Journal of Drug Delivery Science and Technology 59 (2020) 101923

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Journal of Drug Delivery Science and Technology

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

Review article

A review of recent advances in microneedle technology for transdermal

drug delivery
Rigved Nagarkar a, *, Mahima Singh a, Hiep X. Nguyen b, Sriramakamal Jonnalagadda a
a
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, 600 S 43rd Street, Philadelphia, PA, 19104, USA
b
Aurobindo Pharma USA Inc, 2929 Weck Dr, Durham, NC, 27709, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Transdermal devices are used to deliver drugs through the skin. However, limitations such as molecular weight
Microelectromechanical systems and hydrophilicity of the molecules prevent its wider use. Microneedle technology offers an enhanced drug
Biocompatibility delivery option. Depending on the delivery, different types of microneedles such as solid, hollow, dissolving and
Transdermal
coated are discussed. While solid microneedles create micropores in the skin, hollow microneedles provide a
Microneedles
channel into the dermis. Dissolving microneedles have been explored for vaccine delivery while coated micro­
Micromolding
Non-degradable needles use a drug dispersion to effectively load drugs. This review also focuses on the techniques involved in
fabrication of microneedles. Several methods using various solvent techniques, electromechanical systems, laser
ablation and additive manufacturing are discussed. The nature of material used impacts the method used for
fabrication. Various degradable and non-degradable materials used for fabrication are discussed. Microneedles
can be made from metals, silicone, ceramics, synthetic as well as biodegradable polymers like carbohydrates.
Each material has its own advantages and disadvantages. Stainless steel demonstrates good biocompatibility but
are highly corrosive while silicones are easy to fabricate but brittle. Microneedle technology possesses a
tremendous potential considering the variations in types and materials it offers with ease of fabrication and are
the next generation therapeutics.

1. Introduction address the problems associated with transdermal delivery. However,

The transdermal route of drug delivery offers an attractive, non-
invasive route of drug administration. Drugs administered through the
transdermal route show high bioavailability avoiding gastrointestinal
degradation and first-pass metabolism [1]. During transdermal perme­
ation, drug accumulation in the skin prior to release into blood vessels
enables a natural mechanism for sustained drug delivery [2]. Despite
numerous advantages, transdermal drug delivery is limited to a few
molecules with certain physicochemical properties. Ideally, a trans­
dermal candidate should have molecular weight less than 500 Da and
log P within 2–3 [3]. The stratum corneum is the main barrier for
transdermal permeation [4]. Several technologies have therefore been
developed to disrupt the stratum corneum to enhance skin permeability.
These include iontophoresis [5], sonophoresis [6], magnetophoresis [7],
electroporation [8], and laser-microporation [9]. These methods have
major applicability and economic limitations. Traditional drug delivery
systems such as intradermal injections are currently being used to
intradermal injections are associated with limitations such as needle
injuries, phobia, requirements of specially trained staff increasing the
cost of the delivery.
Microneedle drug delivery is the answer to the limitations provided
by the two traditional dosage forms. The technology has been evaluated
to deliver not only small molecules [20] but also various macromole­
cules [21,22], cosmeceuticals [23], and micro/nano-particles [24].
Recently, the application of coated as well as dissolving microneedles
has been evaluated for noninvasive transdermal vaccination [16], pa­
tient monitoring, and diagnostic applications [25]. Research and
development of microneedles have reached the stage of large-scale
manufacturing and commercialization. Microneedles have not only
been researched for transdermal drug delivery but also find their use in
ocular, diagnostic testing and oral delivery. This review focuses on
microneedling which holds significant promise for bypassing stratum
corneum to enhance transdermal drug delivery [26].
Microneedles (micron-sized needling system) are intended to pierce

* Corresponding author.
E-mail addresses: rnagarkar@mail.usciences.edu (R. Nagarkar), msingh@mail.usciences.edu (M. Singh), Bnguyen@aurobindousa.com (H.X. Nguyen), s.jonnal@
usciences.edu (S. Jonnalagadda).

