMS) [22].

Table 2. Type of microneedle system.

Technique
Microneedle Material Approach Type of Product Improvements References
Employed
Dry and Wet
Silicon Docetaxel Liposomes Skin permeation [75]
Etching
Invitro and in vivo
Derma-roller NA Topical 5-FU [76]
anti-tumor activity
10% increase in reduction of
Solid MNs coated with
Photolithography Poke and Patch Paclitaxel tumor size compared to [77]
Microneedles ZnONanowires
conventional method
Combinational
(Mesoporous Nano
Inhibited cell proliferation
Particles) Therapy of
Stainless Steel - and anti-tumor activity by [78]
Phthalocyanine,
reactive oxygen species
Dabrafenib,
Trametinib
Infrared Laser
5-FU, Curcumin and Ink-jet printing on SS
Stainless Steel Cutting, Ink-jet [79]
Cisplatin Microneedles
Printing
PLGA Nanoparticles Effective local delivery for
Stainless Steel Wet Etching [80]
of DOX oral cancer
Coated Induced BRAF gene, which is
Coat and Poke
Microneedles Octa-Arginine siRNA responsible for melanoma
Stainless Steel Manual Coating [81]
Nanocomplexes development, induce tumor
apoptosis and proliferation
Induced humoral and
Immunotherapy using
cellular immunity facilitated
Polycarbonate Dip Coating DNA Polyplexes and [82]
targeting and activation of
Poly Adjuvant
skin
Increased drug diffusion
Nickel - DOX [83]
coefficient
Effective against gastric
Hallow Stainless Steel - 5-FU [84]
Poke and Flow cancer cells
Microneedles
Targeted delivery and
inhibited tumor progression
Silicon Manual Coating HPV 16 E6 siRNA [85]
and observed no major
adverse reactions
Polyvinyl Alcohol
Micro Molding DOX Improved permeation [37]
(PVA)
No improvement for
Tamoxifen and
Zein Micro Molding tamoxifen, observed great [86]
Gemcitabine
Dissolving Poke and Dissolve permeation in gemcitabine
Microneedles
Lipid-XoatedCisplatin Enhanced cytotoxicity and
Sodium CMC Micro Molding [87]
Nanoparticles reduced tumor size
Improved antigen-specific
Cancer Vaccination for
Pluronic F127 Micro Molding humoral and cellular [88]
EG7-OVA Tumor
immunity
Controlled, prolonged release
PLGA Multiple Casting Amphotericin [37,89]
of drug for a week
Ethylene Glycol
Hydrogel Methylvinylether-co- Poke and Swell
Microneedles Molding Metformin HCl Sustained release [39]
maleic
acid
No microbial invasion
PEG-PMVE/MA Micro Molding Anti-Microbial [90]
through skin
Pharmaceuticals 2022, 15, 190 10 of 26

Figure 2. Schematic representation of drug flow of different microneedles.

3.2. Dissolving Microneedle

These MNs are based on the principle of the poke and release approach. Dissolving
microneedles are usually made up of biodegradable polymers including poly (propylene),
dextrin, chondroitin sulfate, and albumin, polylactic acid (PLA), polyglycolic acid (PGA),
polylactic-co-glycolic acid (PLGA), polyvinylpyrrolidone (PVP), poly (vinylpyrrolidone
co-methacrylic acid) (PVPMAA) and poly (methyl vinyl ether-maleic anhydride) (PMVE-
MA). These microneedles are preferred over other types of microneedles due to their own
promising characteristics of self-dissolving and lower risk of associated toxicity. The first
report on dissolving MNs was reported in 2005 by Miyano et al. [34]. In the manufacturing
of dissolving microneedles, polymer selection is a crucial step, which needs to be taken into
consideration as it affects the release kinetics of the drug (Figure 2).
In the literature, there are various examples reported for the application of dissolving
microneedles for synergistic drug delivery in which other techniques are used along with
microneedle drug delivery [91]. The application of dissolving microneedle is not limited
to the drug incorporation but has also enhanced the preparation of the microneedle patch
for the vaccine delivery against influenza, adenovirus vector, etc. (Table 2). Dissolving
microneedles can be prepared using various methods, including solvent casting, laser
machining, droplet-born air blowing, microinjection molding, hot embossing, ultrasonic
welding and lithography. The solvent casting method is widely used in the fabrication of
dissolving microneedles [92]. Solvent casting can be performed by the ultrasonic welding
method in which polymers are fused without heat. While encapsulated drugs are con-
trollably released after penetrating into the skin, dissolving MNs have poor mechanical
properties due to their high hygroscopicity.

3.3. Coated Microneedle

Coated microneedles are covered by the drug solution or dispersion coat, which serves
a rapid and bolus release of drug molecules. There are various reports available where
DNA, protein and peptide delivery weresuccessfully carried out with a coated microneedle
approach [93]. Coating of the drug on the surface of the microneedle enables the drug
dissolution into the skin. It has been demonstrated for the siRNA incorporation with the
minimally invasive method [94].
There are some parameters that need to be taken into consideration, including the
homogenous coating on the surface of microneedles and controlled and precise drug
release from the fabricated microneedle (Table 2). These microneedles possess the long-
term stability of active ingredients. Various methods have been employed in order to
coat the solid microneedle, including dip coating and spray coating. In spray coating, the
droplet is fully covered on the surface of the MN, and this serves as a more scalable method
for the fabrication of coated microneedles (Figure 2).
Gill and Prausnitz highlighted that a reduction in surface area and increase in viscosity
could improve the efficiency of the coating microneedle [95]. In addition, layer coating
is also reported where the MN is immersed in an oppositely charged solution, such as
negatively charged DNA that interacts with a positively charged polymer. Piezoelectric
Pharmaceuticals 2022, 15, 190 11 of 26

inject printing is also reported for the deposition of antifungal drug coating on the surface
of microneedles [96].

3.4. Hydrogel Forming Microneedle

Hydrogel-forming cross-linked polymers are largely influenced by molecular weight,
swelling index and the presence of a foaming agent. There are various parameters that
affect the delivery of drugs through a transdermal route. In this type of microneedle, there
is no restriction on the incorporation of various types of drugs (Table 2). This strategy was
first established by Donnelly et al., who used a super swellable polymer in the microneedle
infrastructure [97]. The array contains no drug as such, but upon penetration, it imbibes
through the skin layer. The range of fluid withdrawal in 1 h was 0.9 to 2.7 µL, which is of
the same order of magnitude as the interstitial fluid withdrawal rates for hollow MNs and
microdialysis.
The limitation associated with conventional microarray techniques can be overcome
by the hydrogel MN, which includes reducing drug loading capacity, control of the extent of
the release and precise drug coating. It serves potential tuning benefits in which the desired
shape and size of hydrogel-loaded microneedle (Figure 2) can be fabricated, which can be
sterilized easily [45]. A hydrogel-based microneedle is a versatile device in which various
drugs with different therapeutic windows can be loaded into the hydrogel for personalized
treatment options [98]. This microneedle therapy is used for the sustained release of
metformin HCl for 24 h and is also used to monitor or quantify drug substances [39,99].

3.5. Hollow Microneedles

This microneedle differs from other types of microneedles in terms of length and
diameter of its structure. It is prepared with a 30 gauge hypodermic needle where the
specific microneedle has a length of 300 micrometers. Numerous materials are mainly
used in the fabrication of these microneedles, which include silicone, glass, ceramic and
polymer, etc. This system can deliver the drug rapidly by passive diffusion compared to
the other types of microneedles. In addition, other stimuli such as pressure and electrically
driven transport are also feasible in this class of microneedle [15]. It has been reported that
various parameters affect the flow rate of the drug through hollow microneedles such as the
inner diameter of MN, tip dimension, pressure, insertion and retraction depth and length
of microneedle (Table 2). Multiple techniques are available for the fabrication of hollow
microneedles, including the MEMS techniques, profound engraving of silicon by reactive
ions, an incorporated lithographic molding technology, advanced X-ray photolithography
and wet chemical printing and microfabrication. In recent years, hollow microneedles have
been employed to be fabricated by 3D printing methods (Figure 2).

4. Mechanism of Drug Delivery with Microneedles

The administration of topical drugs depends on the diffusion mechanism. In the
microneedle drug delivery system, the skin is briefly interrupted [100]. A microneedle
device is made by placing thousands of microneedles in an arrangement on a tiny patch
(identical to a normal commercially available transdermal patch) to deliver sufficient
amounts of a drug to obtain the necessary therapeutic response. It punctures the stratum
corneum, bypassing the barrier layer. The drug is delivered directly into the epidermis
or uppermost layer of the dermis, then passes into the systemic circulation and exhibits
a therapeutic response when it reaches the site of action [101]. The mechanism of drug
delivery by microneedles is demonstrated in Figure 3.
Pharmaceuticals 2022, 15, 190 12 of 26

Figure 3. Mechanism of drug delivery by microneedle device: (1) microneedle device with drug
solution; (2) device inserted into the skin; (3) temporary mechanical disruption of the skin; (4) release
of drug into the epidermis; (5) transport of drug to the site of action. Reprinted with permission from
Ref. [19]. Copyright 2019 Elsevier.

5. Natural Polysaccharides Used in Microneedles

Polysaccharides have been widely explored in the field of drug delivery systems due
to their biocompatibility, biodegradability and low toxicity [102,103]. Exploitation is also
taking place in the fabrication of microneedles [104]. There are various polymers used
in transdermal drug delivery due to their physiochemical properties and tenability and
mechanism of drug release. Polysaccharides are obtained from natural sources such as plants,
animals, and microorganisms, etc. However, polysaccharides are extensively used due to their
biocompatibility, biodegradable nature, ease of fabrication and sustainable delivery. The most
widely explored polysaccharides are not limited to hyaluronic acid (HA), dextran, chitosan
(CS), cellulose, sodium alginate (SA) and blends of other biopolymers [105]. They are more
advantageous than synthetic polymers pertaining to environmental friendliness (Figure 4).

