Biomedical Applications of Polymeric Microneedles for Transdermal Therapeutic Delivery and Diagnosis: Current Status and Future Perspectives

REVIEW
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Biomedical Applications of Polymeric Microneedles
for Transdermal Therapeutic Delivery and Diagnosis:
Current Status and Future Perspectives
Tengfei Liu, Gaoxing Luo,* and Malcolm Xing*
not only avoid problems of hepatic first-pass
effect and gastrointestinal drug destruction
caused by traditional oral administration,
but also the pain sensation and needle infection caused by subcutaneous injection
administration.[3,4] In the past few decades,
transdermal administration has been regarded as a non-invasive alternative way to
traditional oral administration and subcutaneous injections.[5]
However, due to the presence of
lipophilic compact stratum corneum at
the outermost layer of skin as an effective
barrier, transdermal drug delivery fails to
effectively deliver therapeutic drugs with
high molecular mass, such as proteins, genetic materials, and hydrophilic drugs.[6,7]
The stratum corneum with a thickness of
10–15 µm only permits lipophilic drugs
with low molecular mass (<600 Da) to
pass through the skin.[8] To solve the problem, a series of physicochemical methods
have been put forward to improve the
permeability of drugs through the stratum
corneum, such as chemical enhancers,[9]
[10]
electroporation,
ultrasound,[11] iontophoresis,[12] thermal
[13]
and microdermabrasion.[13] Unfortunately, several
ablation,
intrinsic limitations, including inconvenience in the clinical
operation, risks of skin injury and irritation,[14] limited their
practical applications. The global transdermal drug delivery
market is estimated to be worth approximately $95.57 billion by
2025,[15] but it currently remains limited to less than 20 drugs.[16]
Development of novel transdermal drug delivery techniques
is urgently needed to broaden the transdermal market for hydrophilic compounds, macromolecules and conventional drugs
for new therapeutic indications.
In the last two decades, revolutionary progress has been made
in the development of microneedles-based transdermal drug
delivery system.[17] And microneedles have been portrayed as an
attractive and promising transdermal drug delivery way due to
the merits of safety, high delivery efficiency and painlessness.[18]
Microneedles are needles with micron-scale length (usually no
more than 1000 µm), typically assembled in variable numbers
on one side of a supporting base or patch. Micron-sized microneedles can pierce the stratum corneum layer in a minimally
invasive manner and create reversible channels at microns
dimensions. These channels are large enough to allow small
Transdermal drug delivery is a crucial extension of drug administration routes
and has been widely acknowledged as an alternative way to traditional oral
administration and subcutaneous injections due to the advantages such as
increased dosage efficacy, decreased systemic side effect, and improved
patient compliance. The past few decades have witnessed biomedical
applications of microneedles in various cutting-edge fields. Microneedles are
needles with micron-scale length which can pierce the epidermis of the skin in
a minimally invasive manner for transdermal drug delivery. Compared with
inorganic and metal microneedles, polymeric microneedles have attracted
more attention because of their superior biocompatibility, nontoxicity, and
biodegradability. In this review, the state-of-art and future biomedical
applications of polymeric microneedles are summarized. First of all, a brief
introduction to the polymeric microneedles, including types of polymeric
microneedles and methods for the fabrication is included. Then the
biomedical applications of polymeric microneedles in transdermal drug
delivery and diagnosis are summarized in detail. Finally, discussions on the
current limitations and future perspectives of polymeric microneedles are
provided.
1. Introduction
As one of the largest organs in human body, skin functions as a
natural barrier to protect the human body from external harmful stimuli and maintains the homeostasis of human internal
environment.[1] Transdermal administration refers to the delivery of drugs through the skin.[2] Transdermal drug delivery could
Dr. T. Liu, Prof. G. Luo
Institute of Burn Research
State Key Laboratory of Trauma
Burn and Combined Injury
Southwest Hospital
Third Military Medical University (Army Medical University)
Gaotanyan Street, Chongqing 400038, China
E-mail: logxw@hotmail.com
Dr. T. Liu, Prof. M. Xing
Department of Mechanical Engineering
University of Manitoba
Winnipeg, Manitoba R3T 5V6, Canada
E-mail: malcolm.xing@umanitoba.ca
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/adtp.201900140
DOI: 10.1002/adtp.201900140
Adv. Therap. 2020, 1900140
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molecular drugs, macromolecules (peptide, protein, vaccine, nucleic acid), nanoparticles, and interstitial fluid to pass through the
stratum corneum for local or systemic treatments/diagnosis.[19]
Besides, the length of microneedles determine that the maximal
insertion depth only reaches epidermis. Such insertion depth
will not stimulate or damage nociceptive nerves and blood
vessels in the dermis (1–2 mm in thickness), thus causing no
pain or potential skin injury.[20] Generally, the length of the
microneedle is between 100 and 1000 µm, and microneedle
tips range from 1 to 10 µm.[20] As the force required to insert
microneedles into the skin increased with insertion depth,[21] the
mechanical strength, insertion depth, and drug release profile
of microneedles could be adjusted by modulating and altering
microneedle geometry and composition according to the target
drugs and applications. Modulation of microneedle geometry
could change the mechanical strength and insertion depth. Alteration of microneedle composition with dissolving, degradable,
or non-dissolvable materials could adjust drug release profiles
to realize rapid, slow-sustained, or stimuli-responsive drug
release.[22]
The concept of microneedles was first introduced in the 1970s
by Gerstel and Place.[23] But due to the lack of techniques to
fabricate such small needles, transdermal drug delivery efficacy
of microneedles was not reported until 1998 when Prausnitz
et al. fabricated the silicon microneedles for transdermal delivery of calcein. They demonstrated that the drug permeability of
skin was enhanced by fourfold due to the conduits formed by
microneedles.[24] This report was a landmark innovation which
opens the era of microneedle-based transdermal drug delivery.
Since then, a variety of materials have been used to fabricate microneedles for transdermal delivery of drugs, genetic materials,
vaccine, macromolecules, nanoparticles, and even cells. Despite
that no microneedle-based product is currently available in the
clinic, 69 clinical trials regarding microneedle-based transdermal
drug delivery have been completed according to the data obtained
from the clinical trial website.[15]
According to the composition of materials, microneedles can
be classified into inorganic microneedle (such as silicon and
glass microneedles), metal microneedles (such as stainless steel
and titanium microneedles) and polymeric microneedles (such
as hyaluronic acid, chitosan, polyacrylic acid, and polymethyl
methacrylate microneedles).[25] Inorganic microneedles are brittle and prone to be fractured in the skin. Although metal microneedles could pierce the skin and increase the drug permeability, they have limited drug loading capacity, risks of skin
rupture, and expensive and complex fabrication process. These
drawbacks limit the biomedical application of these two types of
microneedles.[26]
Polymeric microneedles are the current research hotspot in
transdermal drug delivery due to unique advantages such as
easy and inexpensive fabrication process, excellent biocompatibility, and high drug loading amount.[27–29] More importantly,
polymeric microneedles could be fabricated by a plethora of polymeric materials with different degradation/swelling profiles,
and biological/physical stimuli-responsive properties, which
increase the tunability of designing microneedles with controllable drug release profile for versatile biomedical applications.
In this review, we attempt to discuss recent advances in the
development of polymer microneedles for transdermal drug
Adv. Therap. 2020, 1900140
Tengfei Liu received his bachelor’s degree and master’s
degree from the Army (Third
Military) Medical University,
Chongqing, China. He is currently pursuing his Ph.D. degree under the joint supervision
of Prof. Gaoxing Luo and Prof.
Malcolm Xing. His research
focuses on the development
of stimuli-responsive biomaterials for wound repair and
infection control.
Gaoxing Luo received postdoctoral training in Yale University
in the United States. He is currently working as the director,
professor, and surgeon in the
Institute of Burn Research,
Southwest Hospital, Army
(Third Military) Medical University, China. He also serves
as the vice chairman of the Chinese Burn Association. His
research interests include the
application of stem cells for
tissue engineering and the development of interdisciplinary
strategies for wound repair and regeneration.
Malcolm Xing is a professor of University of Manitoba, Canada. His research
focuses on smart biomaterials for tissue engineering,
nanomedicine, wearable
biosensors, implantable biorobot and 3D/4D bioprinting.
delivery and biological fluid monitoring and diagnosis. It will be
reviewed in detail from the types of polymeric microneedles to
methods for fabricating polymeric microneedles. Then we focus
on the biomedical applications of polymeric microneedles in
transdermal drug delivery and diagnosis and future perspectives
of this field will be discussed.
2. Types of Polymeric Microneedles
A variety of polymers with different characteristics have been
utilized to fabricate polymeric microneedles, as shown in Table 1.
According to the in vivo performance of microneedles, polymeric
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Table 1. Representative polymers used for fabricating microneedles (references are listed in the corresponding sections).