https://doi.org/10.1016/j.jddst.2020.101923
Received 12 May 2020; Received in revised form 22 June 2020; Accepted 8 July 2020
Available online 16 July 2020
1773-2247/© 2020 Elsevier B.V. All rights reserved.
R. Nagarkar et al.
the epidermal layer, creating micro-channels in the skin without causing
pain, bleeding, or infection [27]. These channels allow therapeutic
agents to diffuse into the dermal layer, which is well perfused with blood
vessels [28]. The length of microneedles can vary to ensure epidermal
penetration, while avoiding stimulation of the nerve fibers or puncturing
blood capillaries [29]. Microneedle delivery does not face limitations
based on the molecular size, since the channels are markedly larger than
the typical therapeutic agents. Microneedles (MNs) have been fabricated
by various microfabrication techniques [30], to represent varied mate­
rials, geometries, and dimensions (50–900 μm height, 2000 mm 2 sur­
face area). A comparison of microneedles with the conventional
injectable forms of drug delivery is shown in Fig. 1.
Regulatory issues remain a concern, as is the case for any new
technology. This paper reviews a range of critical aspects related to
microneedle technology, including types of microneedle, materials of
construction, geometries, penetration depth, drug release, and irritation
possibility.
2. Microneedle classification
Microneedles may be broadly classified on the basis of delivery
profile, or the material used in manufacture.
2.1. Based on variations in drug delivery
Microneedles may be classified as solid, hollow, dissolving, or coated
microneedles (Fig. 2).
2.1.1. Solid microneedles
Solid microneedles can be used as a skin pretreatment, as they are
inserted and removed to form micron-scaled pores on the skin surface.
They work on a ‘poke and patch’ principle, as microchannels are
created. These microchannels enhance the drug permeability by allow­
ing diffusion from a formulation directly into the dermal layer. Studies
on rat skin have shown that the micropores generated by microneedles
remained upon at least 72 h after microneedle treatment, when held
under occlusive conditions [31], such as occlusive tape [32]. In the
absence of occlusion, the micropores closed shortly after microneedle
application. The microchannels created by solid MN were observed to
heal rapidly within 2 h ensuring the absence of secondary infection [31].
A variation of a typical solid microneedle approach is the ‘scrape and
patch’ method, whereby microneedles, microprojections, or micro­
blades are scraped over the skin to generate micro-abrasions. Drug
Fig. 1. Comparison of microneedles with traditional injectable form of delivery.
2
Journal of Drug Delivery Science and Technology 59 (2020) 101923
solutions within a patch then are applied on these microprojections
[33]. Another variation is the use of a roller containing solid micro­
needles, which pierces the stratum corneum multiple times as the roller
spins on the skin. Commercially available Derma-rollers are based on
this concept and are used for skin pore opening therapies. Ita et al.
(2015) conducted a study to deliver drugs for high blood pressure using
cylindrical surface Microneedle Systems®. Transdermal flux values were
shown to increase 5 to 8 times after treatment of porcine skin with
microneedle rollers [34].
2.1.2. Hollow microneedles
These microneedle systems are a miniature version of the conven­
tional hypodermic needles. A microscopic representation of hollow
microneedles is shown in Fig. 3 [13]. Drug delivery is achieved through
a pressure-driven flow of liquid formulation [14]. Substantial doses can
be delivered into the dermal layer through this technique [15]. Hollow
MNs are difficult to fabricate due to their structure and fragility. In one
such study, Davis et al. (2005) fabricated an array of hollow metal
microneedles. These microneedles were studied for the delivery of in­
sulin in diabetic rats [35]. The study concluded that
hollow-microneedles display pharmacodynamic profiles that are com­
parable to a traditional hypodermic injection.
2.1.3. Dissolving microneedles
Dissolving microneedles operate by a ‘poke and release’ principle.
They are easy to manufacture, and use compared to other microneedles,
and have therefore gained tremendous attention in recent years [16].
Dissolving MNs are made with biodegradable materials such as sugars or
biodegradable polymers and can be loaded with therapeutic agents [17].
Once applied, the MNs dissolve into the skin thereby releasing the
conjugated therapeutic agent. These MNs provide an advantage over the
traditional solid and hollow microneedles due to their ease of fabrication
and convenient single-step application principle. Liu et al. fabricated
microarrays consisting of dissolving hyaluronic acid microneedles [36].
The cumulative permeated amount of dextran increased by a staggering
610 times when applied as a microneedle array, with negligible lag time
in drug permeation. Dissolving MN’s are being explored for use in de­
livery of vaccine in the skin. Carboxymethylcellulose and hyaluronan
microneedles were shown to dissolve completely in rat skin within 5 min
of application releasing the antigen-specific IgG payload (Fig. 4) [37].
2.1.4. Coated microneedles
Microneedles that work on ‘coat and poke’ principle are coated
R. Nagarkar et al. Journal of Drug Delivery Science and Technology 59 (2020) 101923

Fig. 2. Types of microneedles

A. Dissolving microneedles
B. Solid microneedles
C. Coated microneedles
D. Hollow microneedles.

Fig. 3. A microscopic representation of hollow microneedles. This work is licensed under the Creative Commons Attribution 4.0 International License, which permits
unrestricted use, distribution, modification, and reproduction in any medium, provided you. To view a copy of the Creative Commons license, please visit http://cre
ativecommons.org/licenses/by/4.0/.