5.1. Hyaluronic Acid (HA)-Based MNs

Hyaluronic acid (HA), also called hyaluronan, is a polysaccharide composed of D-
glucuronic acid and N-acetyl-D-glucosamine, which are linked by β-(1,4) glycosidic bonds.
It is a simple, water-soluble polysaccharide [106]. It is widely present in the skin and
synovial fluid joints [107]. However, it is extracted from rooster combs, shark skin and
microorganisms. It was approved by USFDA for its use in soft tissue damage. It is used to
fabricate dissolving microneedles, which dissolve after penetrating into the skin and release
the drug (Table 3). It also accommodates high amounts of a drug, leading to superior
delivery and quicker onset of action [108]. A study aimed to design insulin delivery via
hyaluronic acid microneedles resulted in the complete dissolution of microneedles into
the rat skin after 1 h of application. This showed the self-dissolving ability into the skin
and release of loaded molecules to the targeted site. The plasma peak levels were also
compared with microneedles and subcutaneous injection, where a higher level of insulin
was achieved with microneedles. This study highlighted the potential of hyaluronic acid
in designing dissolving microneedles for transdermal drug delivery [109]. Hyaluronic
acid has also been shown to have fine mechanical properties that penetrate the thickened
epidermis of mice induced with psoriasis. The dissolving property of hyaluronic acid
microneedles exhibited superior efficacy compared to the oral delivery in treating psoriasis,
highlighting the dissolving microneedle patch as an excellent strategy for the effective
Pharmaceuticals 2022, 15, 190 13 of 26

delivery of the drug [110]. Dissolving microneedles tailored with hyaluronic acid were
also investigated for delivering high molecular weight drug molecules. A high molecular
weight of 4000 Da fluorescein isothiocyanate-labeled dextran was used and assessed for
its permeability and accumulation in the skin. Transcutaneous electrical resistance and
trans-epidermal water loss were found to be increased, revealing the penetrating ability of
hyaluronic acid microneedles [111].

Figure 4. Advantages and sources of natural polysaccharides used in the fabrication of microneedles.

Jinjin Zhu et al. demonstrated that 5-Aminolevulinic acid (5-ALA), which is an endoge-
nous nonprotein amino-acid-loaded HA microneedle, was effective for pharmacodynamics
therapy in the superficial tumor treatment. The results of this study revealed that 5-ALA
effectively reached the target site by penetrating the stratum corneum upon administration
by the HA microneedle. In addition, this HA microneedle showed superior long-term
stability and activity at room temperature due to the acidic and oxygen-free environ-
ment of HA MNs [112]. In another study, hyaluronic acid was used as a matrix for the
fabrication of a microneedle patch in order to incorporate a synergistic combination of
gene therapy and photothermal therapy for cancer treatment. The p53 DNA and IR820
were co-loaded in a HA microneedle patch, and the result showed that the fabricated
microneedle efficiently penetrated through the stratum corneum and could deliver the
drug to a subcutaneous target site. It was concluded that this strategy could be seen as
the best suitable alternative and act as a synergetic strategy [113]. Moreover, near-infrared
sensitive dissolvable microneedles are reported for the treatment of human epidermoid
cancer and melanoma. Thus, microneedles were fabricated by the HA and loaded with
light-responsive 5-fluorouracil (5-Fu) and indocyanine green (ICG)-loaded monomethoxy-
poly (ethylene glycol)-polycaprolactone (MPEG-PCL) nanoparticle (5-Fu-ICG-MPEG-PCL),
and then 5-Fu-ICG-MPEG-PCL. Ying Hao et al. concluded in this study that an HA-based
microneedle was proven to have good penetration ability and heat transfer efficacy. This
also contributed to the controlled release of the incorporated drug and could successfully
develop a synergistic treatment of chemotherapy and phototherapy for cancer [114].
Hongyao et al. prepared an HA-based microneedle for the treatment of psoria-
sis, which enables higher water solubility, biocompatibility, mechanical properties and
biodegradability [110]. Microhyala is an FDA-approved product of microneedle used in the
cosmetic market as it dissolves in intestinal fluid and is degraded by free radicals, which
Pharmaceuticals 2022, 15, 190 14 of 26

are found in the extracellular matrix and lysosomal enzymes [22]. In addition, IvySaha et al.
compiled multiple applications of an HA MN array in the cosmetics and medical field. We
recommend that the interested reader refer to the review paper, which will provide more
knowledge on this specific topic [108]. There are various methods used for the preparation
of HA microneedles, such as micro-molding, photopolymerization, and drawing lithogra-
phy [115]. HA microneedles (MN) have been used to load various therapeutic molecules
for its effective treatment.

5.2. Chondroitin Sulfate-Based MNs

Chondroitin sulfate is a disaccharide sugar moiety comprised of N-acetyl-galactosamine
and D-glucuronic acid bonded by β-(1,3) glycosidic linkages. It is naturally available
in cartilage, porcine skin and bovine trachea. Based on the source, marine or terrestrial
animals, the composition and concentration of chondroitin sulfate varies [116]. It is a water-
soluble saccharide that forms a dissolving microneedle [117]. A dissolving microneedle
of recombinant staphylococcal enterotoxin B was designed with chondroitin sulfate and
trehalose, which showed good penetration ability with 260 µm depth of penetration into
the skin of mice (Table 3). This study showed effective immunization via chondroitin
sulfate microneedle transcutaneously [118]. A two-layered dissolving microneedle was
prepared with chondroitin sulfate and dextran individually as the base polymer for the
delivery of recombinant human growth hormone and desmopressin. Chondroitin sulfate
microneedles showed a higher extent of bioavailability as compared to the microneedles
prepared with dextran [117].

5.3. Cellulose-Based MNs

Cellulose is a naturally occurring, abundant biomaterial composed of herbal cells and
tissues. It is obtained from various sources, including wood, cotton, bacteria and algae.
However, commercially, it is procured from wood and cotton. Cellulose contains glucose
monomers, which are linked only by β-(1,4) linkages (Table 3). There are numerous cellulose
derivatives used in the pharmaceutical sciences. Cellulose esters and cellulose ethers are
widely used derivatives from the cellulose family. Cellulose esters are water-insoluble
and film former polymers such as cellulose esters, including cellulose acetate, cellulose
acetate phthalate and cellulose nitrate [119]. In the literature, one of the patents revealed
the application of cellulose-based microneedles in cancer therapy [120]. Furthermore,
selected inventors from the University of Pittsburgh and Carnegie Mellon University
have divulged carboxymethylcellulose (CMC) MNs that can release a number of different
chemotherapeutic agents and immune-stimulating agents that can be used either alone
or in combination. In this example, doxorubicin, valrubicin, epirubicin, idarubicin and
other known anthracycline agents have been utilized for the treatment of skin cancer [121].
Patent No CN106426729A highlighted that cellulose microneedles are not only used for
gene delivery but are also applicable for the delivery of anti-cancerous agents [122,123].
Yong-Hun Park et al. fabricated a microneedle for transdermal delivery by laser writing and
replica molding processes. A threefold enhancement in permeability was observed. The
authors reported that this fabrication process was best suitable for a CMC microneedle, even
in cosmetics products [124]. Daniela F.S. Fonseca et al. developed dissolvable hyaluronic
acid (HA) microneedles (MNs) combined with bacterial nanocellulose (BC) MN patched for
dermo-cosmetic application. HA- and BC-blended microneedles had sufficient mechanical
strength, and BC contributed to a controlled release of the drug molecule. The in vivo safety
studies also reported that the prepared microneedle was safe and biocompatible [125].

5.4. Chitin and Chitosan(CS)-Based MNs

Chitosan is a marine polysaccharide extracted from chitin [103,126,127]. Naturally,
it is found in the cell wall of fungi. Chitosan is obtained from the deacetylation of
chitin [103,126]. It is a linear biopolymer formed by D-glucosamine and N-acetyl-D-
glucosamine linked by a β-(1,4) bond. It has a molecular weight in the field of 300 and
Pharmaceuticals 2022, 15, 190 15 of 26

1000 kDa (Table 3). It has been observed that the low molecular weight polymer has poor
mechanical strength and in order to improve it, PLGA was added [128]. Chitosan naturally
possesses antibacterial and wound healing properties. It is a water-insoluble polymer and
is degraded by lysozymes and chitosanase. André F. Moreira et al. demonstrated that the
blend of polyvinyl alcohol and chitosan are used for manufacturing micro-needles [129].
Micro-molding and electro-spraying techniques were used in combination in the fabri-
cation of this microneedle intended to deliver doxorubicin and AuMSSnanorods. The
Dox@MicroN patches were observed to have good photothermal ability resulting in a
temperature enhancement of 12 ◦ C under near-infrared irradiation. Nevertheless, the
microneedles were able to penetrate the tumor-mimicking agarose gel and promote layer-
based drug release [129]. It is reported that the addition of the thiol group improves the
mechanical properties of chitosan, and hence, thiolated MNs are prepared with optimum
mechanical strength and sharpness [130].
Mei-Chin Chen et al. introduced chitosan microneedle patches for sustained drug
delivery of hydrophilic drugs. It was reported that 95% in vitro drug release was obtained
through this drug delivery within 8 days. In addition, the incorporated BSA molecule was
diffused by a penetration depth of 300 µm [49]. Water-soluble chitosan is also prepared
by treatment of trifluoroacetic acid followed by a 0.1 M NaCl solution. This method was
found to be suitable for sustained transdermal drug delivery of more than 72 h [131].

5.5. Starch-Based Microneedle

Starch is a biodegradable material available naturally in extensive amounts for various
properties and applications in the biomedical field (Table 3). It has been explored widely
in formulation practices due to its brittleness and multipurpose applications. Yujie Zhang
et al. demonstrated a new microneedle patch that disperses and releases insulin in response
to glucose for type 1 diabetes. It was observed that a fabricated microneedle was complete
and uniform in structure. In this, the nanomaterial was added as an additive to enhance the
mechanical strength [132]. A starch and gelatin blend was also used for the fabrication of
microneedles for the treatment of losartan through transdermal drug delivery [133]. Starch-
based amylopectin is not biodegradable and hence not preferred for the fabrication of
microneedles. Pablo Serrano-Castañeda et al. [134] highlighted microneedles as enhancers
of drug absorption through the skin.