Microneedle type
Polymers
Dissolving microneedles
Hyaluronic acid (HA), sodium alginate, dextran, gelatin, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC),
carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), poly-l-glutamic acid (𝛾-PGA), sodium chondroitin sulfate,
amylopectin
Degradable microneedles
Polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycarbonate (PC), chitosan
Non-dissolvable microneedles
polystyrene (PS), polymethyl methacrylate (PMMA), polyvinyl alcohol (PVA), poly(methyl vinyl ether-co-maleic acid) (PMVE-co-MA),
acrylate modified HA (m-HA), poly(2-hydroxyethyl methacrylate) (PHEMA)
microneedles can be classified into dissolvable microneedles,
non-dissolvable microneedles and hybrid microneedles.[30]
Dissolvable microneedles can be further divided into dissolving
microneedles and degradable microneedles.[31] The polymeric
matrix could incorporate drugs and protect drugs from physical
or biological disruption. After insertion into the skin, microneedles would dissolve, swell, or degrade and then release the loaded
drugs.[32]
The materials for fabricating dissolvable microneedles mainly
include hyaluronic acid (HA), sodium alginate, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), carboxymethylcellulose (CMC), dextran, hydroxypropyl methylcellulose (HPMC),
poly-l-glutamic acid (𝛾-PGA), sodium chondroitin sulfate,
gelatin, and amylopectin.[33–35] Drug-loaded microneedles fabricated by water-soluble polymer matrix generally dissolve rapidly
and completely after being inserted into the skin, producing
no biohazardous medical waste.[36] The rapid dissolution of
microneedles results in the rapid release of loaded drugs. This
indicated that dissolving microneedles can be utilized to realize
instant transdermal drug delivery.[37] For example, Mönkäre et al.
reported that monoclonal IgG-loaded dissolvable HA microneedles were able to penetrate the epidermis of excised human skin
and the majority of inserted needle tips were dissolved after being
inserted into skin for 10 min.[38] Kim et al. fabricated dissolvable
microneedles of which the needle tips and base were made of
HPMC and CMC, respectively.[39] After being inserted into the
skin, HPMC tips which encapsulated the drug (donepezil hydrochloride) dissolved quickly within 15 min. A plethora of materials have been used for the fabrication of degradable microneedles, including polycaprolactone (PCL), polylactic acid (PLA),
polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycarbonate (PC), and chitosan.[40–44] For drug-loaded microneedles
fabricated by degradable polymer matrix, drug release profiles
are closely related to the degradation behaviors of substrate
materials.[45] And the loaded drugs are slowly released with
the degradation of polymers. Fabricating dissolvable composite
microneedles by combining soluble polymeric materials with
degradable polymeric materials is a novel way to realize rapid
separation of support from tips and controlled drug release.[46,47]
For example, Chen et al. prepared a dissolvable composite microneedle of which the tip was made of PCL and the support was
constituted of polyvinyl alcohol (PVA) and PVP.[27] When the microneedles were inserted into the skin, the support dissolved and
separated from tips, leaving the PCL tips containing doxorubicin
and lanthanum hexaboride in the skin to achieve slow-sustained
drug release.
Adv. Therap. 2020, 1900140
Non-dissolvable microneedles are generally utilized for skin
pretreatment. Non-dissolvable microneedles could pierce the
stratum corneum of skin and form micron-sized channels for
the drug in a patch to directly pass through the stratum corneum
or could achieve transdermal drug delivery by coating the drug
solution directly on the microneedle surface.[48] The constitutional materials of conventional non-dissolvable microneedles
mainly include polystyrene (PS) and polymethyl methacrylate
(PMMA).[49,50] With the rapid development in designing and
fabricating microneedles, a new type of non-dissolvable microneedle, namely hydrogel microneedle, has become a research
hotspot in polymeric microneedles due to its unique capability
of swelling. Hydrogel microneedles are fabricated through the
physical or chemical cross-linking of polymeric matrix, which
could confer sufficient mechanical strength to the microneedle
to pierce the stratum corneum of skin.[51] Compared with dissolvable microneedles, crosslinked hydrogel microneedles would
swell but not dissolve when inserted into the skin. This property makes it possible for the extraction of interstitial fluid from
the skin and release of pre-loaded drugs during the swelling
process.[52] For interstitial fluid extraction, hydrogel microneedles swelled and subsequently the interstitial fluid containing
biomarkers would be imbibed into the microneedles. For drug
delivery, drug-loaded hydrogel microneedles swelled and the preloaded drugs subsequently diffused out the microneedles. Furthermore, no substrate would remain in the skin when microneedles are pulled out of the skin. This suggests that hydrogel microneedles have proper biosafety and are suitable for repeated
use over a long period of time.[53] Adjusting the swelling ability of polymers by controlling the cross-linking density could
improve the transdermal drug delivery efficiency and drug release behavior.[54,55] The substrate materials for the preparation
of hydrogel microneedles mainly include PVA, poly(methyl vinyl
ether-co-maleic acid) (PMVE-co-MA), acrylate modified HA (mHA), and poly(2-hydroxyethyl methacrylate) (PHEMA).[56–58] It is
worth noting that the cross-linking process of polymers usually
involves high temperature or UV exposure,[59] it is necessary to
protect the loaded protein drugs from disruption throughout the
fabrication process by loading drugs into the base postmolding
instead of the microneedle tip during cross-linking process.[60]
Furthermore, it should be noted that swellable microneedles require fine tuning of the cross-linking density so as to possess
sufficient mechanical strength in the dry state to pierce the stratum corneum. Besides, they need to maintain good mechanical
strength in the hydrated state so as to be completely removed
from skin.
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Figure 1. Schematic illustration of polymeric microneedle fabrication by A) micromolding. Adapted with permission.[30] Copyright 2016, Elsevier Ltd. B)
3D printing. Adapted with permission.[94] Copyright 2018, Royal Society of Chemistry. C) Drawing lithography. Adapted with permission.[78] Copyright
2012, Elsevier Ltd. (D) Droplet-born air blowing methods. Adapted with permission.[75] Copyright 2013, Elsevier Ltd.
Hybrid microneedles generally use two or more materials
with completely different properties to achieve special functions
through the optimization of microneedle structure.[61,62] It is
worth noting that hybrid microneedles do not necessarily have
to be all polymeric. They could be fabricated through the hybridization of polymers, metals or inorganic substance. For example, Lee et al. reported the fabrication of hybrid microneedles with maltose (MT) and metal electrodes through drawing
lithography technique.[63] Compared with pure metal microneedles, the tip of maltose needle has higher gene loading capacity.
By combining with metal electrodes which can generate pulsed
electric fields, this hybrid microneedle significantly improves the
gene transfection efficiency. Prausnitz et al. reported the preparation of hybrid microneedles made of PVA/PVP and stainless
steel to achieve rapid separation of the tip from the support and
release the drug by using water soluble property of the tip polymer, which provides a rapid, convenient, and safe way of transdermal drug delivery.[64] Cao et al. reported the fabrication of hybrid
PVA/MT microneedles to deliver anti-inflammatory drugs.[65]
The mechanical strength of PVA microneedles were significantly
improved after adding MT. Once inserted into the skin, MT dissolved completely, thus generating micropores for the release of
drugs from polymeric matrix. For hybrid microneedles, it is necessary to fine tune the composition ratio and structural distribution of substitute polymers so as to optimize the drug release
profile and mechanical toughness.
Adv. Therap. 2020, 1900140
3. Methods for the Fabrication of Polymeric
Microneedles
With the rapid development of science and technology, more and
more versatile microneedle fabrication techniques have emerged
in the past few decades. Figure 1 shows several commonly used
fabrication processes of microneedles. Micromolding is the most
commonly used method to fabricate polymeric microneedles
because of excellent reproducibility, cost-efficiency, and convenience for scalable production.[66] Micromolding utilizes laser
etching, ion etching, and other methods to directly or indirectly
fabricate microneedle molds with desired size and morphology.
Then the desired polymers are added to the mold to fabricate corresponding polymeric microneedles.[67] According to the different processing methods of polymers in the microneedle mold,
the micromolding method can be divided into casting method,
hot embossing method, injection molding and investment molding, and so forth.[30] In general, casting method casts the drugloaded polymer solution into the microneedle mold, and promotes the polymer solution into the holes of microneedle mold
by centrifugation, vacuum or ultrasound to eliminate bubbles,
and then dry the mold to obtain the desired microneedle.[26,68,69]
Due to the advantages of low processing temperature, convenient fabrication process and little impact on drug activity, casting method is currently the most commonly used method to
prepare dissolvable polymer microneedles.[70,71] Hot embossing
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method, injection molding and investment molding are usually used to prepare degradable and insoluble microneedles, but
the processing temperature is relatively high in general, which
might easily affect the drug activity.[72,73] Although micromolding method does have some advantages, some limitations such
as time-consuming complex fabrication steps, involvement of
heat or UV irradiation in the fabrication process might reduce
the activity of sensitive drugs.[74] Different from micromolding method, some novel methods, such as drawing lithography, droplet-born air blowing, electro-drawing and 3D printing,
do not require the use of a mold and can achieve rapid (usually within 10 min) microneedle preparation.[42,75–77] The drawing lithography method directly extends the 2D thermosetting
polymer materials to acquire the 3D polymeric microneedles.[76]
Compared with conventional micromolding, drawing lithography method not only can fabricate microneedles with high aspect ratio, but also eliminates the need for molds and UV light
irradiation, thereby avoiding the use of toxic photoinitiators.[78]
However, since the formation of microneedles strongly depends
on the dynamic interaction between the fluid and frame, many
factors including the viscous property of the thermosetting polymer fluid, the patterns of the contacting pillars, and the drawing
rate of the frame would affect the final shape of the microneedles.