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R. Nagarkar et al. Journal of Drug Delivery Science and Technology 59 (2020) 101923

Table 1
A detailed list of advantages, disadvantages, and method of delivery of various
MNs.
MN Advantages Disadvantages Method of Reference
classification drug
delivery

Solid Can be made Microneedle Create Li, J et al.

from a range of fracture under micro [10]
materials skin conduits in Ullah, A
Limited surface skin to et al. [11,
area available for which 12]
drug absorption drug is
applied
Hollow High drug load Must be fabricated Pressure Kim, Y
can be injected with strong driven et al. [13]
materials to flow He, X
withstand flow through et al. [14,
pressure needle 15]
Dissolving Easy Only Dissolve Ita, K et al.
manufacturing biodegradable under skin [16]
materials can be to release Kolli, C.S.
used drug et al. [16,
payload 17]
Coated Used for potent Associated with Coating Chen, X
drugs requiring drug loss while drug et al. [18]
low doses manufacturing, release Chen, J
temperature et al. [18,
limitations 19]

in a polyethylene glycol matrix which showed a significantly higher

Fig. 4. Dissolution of carboxymethylcellulose and hyaluronan microneedles in
rat skin.
This work is licensed under the Creative Commons Attribution 4.0 International
License, which permits unrestricted use, distribution, modification, and repro­
duction in any medium, provided you. To view a copy of the Creative Commons
license, please visit http://creativecommons.org/licenses/by/4.0/.
microneedles. These MNs consists a base of solid microneedles which
have a coat with drug solutions/dispersions. Several methods have been
studied to coat microneedles [18,19,38]. The most common method is
dip coating however, it is complicated due to the need for precise control
to assure that the MNs are inserted accurately into the dipping solution
[38]. Fig. 5 shows steps involved in dip-coating technique. Spray coating
is an alternative approach for drug deposition on the microneedles; this
method cannot avoid drug loss through spraying on the substrate of the
microneedles array, which is unavailable for drug permeation [18].
Aerosol coating methods have improved efficiency; however the need
for high temperatures of up to 200 � C may limit the use of thermolabile
drugs [19]. Ma et al. (2018) coated solid MN with suspended lidocaine
delivery compared to a commercial product [10]. Coated MNs are less
commonly used compared to other MNs, as they offer a relatively small
surface area for drug absorption.
The method of delivery and materials used will directly impact the
applicability of MNs. Solid MNs are easy to fabricate and use. Depending
on the nature of the material, solid MN potentially can be re-used. For
instance, the use of Derma rollers multiple times for pore formation.
Coated MNs consist of a coat of drug on solid MN. They are difficult to
fabricate given that the coating should be consistent throughout the MN
surface area. Due to a small surface area, low doses can be delivered with
this MN type. On the other hand, with hollow MN significant drug
amounts can be injected into the dermis. However, injecting solutions
can be challenging due to the pressure resistance by the opening size of
the MN and thick tissue present in the dermis. Dissolving MNs are easy to
fabricate amongst all other types of MN. They are cheap and can be
fabricated by various materials. They are single use MNs which dissolve
readily under the skin. Dissolving MNs have been researched signifi­
cantly for their use in controlled delivery, vaccine delivery and these
MNs could potentially be the future of immunization (Table 1).
2.2. Based on material selection
MNs may be fabricated from metals, silicone, ceramic, or polymers.
In the context of this review, the material of construction has been
classified into two groups, namely non-degradable and degradable. Non-

Fig. 5. Microneedles coated with dip coating technique.

4
R. Nagarkar et al.
degradable materials include materials such as metals, silicone and ce­
ramics, while degradable consists of polysaccharides and biodegradable
polymers.
2.2.1. Non degradable materials
2.2.1.1. Metals. Soluvia® is one of the first marketed MN-based prod­
uct made from metal. Another product to reach market was a silicone
based product Micronjet® [39]. Stainless steel and titanium are the most
commonly used metals to fabricate MNs. Metal MNs may be fabricated
as solid, hollow, or coated microneedles. Fabrication techniques include
three-dimensional laser ablation, laser cutting, wet etching, or metal
electroplating [14].
Li et al. used modified metal injection molding technology to fabri­
cate titanium porous microneedle arrays (TPMA). TPMA exhibited a
staggering more than 27 times higher flux of calcein across intact skin
[11]. Delivery of calcein dye was evaluated by Assad Ullah et al. (2018),
where stainless steel microneedles were modified by surface plasma
treatment. These porous polymer-coated MNs were used to deliver
lidocaine and rhodamine B dye [12]. An example of a commercially
available hollow stainless steel microneedles are the AdminPen®, which
vary in length from 600 to 1500 μm [40]. Derma rollers made from
stainless steel or titanium are commercially used for cosmetic purposes.
2.2.1.2. Silicone. Silicone is among the most commonly used material
for microneedle devices, and has been explored for over two decades
[48]. Silicone MN arrays could be used as primary molds in micro­
molding (Fig. 6). The use of silicone allows to fabricate MNs of different
geometry. Narayanan et al. fabricated silicone microneedles using an
etching technique [49]. Etching factors such as the use of Tetramethy­
lammonium Hydroxide (TMAH) in varying concentrations, time and
rate of etching, and temperature were used to produce sharper micro­
needles with a higher aspect ratio.
Krieger et al. have shown that high aspect ratio microneedle silicone
master molds may also be printed using a 3D printer [50].
Fig. 6. Silicone microneedle array template.
5
Journal of Drug Delivery Science and Technology 59 (2020) 101923
2.2.1.3. Ceramic. Alumina (Al2O3) is one of the most common type of
material used to produce MN [51]. Alumina holds a defined volume of
active due to the porosity of alumina [52]. Gypsum and Brushite have
also been used to fabricate MNs. A novel material which is made of
organically modified silicon alkoxides and organic monomers called
Ormocer® has been used to fabricate MNs. It forms a 3D network
increasing the area for absorption of drug solutions [53]. In a study
carried out by Ovsianikov et al. (2007) Ormocer® MN were fabricated
using laser two-photon polymerization at different aspect ratios. The
fabricated MNs penetrated porcine adipose tissue without cracking the
MNs [54]. Boks et al. fabricated ceramic nanoporous microneedle arrays
(npMNA) for delivery of vaccines. npMNA enhanced vaccine efficacy by
reaching skin dendritic cells consisting of T and B cell immunity [41].
2.2.1.4. Synthetic polymers. Several synthetic polymers have been
researched for use in MNs such as polyvinylpyrrolidone (PVP), and
polyvinyl alcohol (PVA). Poly (methyl methacrylate) (PMMA) is a
biocompatible polymer used for MN arrays [55]. In a study performed
by Nguyen et al. microneedles were fabricated using PVA by micro
molding technique for delivery of doxorubicin [42].
2.2.2. Degradable materials
2.2.2.1. Natural. Carbohydrates are good alternatives as materials for
fabrication of microneedles. One of the most important attribute of
carbohydrates is that they are cheap and safe [56]. They have not only
an excellent biocompatibility, but also show low toxicity. Some carbo­
hydrates are known to have significant strength/toughness. All of these
materials are available at low cost and are easily biodegradable [57].
Carbohydrates can be easily molded into MNs using master templates
[58]. Carbohydrates can be formulated with active ingredients to form
an active-carbohydrate mixture. This mixture then can be casted into the
molds which dissolve upon insertion into the skin to release their drug
payload [59]. One of the most common sugars used to prepare MN ar­
rays is Maltose [17]. Maltose is a very common excipient in
FDA-approved parenteral formulations. Gouhua et al. investigated
maltose microneedle-mediated in vitro transdermal delivery of a
monoclonal antibody using human IgG as a model protein. The experi­
ment showed that methylene blue was taken up by microchannels
created by maltose MNs. Cryosections microneedles penetrated the
dermis layer. Human IgG showed an increase in the delivery with in­
crease in different MN geometry like number of arrays and length [60].
In addition to Maltose, various sugars like sucrose, trehalose, mannitol,
and galactose have been used in MN fabrication [61]. The use of ma­
terials such as starch and gelation have also been explored for MN
preparation. Starch-gelatin microneedles completely dissolved after
insertion into the skin within 5 min. The microneedle could easily be
inserted into porcine skin. The depth of penetration was around 200 μm
in porcine skin, which was similar in depth to in-vivo rat skin (200–250
μm). MN mediated hypoglycemic effect in rats was similar when
compared to subcutaneous injection [44].
2.2.2.2. Synthetic. A plethora of synthetic macromolecular materials
have been used for fabrication of MNs. These include polylactic acid
(PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA) [45,
47]. For these types of materials, MNs govern the drug release which in
turn depends upon the composition of the MN materials [46,62].
2.2.3. Hydrogel forming microneedles
Hydrogel forming microneedles can be called as in-situ microneedles
where a polymer is crosslinked in dry hydrogel state. When injected into
the skin, they absorb water from interstitial fluid causing MNs to swell.
The swollen hydrogel network produces conduits which act as drug
reservoirs and control the drug delivery. It also maintains the integrity of
the MNs in the skin. These MNs are mostly fabricated by molding process
R. Nagarkar et al. Journal of Drug Delivery Science and Technology 59 (2020) 101923