5.6. Sodium Alginate (SA)-Based Microneedle

Alginate is a natural polysaccharide obtained from algal and bacterial sources. The
commercial source of alginate is brown algae. It is an anionic linear polymer consisting of α-
L-guluronic acid and β- D -mannuronic acid saccharide units [135]. A study was conducted
to determine the delivery potential of sodium alginate microneedles where bovine serum
albumin was used as a model drug (Table 3). The results showed an improvement of
15.4 fold permeation compared to sodium alginate needle-free patches, thus availing
the microneedle for transdermal delivery [136]. Another study reported the delivery
of insulin with alginate and maltose composite as a base polymer for the preparation
of a microneedle. The composite of alginate and maltose revealed higher mechanical
strength for the penetration of microneedles into the rat skin as a transdermal drug delivery
system [137].
GwenaëlBonfante et al. discussed three materials—carboxymethyl cellulose (CMC),
alginate, and hyaluronic acid (HA)—for the manufacture of microneedles. However, the
microneedles have been designed with low concentrations for rapid dissolution while
maintaining the strengthening effect and were used varying from 1 to 5% (w/w) in deion-
ized water [138]. Their overall performance aspects, such as geometric parameters (width,
height, and tip width), piercing capabilities, and dissolution time, are measured and dis-
cussed. To break the skin barrier, two key parameters, a sharp tip and overall mechanical
strength, are highlighted. Each material fails the piercing test at a concentration of 1%
(w/w). Concentrations of 3% (w/w) and 5% (w/w) result in powerful matrices capable of
Pharmaceuticals 2022, 15, 190 16 of 26

piercing the skin. For the purposes of this study, HA at a concentration of 3% (w/w) results
in arrays consisting of microneedles with a tip width of 48 ± 8 m and pierces through the
sheet with a dissolution time of less than 2 min.

5.7. Xanthan Gum (XG)-Based Microneedle

Xanthan gum (XG) is a hetero polysaccharide with β-(1,4)-D-glucopyranose glucan
as a backbone with (3,1)-α-linked D-mannopyranose-(2,1)-β-D-glucuronic acid-(4,1)-β-D-
mannopyranose as side chains (Table 3). It is produced by bacteria called Xanthomonas
campestris, where it is secreted from the surface of the cell wall by enzymatic reaction [1].
Xanthan gum is extensively used as a viscosity enhancer of the coating solution in the
preparation of coated microneedles. A study was reported to use xanthan gum at 1%
w/v concentration as a coating solution to the microneedle coated with an influenza
virus-like particle vaccine where it showed good hemagglutinin activity as compared to car-
boxymethyl cellulose. However, carboxymethyl cellulose was superior in terms of coating
dose than xanthan gum, and thus, carboxymethyl cellulose was used as a viscosity en-
hancer [139]. In another study, xanthan gum at 0.075 % w/v was used along with trehalose
as a viscosity enhancer for the influenza vaccine coated microneedles. Nevertheless, hemag-
glutinin activity was significantly high as compared to the trehalose solution. These studies
suggested further investigation of xanthan gum in the preparation of microneedles [140].

5.8. Pullulan-Based Microneedle

Pullulan is another hydrophilic polymer comprising three maltose saccharide units
linked by α-1,6 glycosidic bonds, which is a trisaccharide sugar moiety. The source of
pullulan is Aureobasidiumpullulans, which is a yeast-like fungus (Table 3). It possesses
sufficient mechanical strength to fabricate microneedles [141]. A dissolving microneedle
patch of pullulan was fabricated for the delivery of insulin by a micro-molding method.
The microneedle showed a penetration depth of 381 µm into the skin and dissolved into
the skin within 2h and released 87% of insulin [142]. The pullulan microneedle was also
assessed for the delivery of small and large biomolecules across the skin. Ex-vivo skin
permeation studies have been performed on porcine skin and concluded that pullulan
dissolving microneedles have huge potential for transdermal drug delivery.

5.9. Bletilla Striata (BS)-Based Microneedle

Bletilla striatum isa herbal-based polysaccharide obtained from the tubers of Bletilla
striata. It is broadly known for its medicinal properties, and it is a water-soluble polysaccha-
ride comprising α-mannose, β-mannose and β-glucose as monosaccharide units [143–145].
A dissolving microneedle-based on Bletilla striata polysaccharide was prepared with rho-
damine B as a model drug. The study showed promising results for its effectiveness in
penetrating the skin and delivery of loaded moiety and was assessed by a texture analyzer.
Confocal laser scanning microscopy signified the dissolution of the microneedle and the
release of molecules into the skin. Thus, this study has highlighted the prospect of novel
polysaccharides in tailoring dissolving microneedles [146]. Panax Noto ginseng is another
herbal-based polysaccharide investigated for the preparation of a dissolving microneedle
for transdermal drug delivery [147]. The prepared microneedles showed good mechanical
properties and sufficient penetrating ability, demonstrating transdermal delivery of drugs
across the skin [148]. Polysaccharides derived from natural sources are, therefore, exten-
sively studied for the generation of microneedles, and the summary of the polysaccharides
used is given in Table 3.
Pharmaceuticals 2022, 15, 190 17 of 26

Table 3. Summary of polysaccharides used for the preparation of microneedles.

Type of Microneedle
Polysaccharide Source Monosaccharide Units Inference Reference
Fabricated
Possess good
Hollow–solid,
Derived from chitin mechanical strength
D -glucosamineand dissolving, and
Chitosan (natural sources of and also availed for [129,149–151]
N-acetyl-D-glucosamine coated layer-by-layer
crustacean family) its adjuvant and
microneedles
antibacterial property
Hollow, dissolving
Rooster combs, shark D -glucuronic acid and Self-dissolving ability
Hyaluronic acid and hydrogel [109–111]
skin N-acetyl-D-glucosamine and good penetration
microneedle
Cartilage, porcine
N-acetyl-galactosamine and Dissolving
Chondroitin sulfate skin and bovine Good penetration [117,118]
D -glucuronic acid microneedle
trachea
High mechanical
α-L-guluronic acid and Dissolving strength when
Alginate Brown algae [136,137]
β-D-mannuronic acid microneedle combined with
maltose
β-(1,4)-D-glucopyranose
glucan as a backbone with
(3,1)-α-linked D-Mann Used as viscosity
Xanthomonas
Xanthan gum pyranose-(2,1)-β-D- Coated microneedles enhancer for coated [139,140,152]
campestris
glucuronic microneedles
acid-(4,1)-β-D-Mann
pyranose as side chains
Owing to its
Dissolving
Starch Corn or potato Glucose brittleness blended [133,153]
microneedle
with gelatin
Exhibited good
Dissolving
Pullulan Aureobasidiumpullulans Maltose mechanical [142,154]
microneedle
properties
Good mechanical
α-mannose, β-mannose, Dissolving strength and
Bletilla striata Bletilla striata [146]
and β-glucose microneedle sufficient penetrating
ability
Good loading
capacity and
Backbone of→4)-α-D-GalAp-
compatible with
(1→4-β-L-Rhap-1
Dissolving hydrophilic and
Panaxnotoginseng Panaxnotoginseng →4)-β-D-Galp-(1→residues, [148]
microneedle lipophilic molecules,
with a branch of α-L-Araf-
producing sustained
1→5)-α-L-Araf-(1→
and stable drug
release

6. The Benefits of Microneedles

6.1. Low Cost
Polymeric MN-based natural polysaccharide is less expensive than silicon MNs or
metal MNs [155]. Polymers such as chitosan, chitin, hyaluronic acid, sodium alginate and
starch are used for the fabrication of microneedles due to their low cost [155]. Furthermore,
the current microneedle manufacturing processes need to be enhanced to achieve large-
scale production to completely transfer microchip-based microneedles into therapeutic
applications. To date, the economic assessments of the technology have not been extensive,
but as with any new technology, it is not difficult to expect that the clinical use of MNs will
be relatively more costly due to the complicated manufacturing and storage procedures
and the long and slow approval process [156].

6.2. Flexibility
Since metal and silicon MNs are fragile in nature, they can harm patients. In this
case, polymeric MNs are the opposite of silicon MNs. Due to the viscoelastic property of
Pharmaceuticals 2022, 15, 190 18 of 26

polymers, polymeric MNs have a greater ability to resist shear-induced failure in the skin
than silicon or metal MNs (Figure 5).
Ian Woodhouse et al. have developed microneedles that successfully raise oxygen
levels by 8–12 ppm when dissolved over a 2-h period, providing a strong bactericidal
effect on liquid and biofilm bacterial cultures of gram-positive (Staphylococcus aureus)
and gram-negative (Pseudomonas aeruginosa) bacterial strains commonly found in dermal
wounds [157]. In addition, the results of ex vivo testing in a porcine wound model have
demonstrated the effective insertion of the microneedles into the tissue while offering
effective bactericidal properties against both gram-positive and gram-negative bacteria in
the complex tissue matrix [158]. In addition, microneedles showed significant levels of
cytocompatibility with apoptosis of less than 10% during 6 days of continuous exposure
to human dermal fibroblast cells [157]. The flexible microneedle presented may provide a
more successful strategy to enhance the effectiveness of topical tissue oxygenation as well
as for treating wounds infected with intrinsically antibiotic-resistant biofilms.

Figure 5. (a) Image of the flexible MAE, (b) Image of the flexible MAE on the curved skin (c) SEM
image of the flexible MAE, and (d) SEM image of a microneedle (MN). Reprinted with permission
from Ref. [159]. Copyright 2019 MDPI.

6.3. Biodegradability, Biocompatibility and Stability

One of the safety aspects of MN systems in clinical use is biocompatibility [36]. To
ensure that MN products are suitable for human exposure, different tests are necessary
to evaluate their biocompatibility based on contact periods of less than 24, 24 to 30 h,
and more than 30 h. For the first two periods, the corresponding tests are cytotoxicity,
sensitization, irritation and intracutaneous reactivity tests. Genotoxicity and subacute/sub-
chronic systemic toxicity tests are further suggested for the last period of use. The use of
biodegradable materials is preferable for microneedles as such materials can be decomposed
and be safely disposed of by the body [14]. Consequently, the use of biodegradable
polymeric systems for the manufacture of MNs has been investigated in recent years [15].
The main advantage of polymeric microneedle systems is their ability to load drugs into
the microneedle matrix for discharge into the skin by biodegradation or dissolution into
the skin’s body fluid [160].
Pharmaceuticals 2022, 15, 190 19 of 26

The possibility of manufacturing microneedle structures from aqueous polymer blends

at room temperature without the need for a warming step could be a significant advantage
in retaining the strategy of stability of an incorporated drug, particularly in the case of
therapies in which proteins and peptides are implicated [161]. However, the stability of the
MN cargo must be evaluated to make sure that fragile and highly degradable therapeutics
are protected during the storage process [160]. This is generally performed by studying
MNs and their cargo at various temperatures, such as −25, 4, 20, 40, and 60 ◦ C, and then
performing analytical measurements. In summary, the protein cargo of MNs has improved
storage stability and prolonged shelf life due to the rigid glassy microneedle matrices that
constrain molecular mobility and limit the availability of atmospheric oxygen. This period
can be prolonged by adding stabilizers, particularly trehalose and sucrose [162]. Careful
attention to water is particularly critical when storage conditions are not evacuated, as it
can destroy not only the stability of the charged cargo but also the mechanical properties of
the MNs. Dissolvable MNs are very sensitive to surrounding moisture; consequently, the
storage environment must be dry and cool for prolonged stability and extended storage
life [163].