Therefore, drawing lithography method exhibits much worse reproducibility than micromolding.[42] Besides, it requires high
temperature for stretching and curing of thermosetting polymers, which limits the delivery of heat-sensitive drugs.[79] On
the contrary, the fabrication processes of droplet-born air blowing method, electro-drawing method, and 3D printing method
(inkjet printing, photopolymerization-based technique) are relatively mild. The droplet-born air blowing method shapes polymer
droplets into dissolvable polymeric microneedles by air flow,[75]
and electro-drawing method uses electrofluid actuation which is
not contacted at room temperature to fabricate degradable polymeric microneedles.[42]
However, conventional microneedle fabrication techniques
mentioned above cannot fabricate microneedles on curved
surfaces. As traditional microneedles are fabricated on the flat
substrate surface, it is difficult to completely insert into uneven
or curved skin surface, which results in the decreased penetration efficiency and drug delivery amount. Due to the versatility
and tunability to rapidly fabricate physical models of any geometrical shape up to micron scale with the computer-aided design
and computer-aided manufacturing,[80] 3D printing technology
has been utilized for the personalized fabrication of polymeric
microneedles with desired shapes and architectures in the
last decade.[81,82] 3D printing is a rapid prototyping technology
based on layer-by-layer printing and layer-by-layer superposition,
which has the advantages of high accuracy, good reproducibility,
and one-step fabrication and can meet personalized needs.[83,84]
The currently commonly utilized manufacturing technologies
of 3D printing for the fabrication of polymeric microneedles
mainly include inkjet printing, photopolymerization-based
technique, and fused deposition modelling (FDM).[85] Inkjet
printing could achieve controllable and selective deposition of
drug droplets onto microneedle surface by numerous thermal or
piezoelectric-driven printing heads.[86] Currently, such technique
has been main utilized to coat pre-fabricated microneedles with
drugs for the personalized and combined drug loading.[87,88]
Adv. Therap. 2020, 1900140
Photopolymerization-based technique refers to the fabrication
of 3D models by selectively polymerization of photo-sensitive
polymers under the laser/light irradiation. Such technique could
fabricate polymeric microneedles by consistent layer-by-layer
polymerization of UV-sensitive polymers through the photopolymerization curing process.[89] Stereolithography (SLA),
digital light processing (DLP), and two-photon polymerization
(2PP) are the commonly used photopolymerization-based techniques to fabricate polymeric microneedles.[90–92] The printing
speed of DLP is generally faster than SLA as the whole layer is
fabricated simultaneously. While 2PP is suitable for the fabrication of elaborate, complex structures in the microscale and
nanoscale. Lim et al. used DLP to fabricate a novel microneedle
on personalized curved surfaces to realize complete insertion of
microneedle into the contoured human skin.[81] The adoption of
SLA, DLP, and 2PP technologies for the fabrication of polymeric
microneedles is an attractive concept because of the versatility
in geometric complexity and high needle resolution provided
by these technologies.[93,94] However, some photoinitiators used
in the photopolymerization process are toxic and have certain
health concerns in transdermal drug delivery.[77] FDM, a subset
of extrusion printing, is a versatile, cost-effective 3D printing
technique on the basis of the melt-extrusion process and could
print biodegradable materials. However, there are some major
disadvantages of such technology, such as poor resolution, and
limited variety of substitute materials.[85,95] Currently its applications in microneedle fabrication are still limited in literature.
Nevertheless, FDM is still an appealing method as the fabrication process eliminates the use of solvents.[96] Besides, there
are currently some reports on the combination of FDM with
post-fabrication chemical etching step to fabricate biodegradable
microneedles with high resolution.[94]
The skin penetration ability of polymeric microneedles is
closely related to the geometry characteristics including shape,
aspect ratio, and tip diameter.[20,31,71] Up to now, the vast majority of microneedles are fabricated typically in cone or pyramid
shapes. Pyramidal shaped microneedles generally possessed better mechanical strength than the conical shaped ones.[97] As for
microneedles with same needle shapes, the mechanical strength
was improved by decreasing the aspect ratio or increasing the
base width.[98] But it is worth noting that excessively increasing the base width to reduce the aspect ratio will decrease the
skin insertion efficiency of microneedles.[99] As for tip diameter, microneedles with sharper tips generally could insert into the
skin more easily than the blunt one. For example, Chen et al. reported that chitosan microneedles with a tip diameter of 10 µm
could penetrate twice as deep as those with a tip diameter of
20 µm.[19] In general, pyramidal shaped polymeric microneedles
with smaller tip diameter and aspect ratio possess better penetration efficiency.
4. Biomedical Applications of Polymeric
Microneedles for Transdermal Drug Delivery
Polymeric microneedles in general could achieve percutaneous
delivery of peptides, proteins, vaccines, and small molecule
drugs. Based on the difference in drug release behavior, polymeric microneedles can be classified into rapid drug-releasing
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Figure 2. A) Brightfield (a) and fluorescence micrographs of exenatide loaded HA microneedles before (b) and after (c) skin insertion for 2 min. Fluorescence (d) and merged brightfield and fluorescence images of porcine skin puncture sites (white arrows) (e). The green fluorescence represents
exenatide. Adapted with permission.[100] Copyright 2014, Springer. B) Images of traditional microneedles and rapidly separating microneedles before
and after insertion into pig skin for different time points. Adapted with permission.[101] Copyright 2016, Elsevier Ltd.
type, slow-sustained drug-releasing type and stimuli-responsive
drug-releasing type.
4.1. Rapid Drug-Releasing Polymeric Microneedles
The rapid drug-releasing polymeric microneedles generally
encapsulate the drugs in water-soluble polymeric tips. There are
various substrate materials for the preparation of microneedle
support, including dissolving polymers, degradable polymers,
and metal matrices. Tuning the composition and architecture of
microneedle tip and support could achieve in situ rapid release
of loaded drugs, which could significantly increase the instantaneous drug concentration. Wang et al. reported the preparation
of hyaluronic acid microneedles which contained exenatide
drug at the needle tip using a casting method (as shown in
Figure 2A).[100] In vitro drug release results showed that the
microneedles released approximately 80% of loaded drugs after
being inserted into the skin for 30 s, and almost all of the
encapsulated drugs were released in 2 min. Furthermore, in vivo
animal experimental results showed that the therapeutic effect
of this microneedle for type II diabetes was comparable to that
of conventional subcutaneous injection of insulin, with a relative
bioavailability of up to 97%. Guo et al. used Rhodamine B as a
model drug to prepare dissolvable PVA/sucrose/PLA composite
microneedles loaded with Rhodamine B at the needle tip.[101]
Adv. Therap. 2020, 1900140
The tip of microneedle was PVA/sucrose which could easily
dissolve in water, and the microneedle support was biodegradable PLA. More than 90% of the loaded drugs could be released
after being inserted into the skin for 30 s, indicating a fast and
highly efficient transdermal drug delivery manner (as shown in
Figure 2B).
4.2. Slow-Sustained Drug-Releasing Polymeric Microneedles
Long-term slow-sustained drug release can maintain a stable
blood concentration, prolong the duration of drugs, and reduce
toxic side effects. Slow-sustained drug-releasing polymeric
microneedles usually use hydrogel microneedles to control the
drug release rate by adjusting the cross-linking density at the
physical or chemical cross-linking point. Jin et al. reported the
fabrication of insulin-loaded PVA phase-change microneedles
which was prepared by using a freeze-thaw physical cross-linking
method.[29] Animal experimental results indicated that the insulin content delivered percutaneously by the insulin-loaded
microneedle patch (dose: 2.0 IU·Kg−1 ) reached a peak at about
1 h, followed by a slow and sustained release for 3 h. The blood
insulin of pigs attached with two insulin-loaded microneedles
(dose: 2.0 IU·Kg−1 ) was comparable to those treated with conventional insulin pen (dose: 0.4 IU·kg−1 ), which indicated that
the relative bioavailability of the insulin microneedle was as high
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Figure 3. A) Schematic illustrations of transdermal delivery of macromolecules using chitosan microneedle patches. Adapted with permission.[99]
Copyright 2012, American Chemical Society. B) Schematic illustrations of sustained transdermal delivery of antigen using a microneedle delivery system,
composed of embeddable chitosan microneedles and a PLA supporting array. Adapted with permission.[105] Copyright 2013, Elsevier Ltd.
as 20%. Due to the absence of chemical crosslinkers during the
microneedle fabrication process, bioactive drugs such as proteins and peptides could be easily loaded on the microneedles in
a mild manner. Donnelly et al. reported the fabrication of hydrogel microneedles using PMVE-co-MA copolymer, polyethylene
glycol (PEG), and sodium bicarbonate as raw materials to achieve
esterification cross-linking at 80 °C.[54] Besides, the integration
of drug-loaded patches into the hydrogel microneedles allows the
construction of a chemically cross-linked hydrogel microneedle
system with slow-sustained drug release for 24 h. Due to the
presence of drug-loaded patch, the drug loading capacity of
the hydrogel microneedles could be increased up to several
milligrams. Meanwhile, the hydrogel microneedles could also
achieve better transdermal drug delivery when combined with
iontophoresis.