which also includes a crosslinking step [63]. Many different materials
have been studied for hydrogel forming MNs. The most common being
polysaccharides [64]. Other polymers like Poly(ethylene glycol) dia­
crylate (PEGDA) and PVA [63], polyacrylic acid-co-maleic acid (PAMA)
[65], methylvinylether-co-maleic acid [66] have been studied for
hydrogel forming MNs. The main advantage of hydrogel forming
microneedle is delivery of high doses of drugs due to swell ability of the
MN base (Table 2).
Several types of materials have been used for fabrication of MNs.
Depending on the material, MNs can be fabricated with non-degradable
or degradable materials. While the choice of materials from degradable
or non-degradable material is vast, one needs to consider supporting
aspects that can impact the material of construction. Factors like method
of fabrication available, drug and excipients of choice, drug compati­
bility with material and fabrication process, final use, type of delivery
have an influence of the selection of material.
3. Fabrication techniques
Skin is an elastic organ which possesses significant tensile strength.
In order for MNs to effectively penetrate, they must have optimum
strength to penetrate without cracking or breaking during insertion.
Hence, fabricating microneedles is a challenging task. The fabrication
methodology varies based on material of choice, MN geometry, and skin
depth requirement [67]. For instance, solvent-casting may be appro­
priate for polymeric microneedles, whereas microelectromechanical
systems are better utilized to design metal microneedles. The fabrication
techniques have been classified based on the technology used for
manufacture.
aqueous solutions could successfully cover the entire mold surface
without generation of voids. The authors fabricated dissolving MNs (5%
solids content) with atomized spraying into silicon micromolds [43].
3.1.3. Droplet-born air blowing (DAB)
In this method, polymer droplet is given the shape of a microneedle
with the use of air blowing, allowing for gentle conditions without the
use of external harsh conditions such as heat and UV irradiation [70].
The process starts with dispensing of solution on two different plates,
upper and lower. The two plates are kept in contact and gradually pulled
apart thus elongating the viscous solution. The elongated viscous solu­
tion is then exposed to blowing air under controlled conditions. The
required shape is given during this drying step. The fabrication method
was proposed by Kim et al. A single polymer drop per MN is used to
control the dimension and concentration of the droplet as well as the
controlled drug loading without the drug loss. This process has been
used in the fabrication of insulin loaded dissolving microneedles by the
authors where a successful use of insulin loaded dissolving microneedles
reduced blood glucose levels in diabetic mice [71].
3.1.4. Pulling pipettes
Pulling pipettes technique is only applicable for fabrication of hollow
glass MNs. Glass is exposed to high temperatures, after which it MNs
arrays are created by pulling the hot glass with micropipette puller. This
technique can be made more robust and consistent by the use of pro­
grammable puller [72].
3.2. Electromagnetic/microsystem/laser technology

3.2.1. Microelectromechanical systems (MEMS)

3.1. Fabrication of polymeric MN using solvent MEMS has been traditionally used for creation of integrated circuit
technology. MEMS is divided into following main processes of (1)
3.1.1. Micromolding deposition, (2) patterning, (3) etching [73].
Micromolding is utilized to fabricate various polymers, ranging from
pectin (natural polymers) to PVA and PVP(synthetic or semisynthetic (1) Deposition includes formation of films on a base material called
polymers) [29]. The technique utilizes multiple approaches to uniformly substrate. The films are formed by a physical or chemical process.
pour a liquid polymeric solution onto mold, followed by elimination of In the physical vapor deposition (PVD) technique, the materials
air voids. The removal of air voids can be facilitated by use of a vacuum are removed from the source and deposited on the substrate
(or alternatively, a centrifuge), followed by drying in an oven, and final whereas in the chemical vapor deposition (CVD) technique hot
removal from the mold [68]. substrate and the carrier gases are reacted chemically the in the
chamber.
3.1.2. Atomized spraying to fill molds (2) The patterning process includes transferring microneedle geom­
Continuous manufacturing microneedles with micromolding tech­ etry pattern, e.g. height, base width, tip angle, bore size details on
niques can be challenging due to centrifugation or vacuuming step the film. Lithography is a common process used for patterning.
involved [69]. Atomized spraying the polymer solution into the molds Briefly, a source of radiation such as light is impinged upon a
can overcome this challenge. McGrath et al. showed that atomization of photosensitive substrate thereby transferring a microneedle
pattern. The source of radiation can be different such as electron
Table 2 beam lithography, ion beam lithography or x-ray lithography
A summary of products made with different types of microneedles. [74]. The commonly used is photolithography. Generally
Product Type of MN Reference following sequential steps are involved in the mask transfer onto
the photosensitive-coated substrate: The first step involves for­
Vaccine Nano-porous ceramics, Boks et al.
carboxymethylcellulose, hyaluronan [41] mation of oxide layer by heating in the presence of steam or
Doxorubicin PVA micro mold Nguyen et al. humidified oxygen. This is followed by spin coating of a thin layer
(chemotherapeutic [42] of an organic polymer, known as a photosensitive/photoresist or
agent) resist material (sensitive to UV radiation) [75]. Then heat is
Dissolving microarrays Hyaluronic acid Liu et al. [36]
Insulin delivery Hollow metal Davis et al.
applied to the resist layer to remove solvent. This is followed by
[35]. exposure to UV lamp, through a mask, allowing a nearly perfect
Derma Rollers Solid MN Ita et al. [34] transfer (in other words “printing”) of the mask image onto the
Lidocaine Solid MN with PEG matrix Ma et al. [10] resist-coated wafers.
Soluvia Metal Donnelly
(3) Etching uses a harsh caustic agent to etch out the unprotected
et al. [39]
Micronjet Silicon Donnelly parts of the substrate to form a microneedle design of interest.
et al. [39] Etching can be done by a wet and dry technique [76].
Calcein TPMA Li et al. [11] 3.1 The dry process may involve etching methods like reactive
AdminPen Hollow stainless steel Yuzhakov ion or ion-beam milling. Dry etching process produces solid
et al. [40]
and hollow microneedles [29].