7. Conclusions and Future Perspectives

Recently, nanotechnology-based transdermal drug delivery platforms have gained
renewed interest. Microneedle (MN) technology shows excellent potential in controlled
drug delivery, which has received increasing attention from investigators and clinics, as
with the transdermal patch. Cellular delivery, DNA vaccine delivery, skin penetration, local
tissue delivery and systemic delivery are enhanced with microneedles and nanoneedles.
Thus, microneedles can be manufactured with a variety of modifications to intelligently
deliver the drug through the skin, offering a new direction and revolution in the field
of transdermal drug delivery systems. This technology thus paves the way for efficient,
painless and convenient delivery of medicated drugs and vaccines.
The future of polysaccharides for MNs development depends largely on the develop-
ment of smart devices for DD, ISF and diagnostics using nanocarriers and nanostructured
polymers. Research is actively investigating the creation of MNs that detect changes in pH
or temperature or changes in temperature. The advent of nanotechnology may enable the
creation of smart diagnostic MNs. As minimally invasive devices, diagnostic MNs could
be successful in the clinic. This is an area of enormous potential and is expected to be very
popular in the future. It is imperative to emphasize that these MN devices are poised to
provide an alternative to conventional oral delivery of pharmaceuticals. Concerning the
limitations of the oral route, portability and well-known acceptability to patients must
be considered.
In conclusion, the use of elegant structures and remarkable combinations of polysac-
charides have allowed the successful delivery of different pharmacological agents using
MNs, with a series of applications in various fields of human activity. As such, biopolymer-
based MNs are playing a crucial role in modern healthcare. These are on the verge of
exciting breakthroughs in the area of DD and may announce an important contribution
to drug delivery. In a nutshell, it is anticipated that within the next few years, some
MN devices will be validated at the clinical level, taking clues from nature in everyday
DD applications.

Author Contributions: Conceptualization, F.D., N.K., S.O.E., R.B., V.G.S.S.J., A.A.S., A.A.A. and
M.B.; methodology, F.D., N.K. and M.B; software, S.O.E., R.B.; validation, N.K. and M.B., formal
analysis, A.A.S., A.A.A. and M.O.G.; investigation, F.D.; resources, F.D., N.K. and M.B.; data curation,
F.D.; writing—original draft preparation, F.D., N.K., S.O.E., R.B., V.G.S.S.J., A.A.S. and A.A.A.;
writing—review and editing, H.S.A.-m., M.Z.N., M.H.R. and M.M.A.-D.; supervision, M.B. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Pharmaceuticals 2022, 15, 190 20 of 26

Informed Consent statement:: Not applicable.

Data Availability Statement: Data sharing not applicable.
Acknowledgments: The authors wish to thank Batterjee Medical College, Saudi Arabia for financial
support in publishing this paper.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Hasnain, M.S.; Nayak, A.K. (Eds.) Natural Polysaccharides in Drug Delivery and Biomedical Applications; Elsevier: Cambridge, MA,
USA, 2019; ISBN 9780128170557.
2. Pushpamalar, J.; Meganathan, P.; Tan, H.L.; Dahlan, N.A.; Ooi, L.-T.; Neerooa, B.N.H.M.; Essa, R.Z.; Shameli, K.; Teow, S.-Y.
Development of a Polysaccharide-Based Hydrogel Drug Delivery System (DDS): An Update. Gels 2021, 7, 153. [CrossRef]
3. Sarnaik, A.; Abernathy, M.H.; Han, X.; Ouyang, Y.; Xia, K.; Chen, Y.; Cress, B.; Zhang, F.; Lali, A.; Pandit, R.; et al. Metabolic
engineering of cyanobacteria for photoautotrophic production of heparosan, a pharmaceutical precursor of heparin. Algal Res.
2019, 37, 57–63. [CrossRef]
4. Ebhodaghe, S.O. Natural Polymeric Scaffolds for Tissue Engineering Applications. J. Biomater. Sci. Polym. Ed. 2021, 32, 2144–2194.
[CrossRef] [PubMed]
5. Maxwell, E.G.; Colquhoun, I.J.; Chau, H.K.; Hotchkiss, A.T.; Waldron, K.W.; Morris, V.J.; Belshaw, N.J. Modified sugar beet pectin
induces apoptosis of colon cancer cells via an interaction with the neutral sugar side-chains. Carbohydr. Polym. 2016, 136, 923–929.
[CrossRef]
6. Kwon, M.-J.; Nam, T.-J. A polysaccharide of the marine alga Capsosiphon fulvescens induces apoptosis in AGS gastric cancer
cells via an IGF-IR-mediated PI3K/Akt pathway. Cell Biol. Int. 2007, 31, 768–775. [CrossRef]
7. Fan, L.; Li, J.; Deng, K.; Ai, L. Effects of drying methods on the antioxidant activities of polysaccharides extracted from Ganoderma
lucidum. Carbohydr. Polym. 2012, 87, 1849–1854. [CrossRef]
8. Sun, S.; Li, K.; Lei, Z.; Xiao, L.; Gao, R.; Zhang, Z. Immunomodulatory activity of polysaccharide from Helicteres angustifolia L.
on 4T1 tumor-bearing mice. Biomed. Pharmacother. 2018, 101, 881–888. [CrossRef] [PubMed]
9. Wang, Z.-J.; Xie, J.-H.; Nie, S.-P.; Xie, M.-Y. Review on cell models to evaluate the potential antioxidant activity of polysaccharides.
Food Funct. 2017, 8, 915–926. [CrossRef]
10. Kim, Y.-C.; Park, J.-H.; Prausnitz, M.R. Microneedles for drug and vaccine delivery. Adv. Drug Deliv. Rev. 2012, 64, 1547–1568.
[CrossRef]
11. Traverso, G.; Schoellhammer, C.M.; Schroeder, A.; Maa, R.; Lauwers, G.Y.; Polat, B.E.; Anderson, D.G.; Blankschtein, D.; Langer, R.
Microneedles for Drug Delivery via the Gastrointestinal Tract. J. Pharm. Sci. 2015, 104, 362–367. [CrossRef] [PubMed]
12. Chi, J.; Zhang, X.; Chen, C.; Shao, C.; Zhao, Y.; Wang, Y. Antibacterial and angiogenic chitosan microneedle array patch for
promoting wound healing. Bioact. Mater. 2020, 5, 253–259. [CrossRef]
13. Barnum, L.; Samandari, M.; Schmidt, T.A.; Tamayol, A. Microneedle arrays for the treatment of chronic wounds. Expert Opin.
Drug Deliv. 2020, 17, 1767–1780. [CrossRef] [PubMed]
14. Donnelly, R.F.; Singh, T.R.R.; Woolfson, A.D. Microneedle-based drug delivery systems: Microfabrication, drug delivery, and
safety. Drug Deliv. 2010, 17, 187–207. [CrossRef] [PubMed]
15. Larrañeta, E.; Lutton, R.E.M.; Woolfson, A.D.; Donnelly, R.F. Microneedle arrays as transdermal and intradermal drug delivery
systems: Materials science, manufacture and commercial development. Mater. Sci. Eng. R Rep. 2016, 104, 1–32. [CrossRef]
16. Tuan-Mahmood, T.-M.; McCrudden, M.T.C.; Torrisi, B.M.; McAlister, E.; Garland, M.J.; Singh, T.R.R.; Donnelly, R.F. Microneedles
for intradermal and transdermal drug delivery. Eur. J. Pharm. Sci. 2013, 50, 623–637. [CrossRef]
17. Grogan, S.P.; Dorthé, E.W.; Glembotski, N.E.; Gaul, F.; D’Lima, D.D. Cartilage tissue engineering combining microspheroid
building blocks and microneedle arrays. Connect. Tissue Res. 2020, 61, 229–243. [CrossRef] [PubMed]
18. Moldovan, N.I.; Hibino, N.; Nakayama, K. Principles of the Kenzan Method for Robotic Cell Spheroid-Based Three-Dimensional
Bioprinting. Tissue Eng. Part B Rev. 2017, 23, 237–244. [CrossRef] [PubMed]
19. Waghule, T.; Singhvi, G.; Dubey, S.K.; Pandey, M.M.; Gupta, G.; Singh, M.; Dua, K. Microneedles: A smart approach and
increasing potential for transdermal drug delivery system. Biomed. Pharmacother. 2019, 109, 1249–1258. [CrossRef] [PubMed]
20. Zhao, Z.; Chen, Y.; Shi, Y. Microneedles: A potential strategy in transdermal delivery and application in the management of
psoriasis. RSC Adv. 2020, 10, 14040–14049. [CrossRef]
21. Jung, J.H.; Jin, S.G. Microneedle for transdermal drug delivery: Current trends and fabrication. J. Pharm. Investig. 2021, 51,
503–517. [CrossRef]
22. Bhatnagar, S.; Gadeela, P.R.; Thathireddy, P.; Venuganti, V.V.K. Microneedle-based drug delivery: Materials of construction. J.
Chem. Sci. 2019, 131, 90. [CrossRef]
23. Guillot, A.J.; Cordeiro, A.S.; Donnelly, R.F.; Montesinos, M.C.; Garrigues, T.M.; Melero, A. Microneedle-Based Delivery: An
Overview of Current Applications and Trends. Pharmaceutics 2020, 12, 569. [CrossRef]
24. Mdanda, S.; Ubanako, P.; Kondiah, P.P.D.; Kumar, P.; Choonara, Y.E. Recent Advances in Microneedle Platforms for Transdermal
Drug Delivery Technologies. Polymers 2021, 13, 2405. [CrossRef] [PubMed]
Pharmaceuticals 2022, 15, 190 21 of 26