In addition, slow-sustained drug releasing polymeric microneedles could also be fabricated using degradable polymeric
matrix which degraded slowly and gradually released drugs in
vivo. There are numerous intricate and complicated factors that
can affect the in vivo polymer degradation behavior including
both internal factors, such as the composition, chain structure,
aggregation state of the polymer, and external factors, such as
temperature, oxygen, water, and light. Chen et al. reported the
preparation of bovine serum albumin (BSA)-loaded chitosan microneedles by casting method using 80% deacetylated chitosan as
raw material (as shown in Figure 3A).[99] It was shown by circular
dichroism spectroscopy that the conformation of the protein in
the microneedle was almost unaffected. On the one hand, as chitosan dissolved easily under weakly acidic aqueous conditions,
no organic solvents or harsh conditions of heat was needed in
the mixture of bioactive molecules with chitosan. On the other
hand, chitosan has excellent biocompatibility, degradability and
nontoxicity, which would not affect the conformation and activity
of bioactive molecules such as proteins.[102] The in vitro drug
release test results demonstrated that the microneedle could
sustained and cumulatively release 95% drugs within 8 days.
Since the skin contains a large number of immunocompetent
cells (Langerhans cells, dendritic cells, etc.) which can trigger the
Adv. Therap. 2020, 1900140
adaptive immune response, compared with the traditional intramuscular injection of vaccine, transcutaneous immunization
requires less antigen to produce a stronger immune effect.[103,104]
The transcutaneous immunization via microneedles was further
studied by Chen et al.,[105] who prepared chitosan/PVP/PLA
composite dissolvable microneedles using ovalbumin (OVA)
as a model antigen, as shown in Figure 3B. OVA is the main
protein found in chicken egg white, which has been widely used
as a model antigen in immunological studies due to its good
immunogenicity. The microneedle tip was chitosan loaded with
OVA model antigen, and the support of microneedle was PLA.
The contact surface between PLA and chitosan was coated with
PVP. When chitosan/PVP/PLA composite microneedles were
inserted into the skin for 5 min, the skin interstitial fluid would
dissolve the PVP coating, resulting in the separation of the PLA
support from the chitosan needle tip and the retention of the
OVA-loaded chitosan needle tip in the skin. The OVA antigen
was continuously released as the chitosan tip slowly degraded
in the skin. On day 7 post microneedle insertion, a strong
OVA-specific antibody response could be detected and lasted
for 6 weeks, indicating excellent long-lasting sustained release
behavior of the microneedle and great potential for sustained
transcutaneous immunization by microneedles.
4.3. Stimuli-Responsive Drug-Releasing Polymeric Microneedles
Constructing stimuli-responsive gene/drug delivery system is
one of the hotspots in gene/drug delivery field.[106–108] Stimuli
from physiological condition (pH value, glucose concentration,
enzyme activity, etc.) or external environment (sound, light,
electric current, magnetic field, temperature, strain, etc.) have
been used as the trigger for the release of drugs in the microneedle. Polymeric microneedles with stimulus-responsive
properties are expected to achieve on-demand administration
and better therapeutic effects. It is worth noting that several
important issues regarding the safety, pharmacokinetics, therapeutic efficacy, costs of manufacture, storage and transportation
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Figure 4. A) Schematic illustration of the design of the PVP microneedle arrays containing pH-responsive PLGA HMs and their mechanism for codelivery of two different model drugs Alexa 488 and Cy5 in sequence. Adapted with permission.[68] Copyright 2012, Elsevier Ltd. B) Schematic of the
glucose responsive system based on a microneedle-array patch. The patch integrated with pancreatic 𝛽-cells but without glucose signal amplifiers (a).
The patch integrated with pancreatic 𝛽-cells and glucose signal amplifiers (b). Adapted with permission.[109] Copyright 2016, Wiley-VCH.
should be thoroughly evaluated prior to clinical translation of
stimulus-responsive microneedles.
4.3.1. Stimuli-Responsive Drug Release Triggered by Internal
Physiological Environment
Stimuli-responsive drug release behavior of microneedles could
be triggered by changes in the human body’s intrinsic physiological signals, such as pH value, glucose concentration and
enzyme activity, so as to release the entrapped drugs, realize on-demand administration and even regulate the speed of
administration.[68,108,109] Stimuli-responsive drug-releasing microneedles would no doubt provide a new approach for personalized treatment in the future.
Taking advantage of the acidic nature of the human skin epidermis, Sung et al. prepared a PVP microneedle with sequential
drug release property in response to pH stimulation, as shown
in Figure 4A.[68] In the first step, they prepared polylactic acidglycolic acid copolymer (PLGA) microspheres which encapsulated the model drug 2 (Cy5) and the foaming agent sodium
bicarbonate (NaHCO3 ). Then, using PVP as the raw material,
PVP microneedle loaded with free model drug 1 (Alexa 488) and
drug-loaded PLGA microspheres was prepared by micromolding
method. When PVP microneedles were inserted into the skin for
5 min, more than 50% of free model drug 1 was released rapidly.
Due to the acidic nature of the skin epidermis, H+ permeated
into PLGA microspheres, dissolved NaHCO3 and produced CO2 .
CO2 could generate micropores on the microsphere surface and
thereby promote the release of model drug 2, allowing more than
50% of model drug 2 to be released within 15 min. Such strategy
using acidic microenvironment of the skin epidermis to regulate
the release order of a variety of drugs has great potential in clinical
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medical applications. For example, cardiovascular agonists are
usually administered 15–20 min before the therapeutic agent.[110]
Diabetes is a metabolic disease characterized by hyperglycemia. In the 21st century, diabetes has become one of the
most serious public health problems in the world. To solve this
public health problem, Gu et al. prepared a smart microneedle
patch which could secrete insulin in response to glucose stimulation, as shown in Figure 4B. They innovatively designed a
glucose signal amplifier (GSA) which is a hypoxia responsive
hyaluronic acid vesicle containing glucose oxidase, 𝛼-linear
amylase, and glucoamylase.[109] The control group was the GSA
free microneedle patch consisting of cross-linked hyaluronic
acid (HA) microneedles loaded with a microgel-containing
pancreatic 𝛽 cells. When the microneedle was inserted into the
skin, as the glucose content in the body increased, glucose would
enter into the microneedle by diffusion, which in turn contacted
with the pancreatic 𝛽 cells in the microgel at the bottom of the
microneedle and then stimulated pancreatic 𝛽 cells to secrete
insulin. However, due to the limited diffusion depth of glucose in
the microneedle, the therapeutic effect was not quite obvious. In
comparison, microneedle patches containing GSA and 𝛼-linear
amylase at the tip of the needle exhibited highly efficient blood
glucose regulation ability. With the increase of glucose content in
the body, local hypoxia was generated under the action of glucose
oxidase, which destroyed the amphipathic structure of GSA vesicles and promoted the release of encapsulated 𝛼-linear amylase,
glucose oxidase and glucoamylase in GSA vesicles. Linear amylase could convert starch into disaccharides and trisaccharides,
and then into glucose under the action of glucoamylase. The
increase of local glucose content in the microneedle significantly
enhanced the sensing ability of pancreatic 𝛽 cells and promoted
rapid insulin secretion into the blood vessels and lymphatic
capillary network, maintaining blood glucose at normal levels
for up to 10 h. This design used a glucose amplifier to improve
the stimulation sensitivity of pancreatic 𝛽 cells, exhibiting good
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Figure 5. A) Schematic illustrations of combination of chemotherapy and photothermal therapy using near-infrared light-activatable microneedles.
Adapted with permission.[27] Copyright 2015, American Chemical Society. B) Schematic illustration of the tensile strain-triggered drug release. Adapted
with permission.[111] Copyright 2015, American Chemical Society.
blood glucose regulation efficiency. It is worth mentioning that
in this microneedle system, the amount of glucose oxidase used
in the microneedle is a key factor to trigger glucose-stimulated
insulin secretion to regulate blood glucose concentration. If the
content of glucose oxidase is too low, the hypoxic stimulation
will lag behind, and pancreatic 𝛽 cells cannot secrete insulin in
a timely and efficient manner to achieve the therapeutic effect.