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R. Nagarkar et al. Journal of Drug Delivery Science and Technology 59 (2020) 101923

3.2 Wet itching: In this process, the substrate is submerged in the Table 3
chemical liquid which helps in elimination of the extra ma­ A summary of products made from various materials is shown in Table 3.
terial [77]. Wet itching can be done at same rate (isotropic) Material Common/commercial Fabrication method Reference
or different rates (anisotropic). It is used to produce metallic product
and silicon arrays. Metals Stainless steel Laser cutting Indermun S et al.
[30]
3.2.2. Laser cutting Titanium Injection molding Li, J. et al. [11]
In this method, an infra-red laser is used to cut metallic sheets in the Silicone TMAH Etching Tarbox, T.N et al.
[43]
shape of microneedles. AutoCAD software is used to design the geometry Natural Maltose, Starch Micromolding Kolli, C.S. et al.
of the MN. The laser beam then removes the metal sheet per the design [17],
which produces in plane MNs. The fabricated MNs are cleaned and Ling, M.H et al.
bended at 90� angle of the sheet. The tips are then tuned by electro­ [44]
Synthetic PLA 3D additive Camovi�c, M. et al.
polishing. This method is used for manufacturing metallic MNs. The
manufacturing [45]
most frequently employed material is stainless steel [30]. PGA Lithography, Park, J.H et al.
micromolding [46]
3.2.3. Laser ablation PLGA Micromolding Nguyen, H.X et al.
As the name suggests, in this method laser is impinged on a metal [47]

plate to form a bulge. Light pulses are used to give a defined shape to the
bulge to form a MN. Similar to laser cutting, laser ablation is also used
for fabricating solid metallic arrays. Metals like tantalum are also
fabricated [78].
3.2.4. Deep x-ray lithography
In this technique a polymer solution is coated and cured on silicon
wafer. An array of triangular columns and channels are generated by
exposing the silicone wafer to vertical deep x-ray. The x-ray mask and
the substrate are continuously adjusted and aligned to provide the
desired MN geometry [79]. This technique is known for high precision
hollow MNs. Metallic, polymeric and ceramic and glass MN arrays can
be fabricated.
3.3. Additive manufacturing
3.3.1. Two photon polymerization
The two-photon polymerization is a layer-by-layer fabrication pro­
cess of three-dimensional structures that offers high throughput at a low
cost. Femtosecond or picosecond laser pulses for the polymerization of
resins into microneedle structure [74]. The polymerization is initiated
by two-photon absorption which generates an energy that is centered at
the laser focal point. The desired structure is initially sliced with the aid
of a computer-aided design (CAD) model. Next, each layer is written in
the photosensitive resin by restoring the path of the laser for the contour
to be filled in for each layer. After fabrication of the MN, resin is washed
with a solvent and cured using ultraviolet light [68].
3.3.2. Microstereolithography (μSL)
Micro-stereolithography (μSL) is a high throughput fabrication
technique. It generates 3D microstructures in a bottom-up addition
fashion. This technology has been widely used in biomedical and tissue
engineering. The fabrication spatially controlled solidification of a
liquid by photopolymerization [30]. Laser beam creates MN pattern on
the surface of a resin which causes the resin to have definite depth. This
helps to adhere to a support platform. Photo-polymerization of the first
layer is followed by separation and realignment after which recoating of
the first built layer takes place. The pattern is cured in this second layer.
These steps are repeated to construct a solid, three-dimensional object.
3.3.3. Continuous liquid interface (CLIP)
CLIP is used to computationally design microneedles. It is a novel
approach which utilizes continuous additive method versus a traditional
layer by layer approach mentioned above. The main advantage of CLIP
over the traditional approach is that it fabricates microneedles with a
significantly higher resolution. It eliminates the separation and
realignment which helps to build efficiency producing MNs at a faster
rate. Johnson et al. used trimethylolpropane triacrylate, polyethylene
glycol dimethacrylate, polycaprolactone trimethacrylate and
polyacrylic acid to manufacture microneedle arrays using CLIP. Pre­
pared microneedles were shown to penetrate murine skin and release
rhodamine dye. The CLIP process can be basically used to design any
microneedle patch in two to 10 min [75]. The CLIP approach provides
huge flexibility for microneedle design and rapid prototyping that en­
ables a varied number of different parameters such as size, shape, and
composition to be investigated in a throughput process (Table 3).
4. Current biocompatibility data
Biocompatibility and safety are of prime importance when consid­
ering the material of construction for microneedles. Stainless steel is an
iron-based alloy that contains about 11–30 wt percent of chromium and
varying amounts of nickel, which affects its properties and biocompat­
ibility. Stainless steel grade 316L demonstrates good biocompatibility
and therefore, is commonly used for surgical processes [80]. However, it
suffers a high corrosion rate when compared to other metals, such as
titanium alloys [81]. Titanium alloys have superior corrosion resistance
as shown by insignificant mutagenicity, indicating that titanium alloys
are safe for humans and animals [82]. Silicones are widely used as im­
plants but there have been concerns with their biocompatibility. Sili­
cones are brittle in nature and possess a risk of being fractured in the
skin [83]. The presence of silicone in skin can be hazardous due to sil­
icone- and glass-related granulomas [84].
Ceramics have been used as replacement of musculoskeletal systems.
The main reason behind this is due to biocompatibility and high strength
of ceramics. The use of alumina for bone and dental implants is very
common from the past two decades [85]. Therefore, its biocompatibility
has been extensively studied. Some studies showed the long term effects
of bone implants with risk of aluminum release [86].
Natural sugars have been extensively used in many drug delivery
systems, as they are safe. Carbohydrates have been known to be
extremely biocompatible, and abundantly used for different types of
application. Due to their excellent biocompatibility, they have been used
for different applications like tissue engineering [87], nanocomposites
[88] and wound care [89].
Biocompatible materials are beneficial than other material as they
offer an additional advantage of controllable biodegradation rate.
Saturated aliphatic polymers are frequently used for decades in the field
of bone tissue engineering. It is common to use PLA, PGA, and PLGA in
scaffold application [90].
5. Geometry of microneedles and penetration depth in skin
Since their inception, there have been many different designs of MNs
with different surface areas since their first manufacture. As expected,
the cumulative delivery of the drug is directly proportional to the

7
R. Nagarkar et al.
surface area of microneedle. This suggests the necessity to consider and
optimize the surface area which in turn is largely affected by its length
while designing the array system of microneedles. Most commonly the
length of MNs is fabricated in range from 150 to 1500 μm with a 50–250
μm base width, and 1–25 μm tip diameter [91].
The penetration of skin by MNs is dependent on several factors. Due
to the presence of protein elastin, skin possesses elasticity which can
prevent MN from penetration. Skin can fold around MN during its
application if the needles are blunt and short. Skin also contains protein
keratin which gives the strength to the skin. Due to this robustness, MN
insertion forces may exceed the tensile forces of the MN causing them to
fracture and/or break. This can happen in the MNs are too long and/or
made of relatively weak materials [92]. Therefore, microneedle geom­
etry is very crucial for efficient MN penetration and delivery into the
skin. MNs are evaluated for different shapes like cylindrical, rectangular,
pyramidal, conical, octagonal and quadrangular with varying needle
lengths and widths as shown in Fig. 7 [75]. The low density of micro­
needle arrays is better than the dense MN array which can cause ‘bed of
nails’ effect.
Al-Qallaf et al. investigated that the drug concentration in the blood
increases with increase in MN length and surface area. Overall, the
optimum MN design should be long enough without breaking or causing
any pain [92].
Studies have concluded that an increase in the length of microneedle
increases the surface area and activates cells in the dermis layer thus
increasing the drug absorption [93]. A study carried out by Romgens
et al. showed that the greater number of cells are activated in the dermis
with increase in MN length. Therefore by exactly knowing the depth and
knowledge of skin cells and layers, MN length can be adapted to activate
Langerhans cells or dermal dendritic cells residing in the dermis [93].
Increasing the microneedle length may have some limitations. Gill
et al. showed that the longer the length of the microneedle, the more the
pain is generated. For instance, when 400 MNs (150 μm in length) were
inserted in human volunteers, it was deemed painless against a 2-mm
deep insertion of a 26-gauge hypodermic needle. Scraping the skin at
a depth of 50–200 μm in length was found to be painless. The authors
compared stimulated pain to a 26-gauge hypodermic needle in healthy
human subjects and concluded that the microneedle geometry has in­
fluences on pain. As the length increased the pain was reported to in­
crease [94]. Thus, a detailed evaluation on MN geometry is required to
ensure optimum penetration without fracture with minimal pain.
Fig. 7. Different shapes of microneedles developed This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unre­
stricted use, distribution, modification, and reproduction in any medium, provided you. To view a copy of the Creative Commons license, please visit http://creative
commons.org/licenses/by/4.0/.
8
Journal of Drug Delivery Science and Technology 59 (2020) 101923
6. Applications of microneedle drug delivery
The effectiveness of a transdermal delivery is determined by the
ability of a molecule to penetrate into the skin. Numerous molecules
have faced challenges in manufacturing and application, mainly pep­
tides and vaccines, due to their molecular weight. MNs have not only
shown a successful intradermal delivery of such molecules but in some
cases were also deemed more effective at delivering lower doses than the
current traditional delivery systems for the same desired clinical effect.
For instance, a similar change in hemagglutinin inhibition antibody titer
was found with less than half the drug concentration when delivered
with MN compared to traditional intra-muscular injection [95]. The
success of the MN systems was evident from the approval from many
regulatory agencies for seasonal influenza vaccine delivered by MN
[96–98]. MN have been studied to address several skin conditions such
as viral warts [99], dermatitis [100], and psoriasis [101]. MN have also
shown their efficacy in treatment of skin cancer [102]. MN have not only
been studied in intradermal delivery, but they also find application in
ocular drug delivery. MN have shown to effectively treat ocular diseases
like glaucoma [103], macular degeneration [104], Uveitis [105] and
retinal vascular occlusion [106]. Currently, most microneedles that are
available on the market are indicated for cosmetic purposes. Derma­