25. Wang, K.; Liu, M.; Mo, R. Polysaccharide-Based Biomaterials for Protein Delivery. Med. Drug Discov. 2020, 7, 100031. [CrossRef]
26. Bhadale, R.S.; Londhe, V.Y. A systematic review of carbohydrate-based microneedles: Current status and future prospects. J.
Mater. Sci. Mater. Med. 2021, 32, 89. [CrossRef]
27. Williams, A.C.; Barry, B.W. Penetration enhancers. Adv. Drug Deliv. Rev. 2012, 64, 128–137. [CrossRef]
28. Khanna, P.; Luongo, K.; Strom, J.A.; Bhansali, S. Sharpening of hollow silicon microneedles to reduce skin penetration force. J.
Micromech. Microeng. 2010, 20, 045011. [CrossRef]
29. Li, J.; Liu, B.; Zhou, Y.; Chen, Z.; Jiang, L.; Yuan, W.; Liang, L. Fabrication of a Ti porous microneedle array by metal injection
molding for transdermal drug delivery. PLoS ONE 2017, 12, e0172043. [CrossRef] [PubMed]
30. Ginebra, M.P.; Traykova, T.; Planell, J.A. Calcium phosphate cements as bone drug delivery systems: A review. J. Control. Release
2006, 113, 102–110. [CrossRef]
31. Bystrova, S.; Luttge, R. Micromolding for ceramic microneedle arrays. Microelectron. Eng. 2011, 88, 1681–1684. [CrossRef]
32. Wang, P.M.; Cornwell, M.; Hill, J.; Prausnitz, M.R. Precise Microinjection into Skin Using Hollow Microneedles. J. Investig.
Dermatol. 2006, 126, 1080–1087. [CrossRef]
33. Donnelly, R.F.; Morrow, D.I.J.; Singh, T.R.R.; Migalska, K.; McCarron, P.A.; O’Mahony, C.; Woolfson, A.D. Processing difficulties
and instability of carbohydrate microneedle arrays. Drug Dev. Ind. Pharm. 2009, 35, 1242–1254. [CrossRef] [PubMed]
34. Miyano, T.; Tobinaga, Y.; Kanno, T.; Matsuzaki, Y.; Takeda, H.; Wakui, M.; Hanada, K. Sugar Micro Needles as Transdermic Drug
Delivery System. Biomed. Microdevices 2005, 7, 185–188. [CrossRef] [PubMed]
35. Yalcintas, E.P.; Ackerman, D.S.; Korkmaz, E.; Telmer, C.A.; Jarvik, J.W.; Campbell, P.G.; Bruchez, M.P.; Ozdoganlar, O.B. Analysis
of In Vitro Cytotoxicity of Carbohydrate-Based Materials Used for Dissolvable Microneedle Arrays. Pharm. Res. 2020, 37, 33.
[CrossRef] [PubMed]
36. Yuan, W.; Hong, X.; Wu, Z.; Chen, L.; Liu, Z.; Wu, F.; Wei, L. Dissolving and biodegradable microneedle technologies for
transdermal sustained delivery of drug and vaccine. Drug Des. Devel. Ther. 2013, 7, 945. [CrossRef]
37. Nguyen, H.X.; Bozorg, B.D.; Kim, Y.; Wieber, A.; Birk, G.; Lubda, D.; Banga, A.K. Poly (vinyl alcohol) microneedles: Fabrication,
characterization, and application for transdermal drug delivery of doxorubicin. Eur. J. Pharm. Biopharm. 2018, 129, 88–103.
[CrossRef] [PubMed]
38. Donnelly, R.F.; Singh, T.R.R.; Alkilani, A.Z.; McCrudden, M.T.C.; O’Neill, S.; O’Mahony, C.; Armstrong, K.; McLoone, N.; Kole, P.;
Woolfson, A.D. Hydrogel-forming microneedle arrays exhibit antimicrobial properties: Potential for enhanced patient safety. Int.
J. Pharm. 2013, 451, 76–91. [CrossRef]
39. Migdadi, E.M.; Courtenay, A.J.; Tekko, I.A.; McCrudden, M.T.C.; Kearney, M.-C.; McAlister, E.; McCarthy, H.O.; Donnelly, R.F.
Hydrogel-forming microneedles enhance transdermal delivery of metformin hydrochloride. J. Control. Release 2018, 285, 142–151.
[CrossRef]
40. Donnelly, R.F.; Majithiya, R.; Singh, T.R.R.; Morrow, D.I.J.; Garland, M.J.; Demir, Y.K.; Migalska, K.; Ryan, E.; Gillen, D.; Scott,
C.J.; et al. Design, Optimization and Characterisation of Polymeric Microneedle Arrays Prepared by a Novel Laser-Based
Micromoulding Technique. Pharm. Res. 2011, 28, 41–57. [CrossRef]
41. Park, J.-H.; Allen, M.G.; Prausnitz, M.R. Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug
delivery. J. Control. Release 2005, 104, 51–66. [CrossRef] [PubMed]
42. McAllister, D.V.; Wang, P.M.; Davis, S.P.; Park, J.-H.; Canatella, P.J.; Allen, M.G.; Prausnitz, M.R. Microfabricated needles for
transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies. Proc. Natl. Acad. Sci. USA
2003, 100, 13755–13760. [CrossRef] [PubMed]
43. Yung, K.L.; Xu, Y.; Kang, C.; Liu, H.; Tam, K.F.; Ko, S.M.; Kwan, F.Y.; Lee, T.M.H. Sharp tipped plastic hollow microneedle array
by microinjection moulding. J. Micromech. Microeng. 2012, 22, 015016. [CrossRef]
44. Ashraf, M.W.; Tayyaba, S.; Afzulpurkar, N. Micro Electromechanical Systems (MEMS) Based Microfluidic Devices for Biomedical
Applications. Int. J. Mol. Sci. 2011, 12, 3648–3704. [CrossRef]
45. Donnelly, R.F.; Singh, T.R.R.; Garland, M.J.; Migalska, K.; Majithiya, R.; McCrudden, C.M.; Kole, P.L.; Mahmood, T.M.T.; McCarthy,
H.O.; Woolfson, A.D. Hydrogel-Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery. Adv. Funct. Mater. 2012,
22, 4879–4890. [CrossRef]
46. Lee, J.W.; Park, J.-H.; Prausnitz, M.R. Dissolving microneedles for transdermal drug delivery. Biomaterials 2008, 29, 2113–2124.
[CrossRef]
47. Banga, A.K. Microporation applications for enhancing drug delivery. Expert Opin. Drug Deliv. 2009, 6, 343–354. [CrossRef]
[PubMed]
48. Davidson, A.; Al-Qallaf, B.; Das, D.B. Transdermal drug delivery by coated microneedles: Geometry effects on effective skin
thickness and drug permeability. Chem. Eng. Res. Des. 2008, 86, 1196–1206. [CrossRef]
49. Chen, M.-C.; Ling, M.-H.; Lai, K.-Y.; Pramudityo, E. Chitosan Microneedle Patches for Sustained Transdermal Delivery of
Macromolecules. Biomacromolecules 2012, 13, 4022–4031. [CrossRef]
50. Banks, S.L.; Pinninti, R.R.; Gill, H.S.; Paudel, K.S.; Crooks, P.A.; Brogden, N.K.; Prausnitz, M.R.; Stinchcomb, A.L. Transdermal
Delivery of Naltrexol and Skin Permeability Lifetime after Microneedle Treatment in Hairless Guinea Pigs. J. Pharm. Sci. 2010, 99,
3072–3080. [CrossRef]
51. Martanto, W.; Davis, S.P.; Holiday, N.R.; Wang, J.; Gill, H.S.; Prausnitz, M.R. Transdermal Delivery of Insulin Using Microneedles
in Vivo. Pharm. Res. 2004, 21, 947–952. [CrossRef]
Pharmaceuticals 2022, 15, 190 22 of 26