However, the human physiological environment is complex
and variable. Even though drug release in response to physiological environmental stimuli can regulate the drug release behavior
according to the magnitude of the stimulus signal, it has poor
spatiotemporal controllability and is difficult to precisely control
the amount of drugs administered.[111]
4.3.2. Stimuli-Responsive Drug Release Triggered by Changes
in External Environment
Stimuli-responsive drug release system triggered by changes in
external environment conditions can generally be achieved by
external stimulation signals such as light, temperature, stress,
magnetic field, and ultrasound.[27,108,112] Such system is simple, convenient to operate, space-time controllable, and highly
targeting. It can achieve administration or interruption at any
time according to actual needs, providing great flexibility to patients. McCoy et al. reported the preparation of a UV lightresponsive drug-releasing polyhydroxyethyl methacrylate hydrogel microneedle.[59] The photo-responsive ibuprofen conjugate
was immobilized in the microneedle matrix via non-covalent
bonds, and the drug was trapped inside the microneedle without illumination. Upon UV illumination, the ibuprofen conjugate disintegrated and generated a water-soluble ibuprofen. Then
ibuprofen diffused into the skin via the tissue fluid in the swollen
microneedle to achieve a therapeutic effect.
Ultraviolet light irradiation can control drug release and administer drugs on demand, but it has potential harm to the skin,
thus limiting the practical application of this design. However,
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other external stimulation factors such as near-infrared light
and stress stretching have received more and more attention in
recent years due to their safety and reliability. The penetration
ability of near-infrared light into human body is strong, and it can
penetrate deep subcutaneous tissue. When combined with photosensitizers or photothermal therapeutic agents, it could achieve
locally targeted and highly effective treatment of tumors. Chen
et al. prepared a near-infrared photostimulation-responsive
drug releasing microneedle system containing doxorubicin
(DOX) and lanthanum hexaboride (LaB6 ) nanomaterials by
micromolding,[27] as shown in Figure 5A. The microneedle
system used drug-loaded PCL as the tip and PVA/PVP as the
support structure. When the microneedle was inserted into the
skin for 5 min, the PVA/PVP support structure detached from
the PCL needle tip, leaving the tip in the skin. Since PCL was
hydrophobic, drugs could not be released. Upon near-infrared
light irradiation, LaB6 nanomaterial underwent photothermal
transformation, which increased the temperature of the targeted
tissue for microneedle action and resulted in photoelimination. Meanwhile, PCL melted at 50 °C and then released the
chemotherapeutic drug DOX, thus realizing the synergistic
photothermal therapy and chemotherapy to kill the tumor. Lightactivated drug release can be precisely controlled and turned on
or off as needed. At the same time, in vivo animal experimental
results showed that when using laser irradiation for 3 times
within 1 week, this collaborative treatment system can completely eradicate 4T1 breast tumors without tumor recurrence
and significant weight loss, showing excellent therapeutic effect.
Strain-responsive drug release, which does not require additional auxiliary equipment, is a simple way to construct wearable
drug delivery system with on-demand release. Wearable drug
delivery systems generally incorporate functional therapeutic carriers into flexible and stretchable supporting materials
such as elastomers, hydrogels, and fabrics for noninvasive
or minimally invasive delivery of pharmacological agents.[5]
Gu et al. reported the preparation of microneedle-based wearable transdermal drug delivery system with stretch-triggered
drug release property. They prepared the insulin-loaded PLGA
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nanoparticles, and then encapsulated the PLGA nanoparticles
into sodium alginate microgel as the drug reservoir, as shown
in Figure 5B.[111] The alginate microgel reservoir was then
integrated with high-performance silicone elastomers (Dragon
Skin 30) and hyaluronic acid microneedles into a wearable
microneedle system with stress stimuli-responsive drug release.
The microneedle system could act anywhere on the skin, no
matter whether it is the flat skin, the bent knuckles, or elbows.
When the microneedle attached place was stretched due to
movement, the elastomer would be stretched, the surface area
of the microgel increased and Poisson’s ratio changed, causing
compression and promoting drug release to achieve therapeutic
effects. Consequently, sustained drug release could be achieved
by daily body motions of patients, and pulsatile drug release
could be activated by intentional administration.
5. Biomedical Applications of Polymeric
Microneedles for Diagnosis
Apart from transdermal drug delivery, polymeric microneedles
have also been utilized for the disease diagnosis and metabolic
analysis due to the fact that they can extract the skin interstitial
fluid (ISF) in a minimal invasive way than other techniques such
Figure 6. A) Schematic representation of the rapid extraction of ISF by crosslinked MeHA-MN patches. Adapted with permission.[118] Copyright 2017,
Wiley-VCH. B) Schematic illustration of the tensile strain-triggered drug release. Adapted with permission.[119] Copyright 2018, American Association
for the Advancement of Science.
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as suction-blister technique and micropipettes insert.[44,113,114]
ISF is generated from blood transcapillary filtration. Therefore,
the constituent in the ISF is quiet similar to the plasma, which
means that the ingredient changes in the ISF could represent
changes in the human body.[115,116] Since hydrogel microneedles
have the capability of swelling in the skin, they have been widely
designed to extract ISF for monitoring and diagnosis. The
extracted ISF samples could be separated from microneedles
by centrifugation.[117] For example, Chang et al. reported the
fabrication of a swellable microneedle made of methacrylated
hyaluronic acid (MeHA), as shown in Figure 6A.[118] Due to
the high water affinity of MeHA, the as-prepared microneedle
could rapidly extract approximately 1.4 mg of ISF, which was
sufficient for the offline detection of metabolites like glucose
and cholesterol. Apart from analyzing metabolites, microneedles
have also been used to monitor immune cells in the skin. For
example, Mandal et al. reported the preparation of a Poly-l-lysine
microneedle which was surface-coated with alginate hydrogel
containing immunologic adjuvants and antigen, as shown in
Figure 6B.[119] Once the microneedle was inserted into the
skin, the outmost hydrogel layer swelled. Leukocyte in the
skin would infiltrate into the hydrogel and be activated by the
embedded adjuvants to recruit T cells into the hydrogel. When
the microneedles were removed from the skin, cells could be
collected by dissolving the hydrogel layer for immunological
analysis. In recent years, polymeric microneedles have been
modified with electrochemical sensors or microfluidic chips to
achieve real-time in situ monitoring of biomarkers for diagnostic
applications.[120–122] For instance, Ciui et al. reported the combination of a wearable wireless bandage sensor with microneedles
for in situ melanoma screening.[123] Lee et al. reported the
fabrication of thermo-responsive polymeric microneedles combined with glucose sensors for continuous glucose monitoring
and on demand drug release.[124] These smart designs endow
Figure 7. A) Optical camera image and schematic (bottom) of the wearable sweat-based glucose monitoring patch with the feedback transdermal
drug delivery function. Adapted with permission.[124] Copyright 2017, American Association for the Advancement of Science. B) Schematic drawings
of the diabetes patch, which is composed of the sweat-control (i, ii), sensing (iii–vii), and therapy (viii–x) components. Adapted with permission.[125]
Copyright 2016, Macmillan Publishers Limited. These pioneering works pave the way for the development of closed-loop microneedle-based monitoring
and therapeutic delivery systems which consist of sensors and chips.
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the microneedles with the novel characteristic of diagnostic
guided therapeutic drug delivery, which would give rise to the
revolutionary change in the field of point-of-care medicine.
6. Conclusions and Future Perspectives
Currently, great progress has been in the fields of transdermal drug delivery and diagnosis by polymeric microneedles.
Novel substrate polymer materials and fabrication techniques are
emerging in an endless stream. Polymeric microneedles can not
only be administered on demand and release drugs in response to
stimulation, but also can be customized individually to improve
the patients’ quality of life and achieve better therapeutic effects.
With the improvement of people’s living standard and the rapid
development of microneedles, development of intelligent and
portable microneedle system is the general trend of the times.
Stimuli-responsive drug delivery microneedle system, diagnostic and therapeutic integrated microneedle system and wearable
microneedle system will become the hotspots in the field of microneedle research. Despite remarkable progress has been made
in the development of microneedles for transdermal drug delivery, disease diagnosis and monitoring, the biomedical application
of microneedles is still in its infancy, and has not yet moved toward large-scale production and practicality. Some cutting-edge
technologies could be integrated with microneedles in the near
future.
First of all, the vast majority of microneedles-based transdermal drug delivery systems are concerned with the on-demand release of drugs, only limited literatures focus on the combination
of microneedles with electrochemical sensors or microchips to
realize the closed-loop control of drug release,[124,125] as shown
in Figure 7. The ideal circumstance of microneedle-based smart
wearable theranostic devices should be like this: the body condition can be monitored in real-time, and once an abnormal situation of the body is found, an early warning will be issued to
the patient’s device through the wireless communication system in the microneedle and the drug release system is activated.
To achieve such goal, it is of vital importance to integrate microneedles with electronic microchip elements. To fully translate microchip-based microneedle into clinical applications, current microneedle fabrication techniques should be improved to
achieve large scale production. Besides, it is necessary to adjust
the accuracy and sensitivity of the electronic sensor and effector
elements inside the microchip by improving programming and
wireless communication techniques. In the future, we envisage
that these microneedle-based smart wearable theranostic devices
are particularly desirable for medical conditions such as chronic
diseases treatment, diabetes management, and control of chronic
pain, where long-term application and multistage drug delivery
are required.