roller helps to improve health of skin, while dissolving microneeldes are
used to treat acne.
7. Current research, challenges and future trends
Microneedles have been constantly evolving since their invention in
1970s. Since then, leaps and bounds of progress has been made in the
field of MNs. MN mode of drug delivery has seen the use of established
materials such as glass and stainless steel to many different poly­
saccharides. A thorough understanding and development of microelec­
tronics industry has made the fabrication technique easy and
commercially productive. Various polymers have been utilized for pro­
duction of MNs. A precise control on the drug delivery has been enabled
through these systems. MNs opens up opportunities and potentials to
give a new face to the realm of drug delivery for various sizes of mole­
cules. However, these delivery systems present several challenges. For
instance, as MNs are injected into the skin with drugs delivered directly
into systemic circulation, do these systems need to be sterile? With
sterility in consideration, this limits the number of materials that can be
used. Also, the type of sterilization technique used will impact the
R. Nagarkar et al.
microneedle type. For instance, heat sterilization can be utilized for solid
microneedles made from metals while a gamma ray sterilization would
be the choice for dissolving microneedles. Challenges with respect to
dose delivery are also evident as relatively low doses can be used with
the MN technology. Additionally, repeated use of MNs at the same site
may lead to erythema, swelling, and skin irritation. MNs can potentially
cause and infection if the skin pores remain open for a longer time while
some MN delivery systems pose a challenge of leaking. At this time, a
plethora of research is carried out on materials and techniques to
improve the current MN delivery. In the coming years, more MN prod­
ucts will be commercialized based on the volume of on-going clinical
studies. A detailed research needs to be performed for regulatory
approval of these systems as they act as the bridge between transdermal
and injectable dosage form.
Several clinical trials have been performed on MN technology. The
first study was done in 2001 by Kaushik el at using silicon microneedles
to compare pain index in human volunteer subjects [107]. Since then,
different researchers and companies have done comprehensive clinical
trials using different active ingredients with MN systems. A similar study
was performed on the oral cavity of 30 human volunteers to determine
the pain index. In another study carried out by Ornelas et al. anesthetic
effect from lidocaine was found to be produced in half the time in human
volunteers using MN compared to topical cream [108]. MN applications
have also extended to pediatric populations. In a recent study, the effects
of MN in 34 children was assessed by applying placebo MN patches.
NanoPass technology is actively involved in clinical trials of their
micronjet injection system. There are two Phase I studies on-going in the
field of allergy immunotherapy for evaluation of safety and immune
response. Another on-going phase II study involves delivery of dendritic
cells targeting viral vector and recombinant protein in combination with
atezolizumab for treatment of metastatic sarcoma [109].
8. Conclusions
A framework has been presented in this paper to review and discuss
the categories, materials, and geometries of microneedles, an innovative
and promising technology to enhance the skin permeability. Biocom­
patibility issues and selection criteria of materials of construction of
microneedles were also elaborated. The design and dimensions of
microneedles have been indicated as the primary parameters to be
customized for the optimal performance of the needle system. Micro­
needle length could be adjusted to achieve a desired depth of penetra­
tion to facilitate the drug release and maximize the drug delivery
enhancement. The discussion in this paper suggests that biodegradable
microneedles appear superior to non-biodegradable needles in almost all
aspects except the risk of possible skin-related toxicity. Microneedling
technology has progressed to a possibility of large-scale production and
microneedle-based drug delivery systems are expected to appear on the
pharmaceutical and cosmeceutical market in the near future.
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgments
Financial supports from Philadelphia College of Pharmacy, Univer­
sity of the Sciences are gratefully acknowledged.
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