52. Gill, H.S.; Prausnitz, M.R. Coating Formulations for Microneedles. Pharm. Res. 2007, 24, 1369–1380. [CrossRef]
53. Shakya, A.K.; Ingrole, R.S.J.; Joshi, G.; Uddin, M.J.; Anvari, S.; Davis, C.M.; Gill, H.S. Microneedles coated with peanut allergen
enable desensitization of peanut sensitized mice. J. Control. Release 2019, 314, 38–47. [CrossRef] [PubMed]
54. Nejad, H.R.; Sadeqi, A.; Kiaee, G.; Sonkusale, S. Low-cost and cleanroom-free fabrication of microneedles. Microsyst. Nanoeng.
2018, 4, 17073. [CrossRef]
55. Wilke, M.S.; Lovering, A.L.; Strynadka, N.C. β-Lactam antibiotic resistance: A current structural perspective. Curr. Opin. Microbiol.
2005, 8, 525–533. [CrossRef] [PubMed]
56. Indermun, S.; Luttge, R.; Choonara, Y.E.; Kumar, P.; du Toit, L.C.; Modi, G.; Pillay, V. Current advances in the fabrication of
microneedles for transdermal delivery. J. Control. Release 2014, 185, 130–138. [CrossRef]
57. Yang, M.; Zahn, J.D. Microneedle Insertion Force Reduction Using Vibratory Actuation. Biomed. Microdevices 2004, 6, 177–182.
[CrossRef]
58. Wilke, N.; Mulcahy, A.; Ye, S.-R.; Morrissey, A. Process optimization and characterization of silicon microneedles fabricated by
wet etch technology. Microelectron. J. 2005, 36, 650–656. [CrossRef]
59. Pere, C.P.P.; Economidou, S.N.; Lall, G.; Ziraud, C.; Boateng, J.S.; Alexander, B.D.; Lamprou, D.A.; Douroumis, D. 3D printed
microneedles for insulin skin delivery. Int. J. Pharm. 2018, 544, 425–432. [CrossRef]
60. Asghar, W.; Li, F.; Zhou, Y.; Wu, Y.; Yu, Z.; Li, S.; Tang, D.; Han, X.; Shang, J.; Liu, Y.; et al. Piezocapacitive Flexible E-Skin Pressure
Sensors Having Magnetically Grown Microstructures. Adv. Mater. Technol. 2020, 5, 1900934. [CrossRef]
61. Melchels, F.P.W.; Feijen, J.; Grijpma, D.W. A review on stereolithography and its applications in biomedical engineering.
Biomaterials 2010, 31, 6121–6130. [CrossRef]
62. Dharadhar, S.; Majumdar, A.; Dhoble, S.; Patravale, V. Microneedles for transdermal drug delivery: A systematic review. Drug
Dev. Ind. Pharm. 2019, 45, 188–201. [CrossRef] [PubMed]
63. Krieger, K.J.; Bertollo, N.; Dangol, M.; Sheridan, J.T.; Lowery, M.M.; O’Cearbhaill, E.D. Simple and customizable method for
fabrication of high-aspect ratio microneedle molds using low-cost 3D printing. Microsyst. Nanoeng. 2019, 5, 42. [CrossRef]
64. Schmidleithner, C.; Kalaskar, D.M. Stereolithography. In 3D Printing; InTech: London, UK, 2018.
65. Johnson, A.R.; Caudill, C.L.; Tumbleston, J.R.; Bloomquist, C.J.; Moga, K.A.; Ermoshkin, A.; Shirvanyants, D.; Mecham, S.J.;
Luft, J.C.; DeSimone, J.M. Single-Step Fabrication of Computationally Designed Microneedles by Continuous Liquid Interface
Production. PLoS ONE 2016, 11, e0162518. [CrossRef] [PubMed]
66. Ito, Y.; Yoshimitsu, J.-I.; Shiroyama, K.; Sugioka, N.; Takada, K. Self-dissolving microneedles for the percutaneous absorption of
EPO in mice. J. Drug Target. 2006, 14, 255–261. [CrossRef] [PubMed]
67. Balmert, S.C.; Carey, C.D.; Falo, G.D.; Sethi, S.K.; Erdos, G.; Korkmaz, E.; Falo, L.D. Dissolving undercut microneedle arrays for
multicomponent cutaneous vaccination. J. Control. Release 2020, 317, 336–346. [CrossRef] [PubMed]
68. Park, S.-H.; Yang, D.-Y.; Lee, K.-S. Two-photon stereolithography for realizing ultraprecise three-dimensional nano/microdevices.
Laser Photon. Rev. 2009, 3, 1–11. [CrossRef]
69. Du, G.; Zhang, Z.; He, P.; Zhang, Z.; Sun, X. Determination of the mechanical properties of polymeric microneedles by
micromanipulation. J. Mech. Behav. Biomed. Mater. 2021, 117, 104384. [CrossRef]
70. Chi, Y.; Huang, Y.; Kang, Y.; Dai, G.; Liu, Z.; Xu, K.; Zhong, W. The effects of molecular weight of hyaluronic acid on transdermal
delivery efficiencies of dissolving microneedles. Eur. J. Pharm. Sci. 2022, 168, 106075. [CrossRef]
71. Ma, G.J.; Shi, L.T.; Wu, C.W. Biomechanical Property of a Natural Microneedle: The Caterpillar Spine. J. Med. Device 2011,
5, 034502. [CrossRef]
72. Yang, J.; Liu, X.; Fu, Y.; Song, Y. Recent advances of microneedles for biomedical applications: Drug delivery and beyond. Acta
Pharm. Sin. B 2019, 9, 469–483. [CrossRef]
73. Aldawood, F.K.; Andar, A.; Desai, S. A Comprehensive Review of Microneedles: Types, Materials, Processes, Characterizations
and Applications. Polymers 2021, 13, 2815. [CrossRef] [PubMed]
74. Ita, K. Transdermal Delivery of Drugs with Microneedles—Potential and Challenges. Pharmaceutics 2015, 7, 90–105. [CrossRef]
[PubMed]
75. Qiu, Y.; Gao, Y.; Hu, K.; Li, F. Enhancement of skin permeation of docetaxel: A novel approach combining microneedle and elastic
liposomes. J. Control. Release 2008, 129, 144–150. [CrossRef]
76. Naguib, Y.W.; Kumar, A.; Cui, Z. The effect of microneedles on the skin permeability and antitumor activity of topical 5-
fluorouracil. Acta Pharm. Sin. B 2014, 4, 94–99. [CrossRef]
77. Zandi, A.; Khayamian, M.A.; Saghafi, M.; Shalileh, S.; Katebi, P.; Assadi, S.; Gilani, A.; Salemizadeh Parizi, M.; Vanaei, S.;
Esmailinejad, M.R.; et al. Microneedle-Based Generation of Microbubbles in Cancer Tumors to Improve Ultrasound-Assisted
Drug Delivery. Adv. Healthc. Mater. 2019, 8, 1900613. [CrossRef]
78. Tham, H.P.; Xu, K.; Lim, W.Q.; Chen, H.; Zheng, M.; Thng, T.G.S.; Venkatraman, S.S.; Xu, C.; Zhao, Y. Microneedle-Assisted
Topical Delivery of Photodynamically Active Mesoporous Formulation for Combination Therapy of Deep-Seated Melanoma.
ACS Nano 2018, 12, 11936–11948. [CrossRef]
79. Uddin, M.J.; Scoutaris, N.; Klepetsanis, P.; Chowdhry, B.; Prausnitz, M.R.; Douroumis, D. Inkjet printing of transdermal
microneedles for the delivery of anticancer agents. Int. J. Pharm. 2015, 494, 593–602. [CrossRef]
80. Ma, Y.; Boese, S.E.; Luo, Z.; Nitin, N.; Gill, H.S. Drug coated microneedles for minimally-invasive treatment of oral carcinomas:
Development and in vitro evaluation. Biomed. Microdevices 2015, 17, 44. [CrossRef]
Pharmaceuticals 2022, 15, 190 23 of 26

81. Ruan, W.; Zhai, Y.; Yu, K.; Wu, C.; Xu, Y. Coated microneedles mediated intradermal delivery of octaarginine/BRAF siRNA
nanocomplexes for anti-melanoma treatment. Int. J. Pharm. 2018, 553, 298–309. [CrossRef]
82. Duong, H.T.T.; Yin, Y.; Thambi, T.; Nguyen, T.L.; Giang Phan, V.H.; Lee, M.S.; Lee, J.E.; Kim, J.; Jeong, J.H.; Lee, D.S. Smart vaccine
delivery based on microneedle arrays decorated with ultra-pH-responsive copolymers for cancer immunotherapy. Biomaterials
2018, 185, 13–24. [CrossRef] [PubMed]
83. Mansoor, I.; Lai, J.; Ranamukhaarachchi, S.; Schmitt, V.; Lambert, D.; Dutz, J.; Häfeli, U.O.; Stoeber, B. A microneedle-based
method for the characterization of diffusion in skin tissue using doxorubicin as a model drug. Biomed. Microdevices 2015, 17, 61.
[CrossRef] [PubMed]
84. Jung, Y.S.; Koo, D.-H.; Yang, J.-Y.; Lee, H.-Y.; Park, J.-H.; Park, J.H. Peri-tumor administration of 5-fluorouracil sol-gel using a
hollow microneedle for treatment of gastric cancer. Drug Deliv. 2018, 25, 872–879. [CrossRef]
85. Tang, T.; Deng, Y.; Chen, J.; Zhao, Y.; Yue, R.; Choy, K.W.; Wang, C.C.; Du, Q.; Xu, Y.; Han, L.; et al. Local administration of siRNA
through Microneedle: Optimization, Bio-distribution, Tumor Suppression and Toxicity. Sci. Rep. 2016, 6, 30430. [CrossRef]
86. Ingrole, R.S.J.; Gill, H.S. Microneedle Coating Methods: A Review with a Perspective. J. Pharmacol. Exp. Ther. 2019, 370, 555–569.
[CrossRef]
87. Lan, X.; She, J.; Lin, D.; Xu, Y.; Li, X.; Yang, W.; Lui, V.W.Y.; Jin, L.; Xie, X.; Su, Y. Microneedle-Mediated Delivery of Lipid-Coated
Cisplatin Nanoparticles for Efficient and Safe Cancer Therapy. ACS Appl. Mater. Interfaces 2018, 10, 33060–33069. [CrossRef]
[PubMed]
88. Kim, N.W.; Kim, S.-Y.; Lee, J.E.; Yin, Y.; Lee, J.H.; Lim, S.Y.; Kim, E.S.; Duong, H.T.T.; Kim, H.K.; Kim, S.; et al. Enhanced Cancer
Vaccination by In Situ Nanomicelle-Generating Dissolving Microneedles. ACS Nano 2018, 12, 9702–9713. [CrossRef]
89. Peng, K.; Vora, L.K.; Domínguez-Robles, J.; Naser, Y.A.; Li, M.; Larrañeta, E.; Donnelly, R.F. Hydrogel-forming microneedles for
rapid and efficient skin deposition of controlled release tip-implants. Mater. Sci. Eng. C 2021, 127, 112226. [CrossRef] [PubMed]
90. Turner, J.G.; White, L.R.; Estrela, P.; Leese, H.S. Hydrogel-Forming Microneedles: Current Advancements and Future Trends.
Macromol. Biosci. 2021, 21, 2000307. [CrossRef]
91. Garland, M.J.; Caffarel–Salvador, E.; Migalska, K.; Woolfson, A.D.; Donnelly, R.F. Dissolving polymeric microneedle arrays for
electrically assisted transdermal drug delivery. J. Control. Release 2012, 159, 52–59. [CrossRef]
92. Mansoor, I.; Liu, Y.; Häfeli, U.O.; Stoeber, B. Arrays of hollow out-of-plane microneedles made by metal electrodeposition onto
solvent cast conductive polymer structures. J. Micromech. Microeng. 2013, 23, 085011. [CrossRef]
93. Cormier, M.; Johnson, B.; Ameri, M.; Nyam, K.; Libiran, L.; Zhang, D.D.; Daddona, P. Transdermal delivery of desmopressin
using a coated microneedle array patch system. J. Control. Release 2004, 97, 503–511. [CrossRef]
94. Chong, R.H.E.; Gonzalez-Gonzalez, E.; Lara, M.F.; Speaker, T.J.; Contag, C.H.; Kaspar, R.L.; Coulman, S.A.; Hargest, R.; Birchall,
J.C. Gene silencing following siRNA delivery to skin via coated steel microneedles: In vitro and in vivo proof-of-concept. J.
Control. Release 2013, 166, 211–219. [CrossRef]
95. Gill, H.S.; Prausnitz, M.R. Coated microneedles for transdermal delivery. J. Control. Release 2007, 117, 227–237. [CrossRef]
96. Boehm, R.D.; Daniels, J.; Stafslien, S.; Nasir, A.; Lefebvre, J.; Narayan, R.J. Polyglycolic acid microneedles modified with
inkjet-deposited antifungal coatings. Biointerphases 2015, 10, 011004. [CrossRef]
97. Donnelly, R.F.; McCrudden, M.T.C.; Zaid Alkilani, A.; Larrañeta, E.; McAlister, E.; Courtenay, A.J.; Kearney, M.-C.; Singh, T.R.R.;
McCarthy, H.O.; Kett, V.L.; et al. Hydrogel-Forming Microneedles Prepared from “Super Swelling” Polymers Combined with
Lyophilised Wafers for Transdermal Drug Delivery. PLoS ONE 2014, 9, e111547. [CrossRef]
98. Jamaledin, R.; Yiu, C.K.Y.; Zare, E.N.; Niu, L.; Vecchione, R.; Chen, G.; Gu, Z.; Tay, F.R.; Makvandi, P. Advances in Antimicrobial
Microneedle Patches for Combating Infections. Adv. Mater. 2020, 32, 2002129. [CrossRef] [PubMed]
99. Caffarel-Salvador, E.; Brady, A.J.; Eltayib, E.; Meng, T.; Alonso-Vicente, A.; Gonzalez-Vazquez, P.; Torrisi, B.M.; Vicente-Perez,
E.M.; Mooney, K.; Jones, D.S.; et al. Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose In Vivo:
Potential for Use in Diagnosis and Therapeutic Drug Monitoring. PLoS ONE 2015, 10, e0145644. [CrossRef]
100. Wermeling, D.P.; Banks, S.L.; Hudson, D.A.; Gill, H.S.; Gupta, J.; Prausnitz, M.R.; Stinchcomb, A.L. Microneedles permit
transdermal delivery of a skin-impermeant medication to humans. Proc. Natl. Acad. Sci. USA 2008, 105, 2058–2063. [CrossRef]
101. Alkilani, A.; McCrudden, M.T.; Donnelly, R. Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on
Disruption of the Barrier Properties of the Stratum Corneum. Pharmaceutics 2015, 7, 438–470. [CrossRef]
102. Liu, Z.; Jiao, Y.; Wang, Y.; Zhou, C.; Zhang, Z. Polysaccharides-based nanoparticles as drug delivery systems. Adv. Drug Deliv.
Rev. 2008, 60, 1650–1662. [CrossRef] [PubMed]
103. Damiri, F.; Bachra, Y.; Bounacir, C.; Laaraibi, A.; Berrada, M. Synthesis and Characterization of Lyophilized Chitosan-Based
Hydrogels Cross-Linked with Benzaldehyde for Controlled Drug Release. J. Chem. 2020, 2020, 8747639. [CrossRef]
104. Fonseca, D.F.S.; Vilela, C.; Silvestre, A.J.D.; Freire, C.S.R. A compendium of current developments on polysaccharide and
protein-based microneedles. Int. J. Biol. Macromol. 2019, 136, 704–728. [CrossRef]
105. Yadav, H.; Karthikeyan, C. Natural polysaccharides: Structural features and properties. In Polysaccharide Carriers for Drug Delivery;
Elsevier: Amsterdam, The Netherlands, 2019; pp. 1–17.
106. Dicker, K.T.; Gurski, L.A.; Pradhan-Bhatt, S.; Witt, R.L.; Farach-Carson, M.C.; Jia, X. Hyaluronan: A simple polysaccharide with
diverse biological functions. Acta Biomater. 2014, 10, 1558–1570. [CrossRef]
107. Zhai, P.; Peng, X.; Li, B.; Liu, Y.; Sun, H.; Li, X. The application of hyaluronic acid in bone regeneration. Int. J. Biol. Macromol. 2020,
151, 1224–1239. [CrossRef] [PubMed]
Pharmaceuticals 2022, 15, 190 24 of 26