Besides, the current microneedle-based transdermal delivery
focuses mainly on delivery of drugs, in the future, microneedles
could be utilized for the local delivery of cells to realize cell-based
therapy. Nowadays, there are only few researches on the development of cell-loaded microneedles for the treatment of myocardial
infarction,[126–128] as shown in Figure 8. In the future, we envisage that microneedles would be widely used to delivery stem cells
for organ repair and regeneration. It is also possible to use microneedles as depot for the delivery of probiotics to the intestinal
tract to regulate the intestinal microecology for the treatment of
some metabolic disease. Some critical issues need to be solved
Figure 8. A) Schematic showing the overall design used to test the therapeutic benefits of microneedle- cardiac stromal cells on infarcted heart. Adapted
with permission.[128] Copyright 2018, American Association for the Advancement of Science. B) Schematic drawings of transdermal melanocyte delivery
using microneedles. Adapted with permission.[127] Copyright 2018, British Association of Dermatologists. These pioneering works pave the way for the
future development of cell-integrated microneedles for organ repair and regeneration.
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Figure 9. A) Schematic illustration of microneedle-based transdermal cancer immunotherapy. Adapted with permission.[129] Copyright 2017, American
Association for the Advancement of Science. B) Schematic of the MN patch-assisted delivery of a PD1 for the skin cancer treatment. Adapted with
permission.[130] Copyright 2016, American Chemical Society. These pioneering works pave the way for the future development of microneedle-based
cancer immunotherapy.
before realizing such goal, such as how to maintain the cell viability in the microneedle and how to realize uniform distribution
of cells within the microneedle.
Last but not least, note that immunotherapy in recent years
have sparkled increasing interest due to the high treatment efficiency and have been widely utilized in many cutting-edge
biomedical fields. Currently, there are already some reports on
the application of microneedles to deliver checkpoint inhibitors
for tumor treatment,[127,129–131] as shown in Figure 9. In the near
future, we envisage that microneedles could be utilized to delivery not only immune inhibitors to treat tumors, but also cytokine
and immune cells for on-demand regulation of the microenvironment of the skin and tumor. Considering current advances in
the microneedles, it is quite possible to achieve this goal in the
near future. With the joint efforts of multi-discipline, it is believed
that microneedle-based immunotherapy will sooner or later be
utilized for clinical practice.
In summary, despite the remarkable achievements that have
been made in the microneedle field, development of the next generation’s microneedle-based multifunctional smart biomaterials
is still urgently needed for future biomedical applications. It is
believed that with the development of science and technology,
microneedles will eventually move toward large-scale production
and practicality, bringing convenience to people’s lives. We hope
that this review would appeal to a broad audience and promote
the development of microneedle-based technique for biomedical
applications.
Acknowledgements
This work was financially supported by the Southwest Hospital Key Program (SWH2016ZDCX2014). M.X. thanks the Discovery grant of Natural
Science and Engineering Research of Canada and Canada Foundation for
Innovation.
Conflict of Interest
The authors declare no conflict of interest.
Adv. Therap. 2020, 1900140
Keywords
diagnosis, drug delivery, microneedle fabrication, polymeric microneedles,
transdermal delivery
Received: July 16, 2019
Revised: October 2, 2019
Published online:
[1] D. Chouhan, N. Dey, N. Bhardwaj, B. B. Mandal, Biomaterials 2019,
216, 119267.
[2] M. R. Prausnitz, S. Mitragotri, R. Langer, Nat. Rev. Drug Discovery
2004, 3, 115.
[3] C. Pegoraro, S. MacNeil, G. Battaglia, Nanoscale 2012, 4, 1881.
[4] S. Babity, M. Roohnikan, D. Brambilla, Small 2018, 14, e1803186.
[5] M. Amjadi, S. Sheykhansari, B. J. Nelson, M. Sitti, Adv. Mater. 2018,
30, 1704530.
[6] E. Larrañeta, M. T. Mccrudden, A. J. Courtenay, R. F. Donnelly,
Pharm. Res. 2016, 33, 1055.
[7] M. R. Prausnitz, R. Langer, Nat. Biotechnol. 2008, 26, 1261.
[8] G. Carneiro, M. G. Aguiar, A. P. Fernandes, L. A. Ferreira, Expert Opin.
Drug Delivery 2012, 9, 1083.
[9] Y. Ye, K. Haripriya, A. K. Banga, Pharmaceutics 2011, 3, 474.
[10] M. R. Prausnitz, V. G. Bose, R. Langer, J. C. Weaver, Proc. Natl. Acad.
Sci. U. S. A. 1993, 90, 10504.
[11] I. Lavon, J. Kost, Drug Discovery Today 2004, 9, 670.
[12] S. Singh, J. Singh, Med. Res. Rev. 2010, 13, 569.
[13] J. W. Lee, P. Gadiraju, J. H. Park, M. G. Allen, M. R. Prausnitz, J.
Controlled Release 2011, 154, 58.
[14] B. M. Medi, J. Singh, Int. J. Pharm. 2006, 308, 61.
[15] J. Richter-Johnson, P. Kumar, Y. E. Choonara, L. C. du Toit, V. Pillay,
Expert Rev. Pharmacoeconomics Outcomes Res. 2018, 18, 359.
[16] K. S. Paudel, M. Milewski, C. L. Swadley, N. K. Brogden, P. Ghosh,
A. L. Stinchcomb, Ther. Delivery 2010, 1, 109.
[17] Y. Hao, W. Li, X. L. Zhou, F. Yang, Z. Y. Qian, J. Biomed. Nanotechnol.
2017, 13, 1581.
[18] T. M. Blicharz, P. Gong, B. M. Bunner, L. L. Chu, K. M. Leonard, J. A.
Wakefield, R. E. Williams, M. Dadgar, C. A. Tagliabue, R. El Khaja, S.
L. Marlin, R. Haghgooie, S. P. Davis, D. E. Chickering, H. Bernstein,
Nat. Biomed. Eng. 2018, 2, 151.
1900140 (13 of 15)
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
www.advtherap.com
[19] X. Jin, D. D. Zhu, B. Z. Chen, M. Ashfaq, X. D. Guo, Adv. Drug Delivery
Rev. 2018, 127, 119.
[20] M. R. Prausnitz, Annu. Rev. Chem. Biomol. Eng. 2017, 8, 177.
[21] S. P. Davis, B. J. Landis, Z. H. Adams, M. G. Allen, M. R. Prausnitz,
J. Biomech. 2004, 37, 1155.
[22] E. M. Cahill, E. D. O’Cearbhaill, Bioconjugate Chem. 2015, 26, 1289.
[23] M. S. Gerstel, V. A. Place (Alza Corporation), US 3964482, 1976.
[24] S. Henry, D. V. McAllister, M. G. Allen, M. R. Prausnitz, J. Pharm.
Sci. 1998, 87, 922.
[25] K. van der Maaden, W. Jiskoot, J. Bouwstra, J. Controlled Release
2012, 161, 645.
[26] M. H. Ling, M. C. Chen, Acta Biomater. 2013, 9, 8952.
[27] M. C. Chen, Z. W. Lin, M. H. Ling, ACS Nano 2015, 10, 5b05043.
[28] M. C. Chen, M. H. Ling, S. J. Kusuma, Acta Biomater. 2015, 24, 106.
[29] S. Yang, W. Fei, J. Liu, G. Fan, W. Welsh, Z. Hua, T. Jin, Adv. Funct.
Mater. 2015, 25, 4633.
[30] E. Larrañeta, R. E. M. Lutton, A. D. Woolfson, R. F. Donnelly, Mater.
Sci. Eng. R 2016, 104, 1.
[31] M. Wang, L. Z. Hu, C. J. Xu, Lab Chip 2017, 17, 1373.
[32] O. Howells, N. Rajendran, S. Mcintyre, S. Amini-Asl, P. Henri, Y. F.
Liu, O. Guy, A. E. G. Cass, M. C. Morris, S. Sharma, ChemBioChem
2019, 17, 20.
[33] T. M. Tuan-Mazlelaa, M. T. C. Mccrudden, B. M. Torrisi, M. A. Emma,
M. J. Garland, T. R. R. Singh, R. F. Donnelly, Eur. J. Pharm. Sci. 2013,
50, 623.
[34] J. Chen, Y. Qiu, S. Zhang, Y. Gao, Drug Dev. Ind. Pharm. 2016, 42,
890.
[35] A. P. Raphael, M. L. Crichton, R. J. Falconer, S. Meliga, X. Chen, G. J.
Fernando, H. Huang, M. A. Kendall, J. Controlled Release 2016, 225,
40.
[36] H. L. Quinn, B. Louise, C. M. Hughes, R. F. Donnelly, J. Pharm. Sci.
2015, 104, 3490.
[37] S. Liu, D. Wu, Y. Quan, F. Kamiyama, K. Kusamori, H. Katsumi, T.
Sakane, A. Yamamoto, Mol. Pharmaceutics 2015, 13, 272.