108. Saha, I.; Rai, V.K. Hyaluronic acid based microneedle array: Recent applications in drug delivery and cosmetology. Carbohydr.
Polym. 2021, 267, 118168. [CrossRef]
109. Liu, S.; Jin, M.; Quan, Y.; Kamiyama, F.; Katsumi, H.; Sakane, T.; Yamamoto, A. The development and characteristics of novel
microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin. J. Control. Release
2012, 161, 933–941. [CrossRef] [PubMed]
110. Du, H.; Liu, P.; Zhu, J.; Lan, J.; Li, Y.; Zhang, L.; Zhu, J.; Tao, J. Hyaluronic Acid-Based Dissolving Microneedle Patch Loaded with
Methotrexate for Improved Treatment of Psoriasis. ACS Appl. Mater. Interfaces 2019, 11, 43588–43598. [CrossRef]
111. Liu, S.; Jin, M.; Quan, Y.; Kamiyama, F.; Kusamori, K.; Katsumi, H.; Sakane, T.; Yamamoto, A. Transdermal delivery of
relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their
characteristics and safety after application to the skin. Eur. J. Pharm. Biopharm. 2014, 86, 267–276. [CrossRef] [PubMed]
112. Zhu, J.; Dong, L.; Du, H.; Mao, J.; Xie, Y.; Wang, H.; Lan, J.; Lou, Y.; Fu, Y.; Wen, J.; et al. 5-Aminolevulinic Acid-Loaded Hyaluronic
Acid Dissolving Microneedles for Effective Photodynamic Therapy of Superficial Tumors with Enhanced Long-Term Stability.
Adv. Healthc. Mater. 2019, 8, 1900896. [CrossRef] [PubMed]
113. Xu, Q.; Li, X.; Zhang, P.; Wang, Y. Rapidly dissolving microneedle patch for synergistic gene and photothermal therapy of
subcutaneous tumor. J. Mater. Chem. B 2020, 8, 4331–4339. [CrossRef] [PubMed]
114. Hao, Y.; Chen, Y.; He, X.; Yang, F.; Han, R.; Yang, C.; Li, W.; Qian, Z. Near-infrared responsive 5-fluorouracil and indocyanine
green loaded MPEG-PCL nanoparticle integrated with dissolvable microneedle for skin cancer therapy. Bioact. Mater. 2020, 5,
542–552. [CrossRef] [PubMed]
115. Hao, Y.; Li, W.; Zhou, X.; Yang, F.; Qian, Z. Microneedles-Based Transdermal Drug Delivery Systems: A Review. J. Biomed.
Nanotechnol. 2017, 13, 1581–1597. [CrossRef] [PubMed]
116. Abdallah, M.M.; Fernández, N.; Matias, A.A.; do Rosário Bronze, M. Hyaluronic acid and Chondroitin sulfate from marine and
terrestrial sources: Extraction and purification methods. Carbohydr. Polym. 2020, 243, 116441. [CrossRef] [PubMed]
117. Fukushima, K.; Ise, A.; Morita, H.; Hasegawa, R.; Ito, Y.; Sugioka, N.; Takada, K. Two-Layered Dissolving Microneedles for
Percutaneous Delivery of Peptide/Protein Drugs in Rats. Pharm. Res. 2011, 28, 7–21. [CrossRef] [PubMed]
118. Liu, S.; Zhang, S.; Duan, Y.; Niu, Y.; Gu, H.; Zhao, Z.; Zhang, S.; Yang, Y.; Wang, X.; Gao, Y.; et al. Transcutaneous immunization
of recombinant Staphylococcal enterotoxin B protein using a dissolving microneedle provides potent protection against lethal
enterotoxin challenge. Vaccine 2019, 37, 3810–3819. [CrossRef] [PubMed]
119. Shokri, J.; Adibki, K. Application of Cellulose and Cellulose Derivatives in Pharmaceutical Industries. In Cellulose—Medical,
Pharmaceutical and Electronic Applications; InTech: London, UK, 2013.
120. Falo, L.D., Jr.; Geza, E.; Burak, O. Microneedle Arrays for Cancer Therapy Applications. US Patent 20160136407A1, 19 May 2016.
121. Lan, X.; Zhu, W.; Huang, X.; Yu, Y.; Xiao, H.; Jin, L.; Pu, J.J.; Xie, X.; She, J.; Lui, V.W.Y.; et al. Microneedles loaded with
anti-PD-1–cisplatin nanoparticles for synergistic cancer immuno-chemotherapy. Nanoscale 2020, 12, 18885–18898. [CrossRef]
122. Seetharam, A.A.; Choudhry, H.; Bakhrebah, M.A.; Abdulaal, W.H.; Gupta, M.S.; Rizvi, S.M.D.; Alam, Q.; Gowda, D.V.; Moin, A.
Microneedles Drug Delivery Systems for Treatment of Cancer: A Recent Update. Pharmaceutics 2020, 12, 1101. [CrossRef]
123. Ye, C.; Zhang, R. Semiconductor Microneedle Assembly Based on Gene Therapy, Manufacturing Method and Manufacturing
Mold. CN Patent 106426729A, 22 February 2017.
124. Park, Y.-H.; Ha, S.K.; Choi, I.; Kim, K.S.; Park, J.; Choi, N.; Kim, B.; Sung, J.H. Fabrication of degradable carboxymethyl cellulose
(CMC) microneedle with laser writing and replica molding process for enhancement of transdermal drug delivery. Biotechnol.
Bioprocess Eng. 2016, 21, 110–118. [CrossRef]
125. Fonseca, D.F.S.; Vilela, C.; Pinto, R.J.B.; Bastos, V.; Oliveira, H.; Catarino, J.; Faísca, P.; Rosado, C.; Silvestre, A.J.D.; Freire, C.S.R.
Bacterial nanocellulose-hyaluronic acid microneedle patches for skin applications: In vitro and in vivo evaluation. Mater. Sci.
Eng. C 2021, 118, 111350. [CrossRef]
126. Fouad, D.; Bachra, Y.; Ayoub, G.; Ouaket, A.; Bennamara, A.; Knouzi, N.; Berrada, M. A Novel Drug Delivery System Based
on Nanoparticles of Magnetite Fe3 O4 Embedded in an Auto Cross-Linked Chitosan. In Chitin and Chitosan—Physicochemical
Properties and Industrial Applications; IntechOpen: London, UK, 2020.
127. Laaraibi, A.; Moughaoui, F.; Damiri, F.; Ouakit, A.; Charhouf, I.; Hamdouch, S.; Jaafari, A.; Abourriche, A.; Knouzi, N.; Bennamara,
A.; et al. Chitosan-Clay Based (CS-NaBNT) Biodegradable Nanocomposite Films for Potential Utility in Food and Environment.
In Chitin-Chitosan—Myriad Functionalities in Science and Technology; IntechOpen: London, UK, 2018.
128. Chen, M.-C.; Huang, S.-F.; Lai, K.-Y.; Ling, M.-H. Fully embeddable chitosan microneedles as a sustained release depot for
intradermal vaccination. Biomaterials 2013, 34, 3077–3086. [CrossRef]
129. Moreira, A.F.; Rodrigues, C.F.; Jacinto, T.A.; Miguel, S.P.; Costa, E.C.; Correia, I.J. Poly (vinyl alcohol)/chitosan layer-by-layer
microneedles for cancer chemo-photothermal therapy. Int. J. Pharm. 2020, 576, 118907. [CrossRef] [PubMed]
130. Ahmad, Z.; Khan, M.I.; Siddique, M.I.; Sarwar, H.S.; Shahnaz, G.; Hussain, S.Z.; Bukhari, N.I.; Hussain, I.; Sohail, M.F. Fabrication
and Characterization of Thiolated Chitosan Microneedle Patch for Transdermal Delivery of Tacrolimus. AAPS PharmSciTech 2020,
21, 68. [CrossRef]
131. Chandrasekharan, A.; Hwang, Y.J.; Seong, K.-Y.; Park, S.; Kim, S.; Yang, S.Y. Acid-Treated Water-Soluble Chitosan Suitable for
Microneedle-Assisted Intracutaneous Drug Delivery. Pharmaceutics 2019, 11, 209. [CrossRef]
132. Zhang, Y.; Wu, M.; Tan, D.; Liu, Q.; Xia, R.; Chen, M.; Liu, Y.; Xue, L.; Lei, Y. A dissolving and glucose-responsive insulin-releasing
microneedle patch for type 1 diabetes therapy. J. Mater. Chem. B 2021, 9, 648–657. [CrossRef]
Pharmaceuticals 2022, 15, 190 25 of 26

133. Pineda-Álvarez, R.A.; Bernad-Bernad, M.J.; Rodríguez-Cruz, I.M.; Escobar-Chávez, J.J. Development and Characterization of
Starch/Gelatin Microneedle Arrays Loaded with Lecithin–Gelatin Nanoparticles of Losartan for Transdermal Delivery. J. Pharm.
Innov. 2020. [CrossRef]
134. Serrano-Castañeda, P.; Escobar-Chavez, J.J.; Rodriguez-cruz, I.M.; Melgoza, L.M.; Martinez-Hernandez, J. Microneedles as
Enhancer of Drug Absorption Through the Skin and Applications in Medicine and Cosmetology. J. Pharm. Pharm. Sci. 2018, 21,
73–93. [CrossRef] [PubMed]
135. Boucelkha, A.; Petit, E.; Elboutachfaiti, R.; Molinié, R.; Amari, S.; Yahaoui, R.Z. Production of guluronate oligosaccharide of
alginate from brown algae Stypocaulon scoparium using an alginate lyase. J. Appl. Phycol. 2017, 29, 509–519. [CrossRef]
136. Demir, Y.K.; Akan, Z.; Kerimoglu, O. Sodium Alginate Microneedle Arrays Mediate the Transdermal Delivery of Bovine Serum
Albumin. PLoS ONE 2013, 8, e63819. [CrossRef]
137. Zhang, Y.; Jiang, G.; Yu, W.; Liu, D.; Xu, B. Microneedles fabricated from alginate and maltose for transdermal delivery of insulin
on diabetic rats. Mater. Sci. Eng. C 2018, 85, 18–26. [CrossRef] [PubMed]
138. Bonfante, G.; Lee, H.; Bao, L.; Park, J.; Takama, N.; Kim, B. Comparison of polymers to enhance mechanical properties of
microneedles for bio-medical applications. Micro Nano Syst. Lett. 2020, 8, 13. [CrossRef]
139. Kim, Y.-C.; Quan, F.-S.; Compans, R.W.; Kang, S.-M.; Prausnitz, M.R. Formulation of Microneedles Coated with Influenza
Virus-like Particle Vaccine. AAPS PharmSciTech 2010, 11, 1193–1201. [CrossRef] [PubMed]
140. Choi, H.-J.; Song, J.-M.; Bondy, B.J.; Compans, R.W.; Kang, S.-M.; Prausnitz, M.R. Effect of Osmotic Pressure on the Stability of
Whole Inactivated Influenza Vaccine for Coating on Microneedles. PLoS ONE 2015, 10, e0134431. [CrossRef]
141. Singh, R.S.; Saini, G.K.; Kennedy, J.F. Pullulan: Microbial sources, production and applications. Carbohydr. Polym. 2008, 73,
515–531. [CrossRef] [PubMed]
142. Fonseca, D.F.S.; Costa, P.C.; Almeida, I.F.; Dias-Pereira, P.; Correia-Sá, I.; Bastos, V.; Oliveira, H.; Duarte-Araújo, M.; Morato,
M.; Vilela, C.; et al. Pullulan microneedle patches for the efficient transdermal administration of insulin envisioning diabetes
treatment. Carbohydr. Polym. 2020, 241, 116314. [CrossRef]
143. Chen, Z.; Cheng, L.; He, Y.; Wei, X. Extraction, characterization, utilization as wound dressing and drug delivery of Bletilla striata
polysaccharide: A review. Int. J. Biol. Macromol. 2018, 120, 2076–2085. [CrossRef]
144. Peng, Q.; Li, M.; Xue, F.; Liu, H. Structure and immunobiological activity of a new polysaccharide from Bletilla striata. Carbohydr.
Polym. 2014, 107, 119–123. [CrossRef] [PubMed]
145. Chen, Z.; Zhao, Y.; Zhang, M.; Yang, X.; Yue, P.; Tang, D.; Wei, X. Structural characterization and antioxidant activity of a new
polysaccharide from Bletilla striata fibrous roots. Carbohydr. Polym. 2020, 227, 115362. [CrossRef] [PubMed]
146. Hu, L.; Liao, Z.; Hu, Q.; Maffucci, K.G.; Qu, Y. Novel Bletilla striata polysaccharide microneedles: Fabrication, characterization,
and in vitro transcutaneous drug delivery. Int. J. Biol. Macromol. 2018, 117, 928–936. [CrossRef]
147. Xu, D.; Pan, Y.; Chen, J. Chemical Constituents, Pharmacologic Properties, and Clinical Applications of Bletilla striata. Front.
Pharmacol. 2019, 10, 10. [CrossRef]
148. Wang, C.; Liu, S.; Xu, J.; Gao, M.; Qu, Y.; Liu, Y.; Yang, Y.; Cui, X. Dissolvable microneedles based on Panax notoginseng
polysaccharide for transdermal drug delivery and skin dendritic cell activation. Carbohydr. Polym. 2021, 268, 118211. [CrossRef]
[PubMed]
149. Sadeqi, A.; Nejad, H.R.; Kiaee, G.; Sonkusale, S. Cost-effective Fabrication of Chitosan Microneedles for Transdermal Drug
Delivery. In Proceedings of the 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology
Society (EMBC), Honolulu, HI, USA, 17–21 July 2018; pp. 5737–5740.
150. Schipper, P.; van der Maaden, K.; Groeneveld, V.; Ruigrok, M.; Romeijn, S.; Uleman, S.; Oomens, C.; Kersten, G.; Jiskoot, W.;
Bouwstra, J. Diphtheria toxoid and N -trimethyl chitosan layer-by-layer coated pH-sensitive microneedles induce potent immune
responses upon dermal vaccination in mice. J. Control. Release 2017, 262, 28–36. [CrossRef] [PubMed]
151. Li, Z.; He, Y.; Deng, L.; Zhang, Z.-R.; Lin, Y. A fast-dissolving microneedle array loaded with chitosan nanoparticles to evoke
systemic immune responses in mice. J. Mater. Chem. B 2020, 8, 216–225. [CrossRef]
152. Bachra, Y.; Grouli, A.; Damiri, F.; Talbi, M.; Berrada, M. A Novel Superabsorbent Polymer from Crosslinked Carboxymethyl
Tragacanth Gum with Glutaraldehyde: Synthesis, Characterization, and Swelling Properties. Int. J. Biomater. 2021, 2021, 5008833.
[CrossRef]
153. Ling, M.-H.; Chen, M.-C. Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to
diabetic rats. Acta Biomater. 2013, 9, 8952–8961. [CrossRef] [PubMed]
154. Vora, L.K.; Courtenay, A.J.; Tekko, I.A.; Larrañeta, E.; Donnelly, R.F. Pullulan-based dissolving microneedle arrays for enhanced
transdermal delivery of small and large biomolecules. Int. J. Biol. Macromol. 2020, 146, 290–298. [CrossRef]
155. Chen, Y.; Xian, Y.; Carrier, A.J.; Youden, B.; Servos, M.; Cui, S.; Luan, T.; Lin, S.; Zhang, X. A simple and cost-effective approach
to fabricate tunable length polymeric microneedle patches for controllable transdermal drug delivery. RSC Adv. 2020, 10,
15541–15546. [CrossRef]
156. Dathathri, E.; Lal, S.; Mittal, M.; Thakur, G.; De, S. Fabrication of low-cost composite polymer-based micro needle patch for
transdermal drug delivery. Appl. Nanosci. 2020, 10, 371–377. [CrossRef]
157. Woodhouse, I.; Nejati, S.; Selvamani, V.; Jiang, H.; Chittiboyina, S.; Grant, J.; Mutlu, Z.; Waimin, J.; Abutaleb, N.S.; Seleem, M.N.;
et al. Flexible Microneedle Array Patch for Chronic Wound Oxygenation and Biofilm Eradication. ACS Appl. Bio Mater. 2021, 4,
5405–5415. [CrossRef] [PubMed]
Pharmaceuticals 2022, 15, 190 26 of 26

158. Mir, M.; Permana, A.D.; Ahmed, N.; Khan, G.M.; ur Rehman, A.; Donnelly, R.F. Enhancement in site-specific delivery of carvacrol
for potential treatment of infected wounds using infection responsive nanoparticles loaded into dissolving microneedles: A proof
of concept study. Eur. J. Pharm. Biopharm. 2020, 147, 57–68. [CrossRef] [PubMed]
159. Ren, L.; Xu, S.; Gao, J.; Lin, Z.; Chen, Z.; Liu, B.; Liang, L.; Jiang, L. Fabrication of Flexible Microneedle Array Electrodes for
Wearable Bio-Signal Recording. Sensors 2018, 18, 1191. [CrossRef]
160. Avcil, M.; Çelik, A. Microneedles in Drug Delivery: Progress and Challenges. Micromachines 2021, 12, 1321. [CrossRef] [PubMed]
161. Vora, L.K.; Moffatt, K.; Tekko, I.A.; Paredes, A.J.; Volpe-Zanutto, F.; Mishra, D.; Peng, K.; Raj Singh Thakur, R.; Donnelly, R.F.
Microneedle array systems for long-acting drug delivery. Eur. J. Pharm. Biopharm. 2021, 159, 44–76. [CrossRef] [PubMed]
162. Yadav, P.R.; Munni, M.N.; Campbell, L.; Mostofa, G.; Dobson, L.; Shittu, M.; Pattanayek, S.K.; Uddin, M.J.; Das, D.B. Translation
of Polymeric Microneedles for Treatment of Human Diseases: Recent Trends, Progress, and Challenges. Pharmaceutics 2021, 13,
1132. [CrossRef] [PubMed]
163. Jamaledin, R.; Di Natale, C.; Onesto, V.; Taraghdari, Z.; Zare, E.; Makvandi, P.; Vecchione, R.; Netti, P. Progress in Microneedle-
Mediated Protein Delivery. J. Clin. Med. 2020, 9, 542. [CrossRef] [PubMed]