[38] J. Mönkäre, N. M. Reza, K. Baccouche, S. Romeijn, W. Jiskoot, J. A.
Bouwstra, J. Controlled Release 2015, 218, 53.
[39] J. Y. Kim, M. R. Han, Y. H. Kim, S. W. Shin, S. Y. Nam, J. H. Park, Eur.
J. Pharm. Biopharm. 2016, 105, 148.
[40] M. C. Chen, M. H. Ling, K. W. Wang, Z. W. Lin, B. H. Lai, D. H. Chen,
Biomacromolecules 2015, 16, 1598.
[41] S. Aoyagi, H. Izumi, Y. Isono, M. Fukuda, H. Ogawa, Sens. Actuators
A 2007, 139, 293.
[42] R. Vecchione, S. Coppola, E. Esposito, C. Casale, V. Vespini, S. Grilli,
P. Ferraro, P. A. Netti, Adv. Funct. Mater. 2014, 24, 3515.
[43] M. Han, D. H. Hyun, H. H. Park, S. S. Lee, C. H. Kim, C. Kim, J.
Micromech. Microeng. 2007, 17, 1184.
[44] D. V. Mcallister, M. Ping, Wang, S. P. D, P. Jung-Hwan, P. J. Canatella,
M. G. Allen, M. R. Prausnitz, Proc. Natl. Acad. Sci. U. S. A. 2003, 100,
13755.
[45] K. T. Tu, C. K. Chung, J. Micromech. Microeng. 2016, 26, 065015.
[46] K. J. Cha, T. Kim, S. Jea Park, D. S. Kim, J. Micromech. Microeng. 2014,
24, 115015.
[47] M. Kim, B. Jung, J. H. Park, Biomaterials 2012, 33, 668.
[48] C. Wang, Y. Ye, G. Hochu, H. Sadeghifa, Z. Gu, Nano Lett. 2016, 16,
2334.
[49] L. Wangtan, J. Supaseth, M. Wijuk, C. Muthita, P. Alongkorn, P. Tanapat, S. Werayut, J. Mech. Behav. Biomed. Mater. 2015, 50, 77.
[50] S. O. Choi, Y. C. Kim, J. H. Park, J. Hutcheson, H. S. Gill, Y. K. Yoon,
M. R. Prausnitz, M. G. Allen, Biomed. Microdevices 2010, 12, 263.
[51] R. F. Donnelly, T. R. Singh, M. J. Garland, K. Migalska, R. Majithiya,
C. M. McCrudden, P. L. Kole, T. M. Mahmood, H. O. McCarthy, A.
D. Woolfson, Adv. Funct. Mater. 2012, 22, 4879.
[52] Y. Qiu, G. Qin, S. Zhang, Y. Wu, B. Xu, Y. Gao, Int. J. Pharm. 2012,
437, 51.
Adv. Therap. 2020, 1900140
[53] R. F. Donnelly, T. R. Singh, A. Z. Alkilani, M. T. McCrudden, S. O’Neill,
C. O’Mahony, K. Armstrong, N. McLoone, P. Kole, A. D. Woolfson,
Int. J. Pharm. 2013, 451, 76.
[54] R. F. Donnelly, T. R. Singh, M. J. Garland, K. Migalska, R. Majithiya,
C. M. Mccrudden, P. L. Kole, T. M. Mahmood, H. O. Mccarthy, A. D.
Woolfson, Adv. Funct. Mater. 2012, 22, 4879.
[55] K. Y. Lee, J. A. Rowley, P. Eiselt, E. M. Moy, D. J. Mooney, Macromolecules 2000, 33, 4291.
[56] S. Y. Yang, E. D. O’Cearbhaill, G. C. Sisk, K. M. Park, W. K. Cho, M.
Villiger, B. E. Bouma, B. Pomahac, J. M. Karp, Nat. Commun. 2014,
4, 1702.
[57] R. F. Donnelly, M. T. Mccrudden, A. A. Zaid, E. Larrañeta, E. Mcalister, A. J. Courtenay, M. C. Kearney, T. R. Singh, H. O. Mccarthy, V. L.
Kett, PLoS One 2014, 9, e111547.
[58] A. V. Romanyuk, V. N. Zvezdin, P. Samant, M. I. Grenader, M.
Zemlyanova, M. R. Prausnitz, Anal. Chem. 2014, 86, 10520.
[59] J. G. Hardy, E. Larraneta, R. F. Donnelly, N. Mcgoldrick, K. Migalska,
M. T. Mccrudden, N. J. Irwin, L. Donnelly, C. P. Mccoy, Mol. Pharmaceutics 2016, 13, 907.
[60] E. Eltayib, A. J. Brady, E. Caffarelsalvador, P. Gonzalezvazquez, A. Z.
Alkilani, H. O. Mccarthy, J. C. Mcelnay, R. F. Donnelly, Eur. J. Pharm.
Biopharm. 2016, 102, 123.
[61] K. Lee, H. B. Song, W. Cho, J. H. Kim, J. H. Kim, W. Ryu, Acta Biomater. 2018, 80, 48.
[62] M. Dangol, H. Yang, G. L. Cheng, S. F. Lahiji, S. Kim, Y. Ma, H. Jung,
J. Controlled Release 2016, 223, 118.
[63] K. Lee, J. D. Kim, C. Y. Lee, S. Her, H. Jung, Biomaterials 2011, 32,
7705.
[64] L. Y. Chu, M. R. Prausnitz, J. Controlled Release 2011, 149, 242.
[65] Y. Cao, Y. Tao, Y. Zhou, S. Gui, J. Drug Delivery Sci. Technol. 2016, 35,
1.
[66] E. Caffarel-Salvador, R. F. Donnelly, Curr. Pharm. Des. 2016, 22, 1105.
[67] S. Duarah, M. Sharma, J. Wen, Eur. J. Pharm. Biopharm. 2019, 136,
48.
[68] C. J. Ke, Y. J. Lin, Y. C. Hu, W. L. Chiang, K. J. Chen, W. C. Yang, H. L.
Liu, C. C. Fu, H. W. Sung, Biomaterials 2012, 33, 5156.
[69] J. Chen, Y. Qiu, S. Zhang, G. Yang, Y. Gao, Drug Dev. Ind. Pharm.
2015, 41, 415.
[70] A. M. Rodgers, A. S. Cordeiro, A. Kissenpfennig, R. F. Donnelly, Expert Opin. Drug Delivery 2018, 15, 851.
[71] R. L. Creighton, K. A. Woodrow, Adv. Healthcare Mater. 2019, 8,
e1801180.
[72] D. H. Keum, H. S. Jung, T. Wang, M. H. Shin, Y. E. Kim, K. H. Kim,
G. O. Ahn, S. K. Hahn, Adv. Healthcare Mater. 2015, 4, 1152.
[73] M. Han, D. K. Kim, S. H. Kang, H. R. Yoon, B. Y. Kim, S. S. Lee, K.
D. Kim, H. G. Lee, Sens. Actuators B 2009, 137, 274.
[74] S. P. Sullivan, N. Murthy, M. R. Prausnitz, Adv. Mater. 2010, 20, 933.
[75] J. D. Kim, M. Kim, H. Yang, K. Lee, H. Jung, J. Controlled Release
2013, 170, 430.
[76] K. Lee, H. C. Lee, D. S. Lee, H. Jung, Adv. Mater. 2010, 22, 483.
[77] A. R. Johnson, C. L. Caudill, J. R. Tumbleston, C. J. Bloomquist, K. A.
Moga, A. Ermoshkin, D. Shirvanyants, S. J. Mecham, J. C. Luft, J. M.
Desimone, PLoS One 2016, 11, e0162518.
[78] K. Lee, H. Jung, Biomaterials 2012, 33, 7309.
[79] Z. Chen, L. Ren, J. Li, L. Yao, Y. Chen, B. Liu, Acta Biomater. 2018, 65,
283.
[80] R. D. Pedde, B. Mirani, A. Navaei, T. Styan, S. Wong, M. Mehrali,
A. Thakur, N. K. Mohtaram, A. Bayati, A. Dolatshahi-Pirouz, M.
Nikkhah, S. M. Willerth, M. Akbari, Adv. Mater. 2017, 29, 1606061.
[81] S. H. Lim, J. Y. Ng, L. Kang, Biofabrication 2017, 9, 015010.
[82] Afsana, J. V, H. Nafis, J. Keerti, Curr. Pharm. Des. 2018, 24, 5062.
[83] C. Y. Liaw, M. Guvendiren, Biofabrication 2017, 9, 024102.
[84] J. Giannatsis, V. Dedoussis, Int. J. Adv. Manuf. Technol. 2009, 40,
116.
1900140 (14 of 15)
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
www.advtherap.com
[85] S. N. Economidou, D. A. Lamprou, D. Douroumis, Int. J. Pharm.
2018, 544, 415.
[86] S. M. Barinov, I. V. Vakhrushev, V. S. Komlev, A. V. Mironov, V. K.
Popov, A. Y. Teterina, A. Y. Fedotov, K. N. Yarygin, Inorg. Mater.: Appl.
Res. 2015, 6, 316.
[87] E. A. Allen, C. O’Mahony, M. Cronin, T. O’Mahony, A. C. Moore, A.
M. Crean, Int. J. Pharm. 2016, 500, 1.
[88] S. Ross, N. Scoutaris, D. Lamprou, D. Mallinson, D. Douroumis,
Drug Delivery Transl. Res. 2015, 5, 451.
[89] M. Layani, X. Wang, S. Magdassi, Adv. Mater. 2018, 30, e1706344.
[90] C. P. P. Pere, S. N. Economidou, G. Lall, C. Ziraud, J. S. Boateng,
B. D. Alexander, D. A. Lamprou, D. Douroumis, Int. J. Pharm. 2018,
544, 425.
[91] I. Xenikakis, M. Tzimtzimis, K. Tsongas, D. Andreadis, E. Demiri,
D. Tzetzis, D. G. Fatouros, Eur. J. Pharm. Sci. 2019, 137,
104976.
[92] S. N. Economidou, C. P. P. Pere, A. Reid, M. J. Uddin, J. F. C. Windmill, D. A. Lamprou, D. Douroumis, Mater. Sci. Eng. C 2019, 102,
743.
[93] Z. Faraji Rad, R. E. Nordon, C. J. Anthony, L. Bilston, P. D. Prewett, J.
Y. Arns, C. H. Arns, L. Zhang, G. J. Davies, Microsyst. Nanoeng. 2017,
3, 17034.
[94] M. A. Luzuriaga, D. R. Berry, J. C. Reagan, R. A. Smaldone, J. J.
Gassensmith, Lab Chip 2018, 18, 1223.
[95] A. Goyanes, J. Wang, A. Buanz, R. Martínez-Pacheco, R. Telford, S.
Gaisford, A. W. Basit, Mol. Pharmaceutics 2015, 12, 4077.
[96] G. Jonathan, A. Karim, Int. J. Pharm. 2016, 499, 376.
[97] J. W. Lee, J. H. Park, M. R. Prausnitz, Biomaterials 2008, 29, 2113.
[98] J. H. Park, M. G. Allen, M. R. Prausnitz, J. Controlled Release 2005,
104, 51.
[99] M. C. Chen, M. H. Ling, K. Y. Lai, E. Pramudityo, Biomacromolecules
2012, 13, 4022.
[100] Z. Z. Zhu, H. F. Luo, W. D. Lu, H. S. Luan, Y. B. Wu, J. Luo, Y. J. Wang,
J. X. Pi, C. Y. Lim, H. Wang, Pharm. Res. 2014, 31, 3348.
[101] D. D. Zhu, Q. L. Wang, X. B. Liu, X. D. Guo, Acta Biomater. 2016, 41,
312.
[102] T. A. Sonia, C. P. Sharma, Adv. Polym. Sci. 2011, 243, 23.
[103] D. G. Koutsonanos, M. D. P. Martin, V. G. Zarnitsyn, S. P. Sullivan,
R. W. Compans, M. R. Prausnitz, I. Skountzou, PLoS One 2009, 4,
e4773.
[104] S. Al-Zahrani, M. Zaric, C. Mccrudden, C. Scott, A. Kissenpfennig,
R. F. Donnelly, Expert Opin. Drug Delivery 2012, 9, 541.
[105] M. C. Chen, S. F. Huang, K. Y. Lai, M. H. Ling, Biomaterials 2013, 34,
3077.
[106] W. Li, Y. Liu, J. Du, K. Ren, Y. Wang, Nanoscale 2015, 7, 8476.
[107] Q. Zhang, C. Shen, N. Zhao, F. J. Xu, Adv. Funct. Mater. 2017, 27,
1606229.
[108] J. Yu, C. Qian, Y. Zhang, Z. Cui, Y. Zhu, Q. Shen, F. S. Ligler, J. B.
Buse, Z. Gu, Nano Lett. 2017, 17, 733.
[109] Y. Ye, J. Yu, C. Wang, N. Y. Nguyen, G. M. Walker, J. B. Buse, Z. Gu,
Adv. Mater. 2016, 28, 3223.
[110] J. J. Iliff, N. J. Alkayed, K. J. Gloshani, R. J. Traystman, G. A. West, J.
Cereb. Blood Flow Metab. 2005, 25, 1376.
Adv. Therap. 2020, 1900140
[111] J. Di, S. Yao, Y. Ye, Z. Cui, J. Yu, T. K. Ghosh, Y. Zhu, Z. Gu, ACS Nano
2015, 9, 9407.
[112] J. C. Yu, Y. Q. Zhang, Y. Q. Ye, R. DiSanto, W. J. Sun, D. Ranson, F.
S. Ligler, J. B. Buse, Z. Gu, Proc. Natl. Acad. Sci. U. S. A. 2015, 112,
8260.
[113] E. V. Mukerjee, S. D. Collins, R. R. Isseroff, R. L. Smith, Sens. Actuators A 2015, 114, 267.
[114] G. Zheng, F. Patolsky, C. Yi, W. U. Wang, C. M. Lieber, Nat. Biotechnol. 2005, 23, 1294.
[115] A. El-Laboudi, N. S. Oliver, A. Cass, D. Johnston, Diabetes Technol.
Ther. 2013, 15, 101.
[116] L. Ventrelli, S. L. Marsilio, G. Barillaro, Adv. Healthcare Mater. 2016,
4, 2606.
[117] K. W. Ng, W. M. Lau, A. C. Williams, Drug Delivery Transl. Res. 2015,
5, 387.
[118] H. Chang, M. J. Zheng, X. J. Yu, A. Than, R. Z. Seeni, R. J. Kang, J. Q.
Tian, D. P. Khanh, L. B. Liu, P. Chen, C. J. Xu, Adv. Mater. 2017, 29,
1702243.
[119] A. Mandal, A. V. Boopathy, L. K. W. Lam, K. D. Moynihan, M. E.
Welch, N. R. Bennett, M. E. Turvey, N. Thai, J. H. Van, J. C. Love, P.
T. Hammond, D. J. Irvine, Sci. Transl. Med. 2018, 10, eaar2227.
[120] G. Valdés-Ramírez, Y. C. Li, J. Kim, W. Jia, A. J. Bandodkar, R. NuñezFlores, P. R. Miller, S. Y. Wu, R. Narayan, J. R. Windmiller, Electrochem. Commun. 2014, 47, 58.
[121] P. R. Miller, X. Xiao, I. Brener, D. B. Burckel, R. Narayan, R. Polsky,
Adv. Healthcare Mater. 2014, 3, 876.
[122] C. Kolluru, R. Gupta, Q. Jiang, M. Williams, H. Gholami Derami, S.
Cao, R. K. Noel, S. Singamaneni, M. R. Prausnitz, ACS Sens. 2019,
4, 1569.
[123] B. Ciui, A. Martin, R. K. Mishra, B. Brunetti, T. Nakagawa, T. J.
Dawkins, M. Lyu, C. Cristea, R. Sandulescu, J. Wang, Adv. Healthcare Mater. 2018, 7, e1701264.
[124] H. Lee, T. K. Choi, Y. B. Lee, H. R. Cho, R. Ghaffari, L. Wang, H.
J. Choi, T. D. Chung, N. Lu, T. Hyeon, S. H. Choi, D. H. Kim, Nat.
Nanotechnol. 2016, 11, 566.
[125] H. Lee, C. Y. Song, Y. S. Hong, M. S. Kim, H. R. Cho, T. Kang, K. Shin,
S. H. Choi, T. Hyeon, D. H Kim, Sci. Adv. 2017, 3, e1601314.
[126] R. P. Gala, R. U. Zaman, M. J. D’Souza, S. M. Zughaier, Vaccines
2018, 6, 60.
[127] B. Gualeni, S. A. Coulman, D. Shah, P. F. Eng, H. Ashraf, P. Vescovo,
G. J. Blayney, L. D. Piveteau, O. J. Guy, J. C. Birchall, Br. J. Dermatol.
2018, 178, 731.
[128] J. N. Tang, J. Q. Wang, K. Huang, Y. Q. Ye, T. Su, L. Qiao, M. T. Hensley, T. G. Caranasos, J. Y. Zhang, Z. Gu, K. Cheng, Sci. Adv. 2018, 4,
eaat9365.
[129] Y. Ye, C. Wang, X. Zhang, Q. Hu, Y. Zhang, Q. Liu, D. Wen, J. Milligan, A. Bellotti, L. Huang, G. Dotti, Z. Gu, Sci. Immunol. 2017, 2,
eaan5692.
[130] C. Wang, Y. Ye, G. M. Hochu, H. Sadeghifar, Z. Gu, Nano Lett. 2016,
16, 2334.
[131] H. T. T. Duong, Y. Yin, T. Thambi, T. L. Nguyen, V. H. P. Giang, M. S.
Lee, J. E. Lee, J. Kim, J. H. Jeong, D. S. Lee, Biomaterials 2018, 185,
13.
1900140 (15 of 15)
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim