Microneedle Polimerization Metode

Review
www.mbs-journal.de
Hydrogel-Forming Microneedles: Current Advancements

and Future Trends
Joseph G. Turner, Leah R. White, Pedro Estrela, and Hannah S. Leese*
reported and can be found in highly detailed

In this focused progress review, the recent developments and trends of MN review publications[3–6] and more tar-
geted publications of MNs used in specific
hydrogel-forming microneedles (HFMs) and potential future directions are
applications.[7] This current progress review
presented. Previously, microneedles (solid, hollow, coated, and dissolving will focus solely on the newest form of MNs
microneedles) have primarily been used to enhance the effectiveness of reported to date, known as hydrogel-forming
transdermal drug delivery to facilitate a wide range of applications such as microneedles (HFMs), first reported in
vaccinations and antibiotic delivery. However, the recent trend in microneedle 2012,[8] and the recent advancements using
development has resulted in microneedles formed from hydrogels which have this technology. This progress report also
complements a recent review which focuses
the ability to offer transdermal drug delivery and, due to the hydrogel swelling
on all types of polymeric microneedles.[5]
nature, passively extract interstitial fluid from the skin, meaning they have the The review discusses the designs, materials,
potential to be used for biocompatible minimally invasive monitoring devices. formulations, and applications of HFMs, as
Thus, in this review, these recent trends are highlighted, which consolidate well as HFMs formation, using a multiple
microneedle design considerations, hydrogel formulations, fabrication pro- step micro-molding technique. Potential
future directions for HFMs and how the
cesses, applications of HFMs and the potential future opportunities for utilizing
recent advancements can be applied to con-
HFMs for personalized healthcare monitoring and treatment. tinuous monitoring medical devices are also
discussed in detail.
1. Introduction
1.1. What Are Microneedles?
Since the first patent for a novel solid microneedle (MN) drug
delivery device in 1971,[1] there has been huge developments in As the name suggests, MNs are needles that are microscale
MN technology. From the original basic metal solid-based MNs in dimension and commonly placed in an array to allow for
used in a two-step “poke and patch” approach, to the recent penetration of the skin barrier, enabling a minimally inva-
advanced polymeric MNs with the ability to undergo controlled sive pathway for the transdermal delivery of drugs, usually
swelling when placed in the skin.[2] Conventional MNs, such as: too large to be delivered through the skin.[3] This skin bar-
solid, hollow, coated, and dissolving MNs, have been extensively rier, also called the Stratum Corneum, is the outmost skin
layer and is the main barrier for transdermal drug delivery.[9]
MNs can penetrate this layer allowing for a clear pathway
J. G. Turner, L. R. White, Dr. H. S. Leese in which drugs can be effectively delivered.[10] The first MN
Materials for Health Lab
device to become available on the market was developed by
Department of Chemical Engineering
University of Bath Dr. Desmond Fernandes in 2006,[11] the device became the
Bath BA2 7AY, UK modern day Dermaroller. The primary use for this device is
E-mail: h.s.leese@bath.ac.uk to utilize solid MNs for commercial healthcare applications.
J. G. Turner, Dr. P. Estrela, Dr. H. S. Leese The instrument creates micro pathways into the skin for better
Centre for Biosensors, Bioelectronics and Biodevices (C3Bio) skin care product penetration, such as serums that encourage
University of Bath
Bath BA2 7AY, UK collagen production, helping to remove scarring.[12] Other
Dr. P. Estrela forms of solid MNs have since been developed (coated and
Department of Electronic and Electrical Engineering hollow MNs) but, to date, no commercial device is available
University of Bath which utilizes these types of MNs. Recently, polymeric forms
Bath BA2 7AY, UK of MNs (dissolving and hydrogel-forming MNs) have been
The ORCID identification number(s) for the author(s) of this article developed, but again there is no commercial product on the
can be found under https://doi.org/10.1002/mabi.202000307. market for drug delivery applications. However, there are mul-
© 2020 The Authors. Macromolecular Bioscience published by Wiley- tiple publications that have investigated the use of polymeric
VCH GmbH. This is an open access article under the terms of the Creative MNs in the pharmaceutical industry for drug delivery[3,4] and
Commons Attribution License, which permits use, distribution and repro-
duction in any medium, provided the original work is properly cited. interstitial fluid (ISF) extraction.[13] The different types of MNs
and how they can be used to deliver drugs or extract ISF are
DOI: 10.1002/mabi.202000307 summarized schematically in Figure 1.
Macromol. Biosci. 2021, 21, 2000307 2000307 (1 of 18) © 2020 The Authors. Macromolecular Bioscience published by Wiley-VCH GmbH
16165195, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mabi.202000307 by Nat Prov Indonesia, Wiley Online Library on [31/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
www.advancedsciencenews.com www.mbs-journal.de
Figure 1. Schematic diagram showing the different types of microneedles reported to date. Also shown is the mechanism in which the different microneedles
are used for transdermal drug delivery and ISF extraction (HFMs only). Solid microneedles work by penetrating through the skin and once removed leave
micropores in which drugs can be delivered using a topical patch. Coated microneedles are drug-coated solid microneedles, once inserted the drug coating
dissolves into the system and is left behind once the microneedles are removed. Dissolving microneedles are a polymer form of microneedles that once
inserted into the skin dissolve, releasing drugs. Hollow microneedles are solid microneedles with a hollow center which can allow for drugs to be delivered
once a pressure is applied. HFMs swell when inserted into the skin and release drugs and uptake ISF. Reproduced with permission.[6] Copyright 2018, Elsevier.
1.2. Fabrication Methods of Microneedles the most common fabrication approach is through a multiple
step micro-molding technique[22] (see Section 2.2).
A variety of different techniques have been developed to fabri-
cate solid and hollow forms of MNs, described in detail at the
respective reference, including wet etch technology,[14,15] injection 2. What Are Hydrogel-Forming Microneedles?
molding,[16,17] laser machining,[18,19] LIGA and hot embossing,[20]
deep reactive ion etching, and isotropic etching techniques.[21] In First reported in 2012, HFMs are the newest form of MNs.[8]
the case of solid and hollow MNs, the direct use after fabrication Consisting of swellable polymers (crosslinked hydrogels),
is possible. However, directly forming HFMs is difficult and an HFMs have a different working mechanism compared to other
established direct method has yet to be reported, meaning that MN forms previously mentioned. When inserted into the skin,
Figure 2. Schematic to show the different mechanisms of HFMs for drug delivery. Using: A) a drug reservoir or B) drug incorporated into the hydrogel
structure and also showing the C) mechanism for the extraction of ISF. All caused by the swelling of the microneedles.
HFMs will swell do the the hydrophilic nature of the hydro- The length of the needle, denoted as L in Figure 4A, is an
gels, meaning they readily uptake water. This makes them suit- important feature to be considered. Pain receptors are located
able for biomedical applications, such as ISF uptake,[23] which deep into the dermis of the skin and a longer needle length
is found surrounding the cells in tissue spaces, mostly in the increases the number of interactions within the skin, which is
dermis layer of the skin.[13] Resultantly, the ISF taken up can more likely to trigger pain receptors on application, resulting in
be used as a source of biomarkers, making HFMs a minimally pain and discomfort for the patient and reduced public accept-
invasive method of diagnosis (see Section 4.1).[13,24–26] Alterna- ance of the MN technology. Gill et al.[29] conducted a study inves-
tively, HFMs can also be used for the transdermal delivery of tigating the length of MNs against the pain scored during appli-
drugs by either incorporating drugs into the polymeric struc- cation and found that increasing the length from 480 to 1450 µm
ture during fabrication[27] or loading drugs into a separate caused the pain to increase sevenfold from 5% to 37%, with 100%
reservoir and attaching on top of the HFMs (Figure 2 and being the pain recorded during the use of standard hypodermic
see Section 4.2).[28] HFMs are considered minimally invasive, needles. The mechanical strength of the needle also decreases
as being on the microscale means they do not penetrate far as needle length increases, risking damage during application.[30]
enough into the skin to interact with and trigger pain recep- If the HFM is below the current reported length (Table 1), the
tors which are located deeper into the dermis layer of the skin. performance of the HFM could be hindered as they would not
HFMs also overcome some of the limitations of conventional penetrate deep enough into the skin.[31] Researchers have used
MNs. For example, HFMs have a higher drug loading capacity a variety of HFM lengths within a 500–800 µm range. The base
and a tuneable drug release rate. These factors are often directly width of MNs, denoted as Db in Figure 4A, should also be con-
linked to the polymer crosslinking ratio,[8] which cannot be sidered. The fragile nature of thinner needles results in a higher
easily controlled in conventional forms of MNs. This novel chance of damage compared to wider needles.[29] However,
technology development is also overcoming the biocompat- despite this fragility, it was observed that increased width did
ibility issues of silicon or metallic MNs, as these materials are not influence the pain caused during application.[32] The width
known to be potentially toxic.[4] HFMs can be easily fabricated of MN bases has been reported within a 150–300 µm range. The
in a variety of geometries, presenting another advantage over interneedle spacing, denoted by IS1 or IS2 in Figure 4A, is a con-
conventional forms of MNs. HFMs can be sterilized prior cern for MN design. Interneedle spacing has two definitions and
to insertion and detached or removed more easily from the depends on the author’s preference. IS1 is the distance between
skin with minimal damage to both the MNs and the Skin.[8] the center of one MN to the center of the neighboring MN,
Figure 3, shows examples of scanning electron microscopy whereas IS2 is the distance between the edge of one MN to the
(SEM) images of HFMs. edge of the neighboring MN. The interneedle spacing influences
the penetration force required due to the “bed of nails” analogy,
in which the penetration force required is dissipated evenly
2.1. Hydrogel-Forming Microneedle Design across the MN array resulting in a potential inability of some
or all of the MNs in the array to penetrate through the skin.[33]
Throughout the development of MNs, a variety of different Furthermore, in the case of HFMs, as the needles swell in appli-
array MN designs have been utilized depending on the application, they risk colliding if placed too close together, resulting
cation. However, specific parameters must be considered when in damage to the MN array. Values for this parameter include
designing MNs, particularly for HFMs, to ensure the balance 400[34] and 450 µm[24] for IS1 and 50[35] and 150 µm[8,27] for IS2.
between the HFM array and size with the HFM swelling ability: Another important dimension is the tip diameter, denoted by Dt
a summary of the design considerations can be found in Table 1. in Figure 4A. The tip diameter heavily influences the penetration
Figure 3. SEM images of HFMs. Showing: A) Crosslinked PEG HFMs, image adapted with permission.[51] Copyright 2016, PloSONE. B) Alginate-PNA
MNs. Adapted with permission.[84] Copyright 2019, American Chemical Society. C,D) PVA and gelatin HFMs. Adapted with permission.[76] Copyright
2013, PLoSONE.
Table 1. Summary of microneedle design parameters for HFM of the MN patch. If the tip diameter is too large, a large force
development. is required to penetrate through the skin, with a reported tip
size below 15 µm producing the best penetration results and
Parameter Size and dimension smoothest entry into the skin.[36] Römgens et al. recorded that
Length of needle (L) 500 µm[34] a force of 20 mN per MN was required to penetrate through
the skin for a tip radius of 5 µm and 167 mN per MN required
520 µm[13]
for a tip radius of 37 µm.[36] Needle shape is also an important
600 µm[8,22,27,35,81] parameter to consider, as a well-designed microneedle shape can
650 µm[82] ease skin penetration.[29] The cone structure is the most popular
800 µm[24] choice of MN shape but recently pyramid needles are becoming
Diameter of needle base (Db) 150 µm[82]
more common.[37] These two needle shapes are often used due
to their increased effect on the MN array mechanical strength
250 µm[2,13,24,34]
during skin penetration compared to other geometries.[30] Cross-
300 µm[8,22,27,35] shaped needles and other shapes have also been explored but are
Tip diameter (Dt) <15 µm[36] less favorable because of difficulties during fabrication, reduced
Interneedle spacing (center to center) 400 µm[34] penetration ability, or difficulties during removal from the skin.[2]
(IS1) Aside from the dimensions of MNs, the size of array used,
450 µm[24]
denoted by Ax versus Ay in Figure 4B, is another important
design parameter. Researchers tend to use what is considered
Interneedle spacing (edge to edge) (IS2) 50 µm[35]
“low needle density,” consisting of smaller array sizes to help
150 µm[8,27] prevent the “bed of nails” effect occurring. However, Ramöller
Array size (Ax vs Ay) 1 × 9[82] et al.[38] have explored the use of “high needle density” arrays.
10 × 10[13,27,39] For an applied force of 32 N, there was no significant differ-
ence between the penetration of “low” and “high” density MN
11 × 11[9,28,60]
arrays. They reported that a low needle density can be consid-
19 × 19[8,35]
ered around 220 needles cm−2, whereas a high needle density
Figure 4. Schematic diagrams showing the different dimensions taken into consideration for microneedle arrays. Showing A) side view of microneedles
and B) top view of microneedle array. Where: IS—Interneedle spacing, D—Diameter, L—Length, A—Array.
is reported around 800 needles cm−2. The “high needle den- using poly(dimethylsiloxane) (PDMS). The PDMS is poured
sity” allows for increased amount of drug release or increased around a solid MN master template and cured for 2 h at 70 °C.
volume of ISF extraction.[38] The master template can be removed, producing a negative
micro-mold which can be used to produce HFMs (Figure 5).[41]
The main variation of the polymer casting micro-molding pro-
2.2. Fabrication of Hydrogel-Forming Microneedles cess is how the solid MN master template is formed. Methods
for the fabrication of solid MNs that are used in this process
2.2.1. Micro-Molding to form HFMs can be found in Section 1.2. Other methods of
fabricating the micro-molds have been used. Donnelly et al.[42]
The most established and widely accepted method of fabricating used laser machining controlled by a galvanometer based on
HFMs is through micro-molding,[22] which includes the use of a premade computer-aided design (CAD). They showed that
either laser drilling, injection molding, or the use of polymer micro-molds could be produced and reused in the production
materials in casting, to produce a micro-mold.[38] This method of HFMs, also allowing for the easy production of specialized
is commonly used since the micro-molds are reusable and can molds. Lutton et al.[43] successfully used injection molding to
form multiple HFM arrays at one time.[39] Micro-molding also form micro-molds. Manufactured metal MN master templates
allows for easy and quick production of HFMs, especially useful were used which were housed in an injection molding machine
when optimizing parameters,[40] see Section 2.1. The most and premade silicone elastomer was injected into the molds
common micro-molding method involves polymer casting, and cured, resulting in micro-molds.
Figure 5. Schematic to show the micro-molding method for the production of HFMs. First, A) a master structure is placed inside an aluminum con-
tainer and B) premixed PDMS is poured around the mold and air bubbles removed. C) Heat curing of the PDMS allows the master structure to be
removed leaving a negative mold. D) This negative mold can be used by adding premixed polymer solution and E) vacuuming to ensure complete
filling. F) Curing the polymer solutions allows the mold to be peeled away, leaving HFMs.
Figure 6. Schematic diagrams showing the potential methods of directly fabricating HFMs by 1A–1F) droplet-born air blowing, image adapted with
permission.[44] Copyright 2013, Elsevier and 2A–2F) hot embossing, image adapted with permission.[50] Copyright 2009, Elsevier.
2.2.2. Potential for Direct HFM Fabrication (Figure 6). Another potential method for directly fabricating
HFMs is through drawing lithography.[46,47] As described by Lee
Despite micro-molding being an accepted, widely used approach and Jung,[46] briefly a liquid polymer solution is placed between
for the fabrication of HFMs, other methods have been used to two identical circular plates. The plates are separated while
fabricate other types of polymeric MNs (dissolving MNs). Some the polymer cools causing the polymer to become viscous and
of these methods have the potential to be applied to HFMs by produce elongated 3D structures. Fracture eventually occurs,
altering the polymer used. First, droplet-born air blowing has resulting in separation of the elongated structure leaving behind
been used as a novel method to fabricate dissolving MNs.[44,45] MNs. Injection molding has also been used to produce dissolving
Simply, a base droplet of polymer is deposited onto a flat lower MNs.[48,49] This method involved injecting molten polymer into
plate and dried. Following this, a drug-loaded droplet of polymer a metal mold with the desired MN shape; the molten polymer
is deposited onto the dried base droplet. An upper plate is then solution is then rapidly cured and cooled and removed from
brought into contact with the drug-loaded droplet and following the mold. This method allows for rapid production of dis-
adhesion to the plate, the plate is lifted while air is blown through solving MNs using reusable molds. Similarly, Han et al.[50] used
the plates to form the MN structures, which is then dried hot embossing to produce dissolving MNs. Similar to injection
Table 2. Summary of fabrication methods used for polymeric MNs.
Fabrication method Description of method Positives Negatives

Polymer casting • PDMS is casted around a solid master MN • Widely used method. • Vacuum suggested to remove air bub-
(micro-molding)[2] template. • Molds can form multiple HFMs at once. bles in PDMS mixture before curing.
• PDMS is heat cured • Molds can be reused. • Cured air bubbles can alter design.
• Master template is removed. • Quick fabrication method. • Multi-step process
• Produces a negative mold. • Cheapest micro-molding method. • Requires fabrication of master mold.
• 70 °C heat required.
Laser drilling • Laser drilling controlled by a pre-made CAD. • Molds can form multiple HFMs at • Less widely used.
(micro-molding)[40] • Produces a negative mold. once. • Expensive equipment required.
• Molds can be reused.
• Quick fabrication method.
• No master mold required.
Injection molding • Metal master templates are used. • Molds can form multiple HFMs at once. • Less widely used.
(micro-molding)[42] • Housed in injection molding machine. • Molds can be reused. • Expensive equipment required.
• Pre-made silicone elastomer injected • Quick fabrication method. • Requires fabrication of master mold.
around template.
• Produces a negative mold.
Droplet-born air blowing • Base polymer droplet is deposited and dried • Gentle fabrication conditions • Limited reports of this method.
(dissolving MNs)[43] onto a lower plate. • Quick fabrication method • Only referenced of dissolving MNs
• Drug-loaded droplet deposited on top. • Cheaper equipment used. • Human error when dispensing drops.
• Upper plate brought into contact and lifted. • Forms dissolving MNs directly. • May lead to un-uniform MN arrays.
• Air is blown through the plates to form MN • Allows for sensitive drugs to be used.
structures.
Drawing lithography • Liquid polymer solution placed between two • Cheaper than other methods. • Limited by alignment of equipment
(dissolving MNs)[44,47] circular plates. • Can produce MNs with very sharp tip. • Limited in material loading
• Plates are separated as polymer cools. • Limited in design of MNs produced.
• Fracture occurs producing MNs.
Injection molding • Premade mold used. • Widely used method for other • Expensive process and equipment.
(dissolving MNs)[46] • Molten liquid polymer solution injected. applications. • Issues with complete filling of molds.
• Cured and cooled producing MNs. • Little waste
• Continuous process
• Can be automated
Hot embossing • Molten polymer solution compressed into • Can be scaled up easily • Limited reports of this method for
(dissolving MNs)[48] metal mold. • Little waste MNs.
• Cured and cooled producing MNs • Produces consistent MNs. • Difficult to use
• Reported polymer deformation.
molding, a molten polymer solution is compressed into a metal property is also desirable as research is tending toward HFMs
mold which caused the molten polymer solution to fill the micro- for minimally invasive ISF extraction, which can be used for
molds. The polymer is then cured, cooled and removed from the consequent analysis for biomarkers.[52] Table 3 summarizes the
micro-mold producing HFMs (Figure 6). Johnson et al.,[51] used commonly used materials for HFMs, along with positives and
contentious liquid interface production (CLIP) to produce PEG setbacks of using these materials.
HFMs through additive manufacturing. This method involves
continuously raising a build platform submerged upside down in
a photo reactive material that is continuously cured while rising. 3.1. Biocompatibility
Based on a CAD, an imaging unit exposes the liquid resin to UV
light using a digital light processing (DLP) chip. The fabrication The chosen materials for HFMs must be biocompatible since the
methods of polymeric MNs are summarized in Table 2. needles disrupt the protective skin barrier and penetrate the body,
acting as a foreign entity. Materials that are biocompatible exist
in harmony with tissues without causing an immunogenic
3. Materials for Hydrogel-Forming Microneedles response where the body tries to break down the invading nee-
dles.[10] Hydrogels are typically biocompatible and if any damage
The recent rise in the use of HFMs is due to the high potential is caused to the HFMs during application, the resulting material
hydrogels have within biomedical applications and specifically fractures will have no effect on the patient and will be degraded
for the use in MN technology.[3] Hydrogels have a high mechan- in the body by natural processes thereby preventing negative
ical strength in the dry state allowing for penetration through effects to the patient.[53] Polymers with both biocompatibility and
the skin, while also maintaining its structure in the swollen biodegradability properties are the most widely used and accepted
state and remaining intact during removal.[22] The swelling materials for HFMs, with many of the polymers being previously
Table 3. Summary of materials used for HFMs.
Primary polymer Positives Negatives Reference(s)

PMVE/MA • Excellent mechanical strength • Low swelling rate [8,27,28,55]
• Low toxicity
• Biocompatible
• Good antimicrobial properties
PMVE/MAH • Excellent mechanical strength • Low swelling rate [56]
• Low toxicity
• Biocompatible
PMVE/MA + Na2CO3 • Excellent mechanical strength • Not widely reported [28]
• Low toxicity
• Biocompatible
• High swelling rate
MeHA • Increased swelling rate • Difficult synthesis of MeHA [24,34]
• Excellent biocompatibility
• Excellent mechanical strength
PVA • Can easily incorporate other polymers to enhance certain properties • Slow swelling rate [70,71]
• Prolonged drug release
• Extensively researched
pHEMA • Proven light-responsive drug release • Difficulties in HFM fabrication [72]
• Slow swelling rate
PS-b-PAA • Biodegradable • No extensive research [73]
Silk • Nonharsh • No extensive research [78]
• Biodegradable
• Can release large molecules
researched and extensively used for other medical purposes.[54] PMVE/MA and 7.5 wt% PEG (MW of 10 kDa), left for 48 h to allow
To demonstrate biocompatibility of the HFM arrays, researchers for evaporation and cured at 80 °C for 24 h.[7,26,52,55] Romanyuk
often use a skin irritancy test in which HFMs are placed into et al.[55] showed PMVE/MA HFMs excellent swelling properties,
willing patients for a set period of time and the resulting area of recording a 50-fold increase after swelling for 24 h in water; they
the surrounding skin is monitored (see discussion in Section 4.4). also showed PMVE/MA HFMs remained intact after application
in rodent skin, allowing for complete removal. PMVE/MA HFMs
also exhibit good antimicrobial properties. Donnelly et al.[59]
3.1.1. PMVE/MA subjected HFMs to an enumeration of microorganisms’ test, in
accordance with the harmonized European Pharmacopeial test
One of the most commonly used polymers for HFMs is Gan- (Ph Eur) to determine the total aerobic microbial count (TAMC)
trez S-97, a co-polymer of poly(methylvinylether co. maleic acid) for both aqueous hydrogel mixtures and the crosslinked HFMs.
(PMVE/MA), which is crosslinked using poly(ethylene glycol) According to the Ph Eur, the acceptance criteria for transdermal
(PEG), left to allow for evaporation and then heat cured. This patches are at 102 colony-forming units per gram (CFU g−1).
material is often used because of the reported superior prop- The results showed no growth of CFU of microorganisms high-
erties desirable in application of HFMs, such as mechanical lighting the hydrogels’ excellent biocompatibility. Migdadi et al.[27]
strength, biocompatibility, and low toxicity, compared to other applied a maximum compression force of 36.3 N, while not dam-
polymers previously used.[8,27,28,55] Similarly, Gantrez AN-139, aging the HFMs, demonstrating that in the dry state, PMVE/
a co-polymer of poly(methylvinylether co. maleic anhydride) MA HFMs have excellent mechanical strength to withstand the
(PMVE/MAH), has been used.[35,56] Caffarel-Salvador et al.[35] applied compression force used to penetrate the skin.
successfully used 11.1 wt% of PMVE/MAH, crosslinked with
5.6 wt% of PEG (molecular weight (MW) of 10 kDa) for the detec-
tion of glucose through porcine skin and caffeine detection in 3.1.2. Crosslinking Density Versus Swelling Ability
rodents. Both the acid and anhydride variations have been used
in bio-adhesives in dentures, due to their low toxicity. However, Increasing the weight percentage of crosslinker, e.g., PEG,
there is currently no extensive research into the biocompatibility results in a higher crosslinking density, which decreases
of HFMs; it should be mentioned that there are examples of the swelling ability of HFMs.[60] This tuneable swelling
work that have demonstrated in vivo operation over a prolonged ability is linked to drug release rate[22] and ISF extraction.[61]
period (see Section 4.5 for the details of clinical trials).[57] Controlling the swelling ability means that the drug release
The most common polymer ratio used is 2:1 (PMVE/ rate can be manipulated to a desired rate by altering the degree
MA:PEG), giving a hydrogel with a composition of 15 wt% of of crosslinking.[28] Similarly, controlling the swelling rate can
control the rate of ISF extraction through the same mecha- HFMs. It has been reported that the mechanical strength of
nism. The kinetics of drug delivery is dependent on the size MeHA MNs is not influenced by the UV exposure/crosslinking
of the hydrogel pores and size of the solute being delivered, as and the degree of crosslinking has minimal influence on the
the hydrogel matrix acts as a permeable barrier. The mesh size swelling rate;[24] an observation different to other polymers.
of the hydrogel indicates the size and spacing of the pores. If Rather counter-intuitively, Than et al.[34] report that MeHA-
the solute to be delivered is larger than the mesh size, the drug crosslinked HFMs are mechanically inferior compared to HA
cannot be delivered but upon swelling, the mesh size increases HFMs, but in this instance they developed a double layer HFM
and allows the drug to be released.[62] Therefore, more rapid consisting of an unmodified, mechanically stronger HA HFM
swelling results in a more rapid drug release. center, surrounded by a more chemically stable but mechani-
Alternatively, altering the MW of the crosslinker alters the cally weaker MeHA layer to penetrate through the cornea.
crosslinking density. Singh et al.[58] discovered that the swelling
degree of PMVE/MA decreased with increased crosslinking
by comparing the swelling of 2:1 ratio to 4:3 ratio (PMVE/ 3.3. PMVE/MA + Na2CO3
MA:PEG), recording 294% and 250% increase, respectively.
They also observed that a lower MW of PEG (MW of 200) gave An alternative so-called “super-swelling” HFM was reported
more rigid networks with higher crosslinking densities and by Donnelly et al.[28] This “super-swelling” HFM involved the
lower swelling rates. Both Garland et al.[63] and Tsou et al.[64] use of 20 wt% PMVE/MA, cross-linked with 7.5 wt% PEG, as
found that using the higher degree of crosslinking, achieved by above, but also contained 3 wt% sodium carbonate (Na2CO3).
increasing the weight percentage of crosslinker, gave a reduced They observed a 1119% mass increase after 1 h compared to the
rate of swelling. This increased crosslinking density resulted in 250% increase of the control 15 wt% PMVE/MA and 7.5 wt%
a lower and more prolonged drug release rate. Resultantly, the PEG sample. This composition holds an advantage as the
greater the crosslinking, the more the drug release mechanism swelling was more rapid in relation to the control swelling rate.
tended toward anomalous diffusion, with the limiting step being The modifying agent caused sodium salt formation on the acid
the relaxation of the polymer chains rather than the diffusion of groups on the copolymer, resulting in a reduction of ester-based
the drug, due to a tighter, denser polymer matrix structure. crosslinking and, hence increasing swelling potential.
Multiple other polymers have been utilized for HFMs
including: poly(vinyl alcohol) (PVA),[13,69–71] poly(2-hydroxyethyl
3.2. MeHA methacrylate) (pHEMA),[72] and poly(styrene)-block-poly(acrylic
acid) (PS-b-PAA).[73]
Despite being commonly used, there are known setbacks with
PMVA/MA and hence other alternative hydrogels have been
explored.[24] The main issue of PMVE/MA is the slow swelling 3.4. PVA
rate. This means that for ISF extraction, the collection of suf-
ficient volumes of ISF is too slow, as collection for analysis PVA is a commonly used polymer in biomedical applications
is time sensitive.[24] Resultantly, alternative materials with because it is highly biocompatible and nontoxic,[74] hence it
increased swelling rate are being investigated for use in ISF has also been used in the development of HFMs. The use of
extraction. Another upcoming material used for HFMs is meth- different PVA/polymer blends have been used, e.g., dextran
acrylated hyaluronic acid (MeHA).[24,34] Hyaluronic acid (HA) is and carboxymethyl cellulose (CMC)[71] and chitosan (CS),[70] to
a naturally occurring acid found in the body and hence the bio- accentuate desired properties. Yang et al.[71] mixed PVA and
compatibility of HA is excellent. However, HA HFMs on their dextran powders in a 98:2 ratio and added water to form a
own are water soluble and do not withstand the HFM appli- 36 wt% polymer solution. They reported that a 12 mm patch
cation, as the structure breaks down in skin.[65] Synthesizing diameter successfully penetrated porcine skin with a 5 N force
HA with methacrylic acid (Me) results in a stronger material, applied to the patch. When swollen, they reported that the
due to the resultant crosslinks formed during hydrogel fabrica- CMC dissociated into long negatively charged chains which
tion, that is also biocompatible, making it useful for biomed- repelled each other and produced large spaces to hold water.
ical applications.[66] Another advantage reported is a quicker However, the rate of swelling of PVA is slower compared to
swelling rate in comparison to PVME/MA.[24] However, it is cur- other polymers.[75] When mixed with PVA, dextran dilutes and
rently unavailable to purchase and hence must be synthesized, aids in the controlling of drug release rate.[71] When insulin
as described by Burdick et al.[67,68] Chang et al.[24] performed in was introduced into PVA HFMs and swollen, 30% of the total
vivo experiments using MeHA HFMs and reported that within insulin was released in the initial 30 min and an additional
10 min MeHA HFMs extracted 2.3 ± 0.4 µL of ISF giving an 26% within 4 h, highlighting the sustained drug release.
extraction of 3.3 mg mm−2. This is a larger extraction in the Samant and Prausnitz[13] used crosslinked PVA to dem-
same 1 h period compared to PMVE/MA HFMs which reported onstrate the ability of HFMs to extract ISF. They reported a
to extract 0.84 ± 0.24 µL of ISF[55] giving an extraction of 1.8 mg 0.0030 µL extraction per MN volume after 12 h in porcine skin
mm−2, further highlighting the superior swelling rate of MeHA. and compared this to the removal of ISF through micropores,
In these cases, the array dimensions of the MeHA and PMVE/ which obtained 0.0039 µL after 20 min. This study further con-
MA HFMs were very similar (100 MNs, Db of 300 µm and L of firmed the statement that crosslinked PVA without added pol-
1000 and 600 µm, respectively), further supporting the superior ymers has a slow swelling rate.[75] Demir et al.[76] used 20 wt%
swelling rate of the MeHA HFMs compared to the PMVE/MA PVA and 10 wt% gelatin HFMs to optimize the micro-molding
technique. They froze the loaded micro-molds at −20 °C for 12 h 3.7. Silk
before thawing at 25 °C for 12 h. This process was repeated three
times resulting in an average needle height of 894.94 ± 4.81 µm, Yin et al.[78] used 6 wt% silk fibroin combined with urea,
base diameter of 249.84 ± 1.47 µm, and interneedle spacing (IS1) N-dimethylformamide, glycine, and 2-ethoxytheanol to form silk-
of 498.89 ± 1.34 µm compared to the master template of height based HFMs. Silk HFMs with a 200–700 nm pore size produced
900 µm, base diameter of 250 µm, and interneedle spacing of a 650% swelling ratio after submerged in PBS, 500% swelling
500 µm. More recently, He et al.[70] used PVA/CS HFMs to high- ratio with 50–400 nm pore size, and 250% with 50–100 nm pore
light the use of HFMs for ISF extraction and biomarker detec- size. Silk is a fairly rare material used for HFMs, but it has pre-
tion. They showed the surface of the PVA/CS hydrogel to be viously been used as a material for MNs. Tsioris et al.[79] pro-
highly porous, with the porosity controlled by the decrease of duced silk-dissolving MNs to demonstrate favorable properties
PVA concentration and subsequent increase of CS concentra- of the biomaterial, the ability to incorporate sensitive drugs such
tion. On comparison to crosslinked PVA, PVA/CS containing 20 as antibiotics into the HFMs to release large molecules.
wt% CS and 50 wt% CS would swell 3.3 times and 8.5 times
greater, respectively. Upon application in a mimicking skin appli-
cation, they found a mass increase of 50% after the first 3 min, 4. Applications of Hydrogel-Forming Microneedles
with swelling rates reducing beyond this point highlighting that
the presence of CS increases the rate of swelling for PVA hydro- 4.1. ISF Extraction and Analysis
gels. Tang et al.[77] used 10 wt% PVA modified with Cy5.5 and
poly(ethylene glycol) methyl ether amine (PEG-NH2). The modi- Within the development of HFMs, minimally invasive extrac-
fication increased the water solubility and water retention of the tion of ISF has been intensely investigated with the current
HFMs, while also allowing for the easy detection of the HFMs aim for clinical monitoring and diagnosis. However, one of the
in application using fluorescence since Cy5.5 is a common dye. main concerns with using ISF for monitoring and diagnosis is
the composition of ISF relative to blood plasma.[13] As a result,
research is ongoing into the investigation of ISF contents, bio-
3.5. pHEMA marker concentrations, and delays associated with biomarkers
concentration in ISF relative to blood plasma. Tran et al.[26]
Hardy et al.[72] used pHEMA and light-responsive drug conju- investigated the composition of ISF extracted from volunteers
gates to fabricate light-responsive pHEMA HFMs, which have using MNs compared to the plasma and serum matching
the ability to retain drugs until the application of light. Varying the volunteer. They concluded that ISF was indistinguishable
crosslinking ratios (1–5 wt%) of ethylene glycol dimethacrylate between plasma and serum in terms of protein diversity, but
(EGDMA) were introduced to the pHEMA HFMs. The presence differences were found between the quantitative concentra-
of EGDMA resulted in more HFM damage with applied force tion levels between the three different sources. It is not known
compared to pHEMA HFMs, with higher percentages of EGDMA whether the concentration of biomarkers in ISF compared
(5 wt%) causing mechanically unstable gels. However, the pres- to blood plasma is consistently high enough and an accurate
ence of 1 wt% EGDMA resulted in more uniform, easily repro- representation for analysis, but reports claim ISF is fairly rep-
ducible hydrogels. Swelling of pHEMA hydrogels with 1 wt% resentative of true biomarker concentrations. This finding
EGDMA in phosphate buffered saline (PBS) resulted in a 35% indicates that ISF is a potential alternative for some (but cur-
mass increase after 24 h. This swelling rate is slower compared to rently not all) biomarkers, such as glucose,[80] for monitoring,
PMVE/MA, which has the capability to reach maximum swelling compared to the use of blood plasma, which can be invasive to
in 24 h. Interestingly, they reported difficulties during micro- extract. Samant and Prausnitz[13] used crosslinked PVA HFMs
molding of pHEMA HFMs with the produced MNs shorter than to extract ISF, showing that the use of HFMs is more effec-
the master solid MN template. This difference is caused due to tive than other methods, such as hollow MNs and osmotically
the polymerization of monomers used to produce pHEMA HFMs driven flow for ISF extraction. He et al.[70] used 80 wt% PVA
resulting in a solid hydrogel which used less volume compared crosslinked with 20 wt% CS to successfully extract ISF from
to the evaporation method used to fabricate PMVE/MA HFMs. rabbits within 3 min. From this extraction, they recovered the
Ibuprofen was introduced into the polymer matrix to demonstrate targeted biomarkers using heat and analyzed the resultant con-
the ability of these light-responsive HFMs in a clinical application. centration after 10 min at 60 °C. However, it is worth noting
Drug release profiles of a 3 × 3 MN array showed that the majority that recovering biomarkers with temperature risks dena-
of ibuprofen is released after two periods of 1 h of irradiation, with turing. To overcome this risk, they concluded that a decreased
the last irradiation having a significantly lower release rate. crosslinking density of the HFMs can allow for a lower temper-
ature used to recover biomarkers. Romanyuk et al.[55] also used
15 wt% PMVE/MA with 7.5 wt% PEG to successfully extract ISF
3.6. PS-b-PAA from rodents after 1 h of insertion.
Chang et al.[24] used a crosslinked MeHA HFM patch to
Yang et al.[73] fabricated an MN array with swellable tips formed extract ISF from rodents. They showed that MeHA HFMs
from amphiphilic PS-b-PAA with biodegradable polystyrene extracted sufficient ISF in 10 min, reported 1–10 µL for anal-
as a nonswelling core, with the aim to help increase tissue ysis of glucose, faster than the previously stated examples.
adhesion to soft tissue. They reported a ninefold increase of PS- These examples show that HFMs can be used as a platform
b-PAA volume within 10 min of swelling. for biosensors that can use ISF for detection. Currently, HFM
MN array coated with alginate polymers functionalized with

peptide nucleic acid capture probes, they were able to allow
for specific immobilization of the RNA of interest. They tar-
geted a recently identified biomarker, miR-210, which is used
for early detection of systemic melanoma, on the basis that
patients with elevated levels were more likely for the cancer to
recur. A 7-mer PNA was designed to be complementary to the
5’-end of miR-210. In application, these hydrogel-coated MNs
extracted up to 6.5 µL of ISF in 2 min with the added feature
of specific sampling of ISF. Zhu et al.[61] developed swellable
gelatin methacryloyl HFMs. They concluded that gelatin meth-
acryloyl possesses good biocompatibility. They used a variety of
different crosslinking densities and reported that altering this
parameter, the swelling properties and mechanic properties
were impacted, altering the recorded rate of ISF extraction.
Figure 7. Schematic diagram showing HFMs for extraction and “off-line”
analysis of ISF. A) The HFMs are inserted into the skin and B) swell up 4.2. Transdermal Drug Delivery
taking ISF. C) Once removed intact, D) the HFMs are centrifuged to
extract the ISF for analysis off-line. HFMs have been used to improve the transdermal delivery of
small molecular drugs, such as donepezil, caffeine, lidocaine
devices that are used to uptake ISF use offline analysis, with hydrochloride, ibuprofen, and metformin HCl. One example
the ISF extracted from the HFM following the removal from where HFMs have been utilized is for the treatment of mild
skin.[81] Once collected, the HFMs are centrifuged to extract the dementia in Alzheimer’s disease, where Kearney et al.[56] devel-
ISF and concentrate the biomarker of interest to be analyzed oped the “super swelling” 15 wt% PMVE/MA with 7.5 wt% PEG
using analytical techniques (Figure 7).[82] The future of this is to and 3 wt% Na2CO3 HFMs to deliver donepezil hydrochloride
develop a device with on-patch analysis and the goal of a “real and acetylcholinesterase inhibitor. They achieved an average
time” HFM point of care device. Caffarel-Salvador et al.[35] uti- release of 854.7 µg over a 24 h period, with serum concentra-
lized 20 wt% PMVE/MA for the extraction of ISF to be used tions of the drug increasing over time, highlighting successful
in glucose sensing and insulin delivery. The extracted glucose delivery. During drug delivery, the preloaded drug does not
concentration was determined using high performance liquid have to be contained within the needles but can be loaded into
chromatography. Upon comparison to glucose concentrations a separate reservoir, since the swelling allows the drug to dif-
in plasma, they concluded that the glucose concentrations fuse through the hydrogel material[27] as pore size increases.[62]
taken using the HFMs accurately represent the glucose levels Caffarel-Salvador et al.[35] used 15 wt% PMVE/MA crosslinked
present in plasma and hence further improves confidence in with 7.5 wt% PEG HFMs to deliver caffeine and lidocaine hydro-
the potential use of HFMs for minimally invasive patient moni- chloride. They successfully demonstrated a 6.1-fold increase in
toring and diagnosis. caffeine delivery during application compared to prior delivery.
He et al.,[70] as mentioned previously, fabricated PVA/CS Donnelly et al.[28] produced “super swelling” HFM arrays, as
HFMs for the extraction of ISF for the use in glucose, chlo- previously described, and utilized a drug reservoir of lyophi-
ride, lactate, or desired protein monitoring. To show the lized wafer-like design. During in vitro delivery across porcine
capability of these HFMs, they extracted ISF from rabbit skin skin, roughly 44 mg (37%) of the model high dose smaller
and achieved 1.25 ± 0.37 µL after 10 min of application. They molecule drug ibuprofen was delivered in 24 h. More recently,
repeated this extraction throughout 1 day to demonstrate the Courtenay et al.[85] developed a “super swelling” HFM patch for
possibility of repeated use. The results taken from the ISF were transdermal esketamine delivery. Esketamine is an anesthetic
compared to the blood of the rabbit using a standard glucom- agent that has shown antidepressant effects and when added
eter. Their results show that the glucose concentrations from into a HFM patch was demonstrated to cause rodent plasma
the ISF matched qualitatively and quantitatively from the glu- concentrations of 0.260–0.498 µg mL−1 over a 24 h period. Mig-
cometer, hence highlighting the potential use of HFMs for dadi et al.[27] developed 20 wt% PMVE/MA and 7.5 wt% PEG
glucose monitoring. Most recently, Zheng et al.[83] developed HFMs to deliver the high dose drug metformin HCl in a sus-
HFMs composed of MeHA and an osmolyte (maltose) for the tained manner. Normal delivery of metformin HCl causes some
osmosis-powered extraction of ISF. They showed that a patch gastrointestinal side effects which the transdermal delivery will
of 100 MNs can extract 7.90 µL of ISF from porcine skin and help to reduce. Metformin HCl reservoir patches containing 75
3.82 µL from rodent skin within 3 min. They compared this and 50 mg metformin HCl were combined with the HFMs and
to a MeHA patch without the osmolyte which took more than delivered 9.71 ± 2.22 and 10.04 ± 1.92 mg at 6 h, respectively,
10 min to achieve the same volume of ISF, highlighting the and 28.15 ± 2.37 and 23.25 ± 3.58 mg at 24 h, respectively. They
rapid extraction potential of ISF using MeHA or adapted MeHA monitored the plasma concentration over time and found an
HFMs. As a modified approach, Al Sulaiman et al.[84] fabricated increase of 3.77 ± 2.09 mg at 3 h after administration. Hardy
hydrogel-coated MN arrays for the minimally invasive sampling et al.[72] developed light-responsive materials for on-demand
and sensing of nucleic acids from skin ISF. By fabricating an transdermal drug delivery using a light-responsive ibuprofen
conjugate. They successfully delivered three doses of 60 mg of develop in the upper layers of the skin. Currently, established
ibuprofen over a period of 160 h after three doses of 1 h applica- and effective methods of treatment include topical imiquimod,
tions of light with breaks in between. 5-fluorouracil, and photodynamic therapy but these come
HFMs could also be used to tackle antibiotic-resistant with side effects, such as burning pain, blistering, and derma-
infections. Shi et al.[86] formulated a hydrogel-based wound titis.[91] Hence, Cárcamo-Martínez et al.[91] investigated the use
dressing containing a commonly used antibiotic, ciproflox- of GnRs contained within crosslinked polymeric films for the
acin. Once triggered by light, the dressing successfully deliv- induction of hyperthermia to trigger cancer cell death. 50 mL
ered a high concentration of the antibiotic to the wound area, GnR solution was mixed into 25 wt% PMVE/MA with 10 wt%
which was effective against the antibiotic resistant bacterium, PEG (MW of 200 Da) and cured. The mechanical properties
methicillin-resistant Staphylococcus Aureus (MRSA). Applying and adhesion properties showed no significant difference
this hydrogel dressing advancement to HFMs could allow for between the polymeric films with or without the presence of
the transdermal delivery of antibiotics as an alternative to the the GnRs. During the swelling experiment, no GnRs were
direct application to an open wound. Another advantage of seen to be released from the polymeric film, hence indicating
hydrogels for drug delivery is their ability to sustain a constant that in application there is no risk of GnRs exposure. Thermal
drug concentration, as shown by Migdadi et al.,[27] when they analysis showed that the polymeric films could be heated to
explored the transdermal drug delivery of metformin HCl. 45 °C, which is required to induce apoptosis but does not
In vivo studies in rodents showed rapid uptake by dermal damage surrounding tissue. Although these tests were not
microcirculation, quickly resulting in a constant plasma drug performed in HFMs, this theory can be applied to HFMs.
concentration. GnRs encapsulated in HFMs will result in direct application to
As discussed, HFMs are being developed to determine glu- the skin cancer cells. Figure 8 shows a schematic diagram of
cose concentrations in ISF.[35] MNs have also been extensively how the three previously stated applications of HFMs are used
researched for the use in insulin delivery, as highlighted by a in application.
recent review.[87] Recently, there is growing interest into the
development of glucose-responsive systems based around
HFMs for smart insulin patches. Recently, Chen et al.[88] devel- 4.4. Antibody Delivery
oped an integrated PVA-coated PLA MN patch composed of
a basal-bolus insulin regiment. This allows for percutaneous In addition to drug delivery, Courtenay et al.[92] demonstrated
delivery of insulin with multiphasic release kinetics. The idea “super swelling” HFMs for the delivery of Bevacizumab (BEV),
was to help improve intraday glucose fluctuations and pre- a recombinant humanized monoclonal antibody used as a
vent associated complications. Hu et al.[89] developed MeHA chemotherapeutic. They delivered BEV into rodents and recov-
HFMs containing a closed-loop glucose-responsive mecha- ered the resultant concentrations using BEV-specific enzyme-
nism. This was achieved by developing a hydrogen peroxide linked immunosorbent assay (ELISA) from samples taken
(H2O2) responsive polymeric vesicle, self-assembled from from serum and lymph nodes. They reported BEV detection in
block copolymer incorporated with PEG and phenylboronic plasma across 7 days after one single application of the HFMs
ester (PBE)-conjugated polyserine (mPEG-b-P(Ser-PBE)), and reported accumulation at the lymph nodes, showing this
which was loaded with glucose oxidase (GOX) and insulin. In as a viable technology for the treatment of lymphomas and sec-
application, uptake of ISF into the HFMs occurred and glu- ondary metastatic tumors.
cose interacted with GOX. This resulted in the oxidation of
glucose to gluconic acid and production of H2O2, causing the
mPEG-b-P(Ser-PBE) to become water soluble and release the 4.5. Wound Healing
preloaded insulin. Yu et al.[90] developed a glucose-responsive
phenylboronic acid-based HFM patch. They regulated blood A recent review publication highlighted the use of poly-
glucose in insulin-deficient diabetic mice and minipigs. meric MNs for treating chronic wounds.[93] HFMs have
They reported that for minipigs over 25 kg, the glucose regu- been specifically been designed to help with wound closure
lations lasted over 20 h with patches around 5 cm2. Under by mechanically interlocking when inserted; this is caused
hyperglycemic conditions, phenylboronic acid units in the by the swelling of the HFMs. The interlocking HFMs help
polymeric matrix reversibly form glucose-boronate complexes wound healing by protecting the tissue from mechanical
that induce the swelling of the polymeric matrix and weaken stress and promoting wound closure. Yang et al.[94] developed
the electrostatic interactions between the negatively charged HFMs with a PS-b-PAA swellable tips with a polystyrene
insulin and negatively charged complex. This promotes the nonswellable core. PS-b-PAA is a well-known absorbance
release of insulin. polymer material and polystyrene provides mechanical
strength without swelling. Upon application, the HFMs tips
swell causing the proboscis to attach to the internal wall of
4.3. Skin Cancer Treatment the wound causing a mechanical interlock. They reported a
3.5 increase in adhesion strength compared to the traditional
Recently, gold nanorods (GnRs) have been incorporated into staples used in skin graft fixations. Similarly, Jeon et al.[95]
HFMs to aid the treatment of nonmelanoma skin cancers developed a double layer adhesive HFM patch consisting of
using near-infrared radiation.[57,91] Superficial nonmelanoma a swellable muscle adhesive protein shell and a nonswellable
skin cancer refers to a group of skin cancers that slowly silk fibroin-based core.
Figure 8. Schematic diagram showing the applications of HFMs including; gold nanorod-based microneedles for basal cell carcinoma treatment, high
dose drug delivery, and patches for drug monitoring and diagnosis. Reproduced with permission.[57] Copyright 2020, SpringerLink.
4.6. Clinical Trials the application of patches after immediate application and
24 h following. There was also no significant difference between
To date, preclinical studies have been carried out for HFMs, as removal of the patches at varying times within the 24 h period.
previously discussed throughout, but there are limited exam- These results were compared to water-proof plasters, used as
ples of HFMs used in clinical trials. However, one example control patches. As mentioned, researchers have demonstrated
is from Al-Kasasbeh et al.,[57] who successfully implemented delivery of clinically relevant model drugs, such as ibuprofen,[72]
HFMs in a clinical setting, by repeating the application of HFM but to date this has not been demonstrated in a clinical setting.
arrays formed of PMVE/MA crosslinked with PEG (MW of A key aspect when performing clinical trials is the sterili-
10 kDa). They found that during repeated usage, no measurable zation of the HFMs prior to testing. McCrudden et al.[96] per-
amounts of polymer was present in the visible skin layers, with formed various sterilization methods on the “super swelling”
the resultant visual marks after removal of the HFMs quickly HFMs loaded with ovalbumin and ibuprofen sodium. They
disappearing with no evidence of application 18 h after removal. discovered that moist and dry heat methods of sterilization
Some patients experienced mild erythema, but this fully cleared damages the HFMs and hence cannot be used. They concluded
after 7 days, showing that HFMs do not cause long-term that gamma sterilization was the most effective method and
skin damage to the skin or damage the skin barrier function. resulted in no measurable bioburden and endotoxin levels
Other examples follow a similar approach but study the effect below the US FDA limits (20 endotoxin units per device). For
of HFM application after a single use. For example, Donnelly gamma radiation of 25 kGy, physical properties and capabilities
et al.[59] used healthy non-smoking patients and applied PMVE/ of drug delivery were not affected.
MA HFMs into their forearms for a maximum of 24 h. Pain As HFMs become more common, research is progressing
scores were recorded immediately after the application of the toward an HFM medical device for clinical applications and
patches and immediately after removal. They concluded no sig- hence further clinical research will be conducted in the future
nificant difference between the pain scores measured following beyond what is currently available.
5. Advantages and Disadvantages of crosslinking mechanism should occur rapidly to decrease the
Hydrogel-Forming Microneedles probability of unreacted polymers.[100]
HFMs have shown to overcome limitations of other MN

forms, including increased loading (swelling) capacity, over- 6. Future Direction of Hydrogel-Forming
coming difficulty in coating MNs, and precise, controllable
Microneedles
drug release.[27,97] The polymers used in HFMs are highly
biocompatible, have excellent degradability, and are nontoxic, 6.1. Quicker ISF Extraction
eradicating such risks during application. HFMs can be used
to intrinsically control drug release due to their hydrogel struc- To further aid the extraction of ISF, a recent publication dis-
ture, a property other MN types do not possess. The swelling cussed the use of a plasmonic paper HFMs patch for ISF
properties of hydrogels also allows for passive extraction of extraction.[82] This technology uses a linear MN array with
ISF.[97] HFMs, after being applied in the skin, can be removed a plasmonic strip adhered to the base of the needles. This
intact, leaving no polymer behind,[27] or if some is left behind patch was applied several times into rodent skin until the
due to breakage then the polymer can be dealt with naturally, patch was seen to be saturated and hence had extracted suffi-
due to their biocompatibility and biodegradability. Contrast- cient ISF for analysis. The addition of plasmonic paper over-
ingly, breakage is a serious issue with solid MNs if any metal is comes a negative of HFMs not being able to extract sufficient
left behind in application.[2] HFMs also do not become blocked ISF. They discussed how this plasmonic paper allowed for
by the compression of dermal tissue in application, which is on-patch analysis using surface-enhanced Raman spectros-
a common problem with hollow MNs.[8] HFMs also offer a copy (SERS). This technology allowed for quicker analysis
one-step application process for drug delivery or ISF removal, of biomarkers, while also aiding the ISF extraction process
which is more effective than the two-step process required for and hence improving the HFMs ability to be used in medical
solid and hollow MNs.[8] One of the main advantages of HFMs devices.
is that they are not only limited to drug delivery, but they also
have the ability to passively uptake ISF which other MNs
cannot perform.[27] These advantages are specific to HFMs, 6.2. High Needle Density
MNs in general hold advantages over other delivery methods,
as described in detail in various MN review publications.[3,4] Recently, as mentioned, Ramöller et al.[38] fabricated MN arrays
One setback that has occurred for PMVE/MA HFMs for with a “high needle density”, resulting in 800 needles cm−2,
ISF extraction is extracting sufficient volume of ISF quickly which is considerably higher compared to previous studies.
for analysis. However, to overcome this barrier, research is They concluded that the increase in needle density had no
ongoing toward alternative materials for ISF extraction, such effect on the force required to penetrate the skin and hence
as MeHA[24] and novel ideas to enhance ISF extraction, such concluded that higher density needle patches could be the trend
as plasmonic paper[82] (see Section 6.1). Depending on the in future applications, since a higher MN density equates to a
polymers and degree of crosslinking, the rate of absorption higher drug delivery rate and a higher volume of ISF extraction.
of the drug into the plasma may be slower than that of oral
delivery due to the delay in swelling of the HFMs. However,
by modifying crosslinking to allow ISF to penetrate the struc- 6.3. Smart Devices and Stimuli-Responsive Microneedles
ture quicker and increase the rate of swelling, a high rate of
delivery can be achieved.[27] Despite its potential, the degree The development of HFMs for ISF extraction means that there is
and rate of drug delivery from hydrogels are limited. The ini- a potential to utilize them into smart devices. Currently metallic
tial release of a drug from a hydrogel is often in high concen- MNs are used in smart devices with the aid of sensors, actua-
trations, known as a burst-release, followed by a steady rate of tors, or drug formulation, forming a network of personalized
release. Not accounting for the burst-release in the hydrogel treatments only applied when triggered and hence needed.[10]
drug dosing can cause serum levels to exceed the toxic limit An example of how a smart MN device could work is by using
and result in localized tissue damage.[98] To ensure the serum sensors to track the physiological conditions, such as pH and
levels are high enough to remain within the therapeutic range temperature, feeding the information to an actuator to control
of the drug, it is required to have a full understanding of the drug release. These smart patches have the scope to be tailored
in vivo half-life, the rate of release and the percentage release to a specific patient, which is advantageous as it would reduce
of the delivered drug.[99] Hydrogels must be highly biocompat- the need for medical involvement, especially in areas with lim-
ible and not cytotoxic for use in drug delivery. If the polymers ited medical resources. MNs can also be made responsive to
used to produce the hydrogel are not sufficiently crosslinked, external exogenous stimuli (such as light or temperature), regu-
they may dissolve when in contact with the ISF. If the poly- lated by patients.[101,102] Lee et al.[103] developed a thermo-respon-
mers possess cytotoxic properties, an accumulation of toxic sive wearable sweat-based glucose monitoring device with MNs.
polymers in the body can occur. Additionally, the hydrogel In application, the smart device was used on diabetic rodents,
may undesirably degrade if left in the body for a long period. thermal actuators controlled an MN transcutaneous drug release
Two factors should be considered in hydrogel design to mini- reducing blood glucose levels. Yu et al.[104] used crosslinked HA
mize the risk of cytotoxicity. Polymers with high quantities of and glucose-responsive vesicles (GRVs). The purpose of the HA
reacting functional groups should be used, and the chosen was to provide mechanical strength and encapsulate the GRVs. In
application, when blood glucose levels increased above the normal in medical devices due to their ability to extract ISF, which can
physiological range, the GRVs collapsed and released insulin. be analyzed for diagnosis on-patch with the use of functionalized
Zhang et al.[105] used MeHA HFMs altered with a thrombin cleav- electrodes and either simultaneously deliver drugs or use the
able peptide to integrate heparin (blood thinner) to MeHA. In positive diagnosis to trigger a therapeutic response.
application, an increase in thrombin concentration resulted in the
bonds between heparin and MeHA to break and heparin to be
released. Although current smart MN devices utilize conventional Acknowledgements
MNs, research is ongoing into the use of HFMs for smart devices.
As discussed, ISF has the potential for the use in diagnosis since J.G.T. thanks Abbott Diabetes Care Ltd. and EPSRC for their support.
it can replicate biomarkers present in plasma. HFMs are used in H.S.L. acknowledges the Royal Society Research Grant RSG\R1\201185
for their support.
a minimally invasive method for the extraction of ISF, with cur-
rent analysis performed offline, which is slow and requires mul-
tiple steps to achieve. Hence, future work should investigate the
analysis of ISF on-patch for quicker results and as a result quicker Conflict of Interest
treatment.[24] HFMs also have the capability for transdermal The authors declare no conflict of interest.
deliver drugs, “pain-free” and at a relatively inexpensive cost,
hence a drug delivery medical patch could be fabricated to aid the
delivery of antibiotics or vaccinations in low resource settings.
Keywords
hydrogel-forming microneedles, interstitial fluid extraction, micro-
6.4. Layered MNs molding, polymers, transdermal drug delivery
Than et al.[106] developed a multi-layered MeHA and HA HFMs, Received: September 7, 2020
Revised: October 21, 2020
resulting in increased mechanical strength and biocompat-
Published online: November 26, 2020
ibility compared to standard MeHA HFMs. HFMs with mul-
tiple layers have the potential to balance the multiple properties
required for multi-functional HFM smart monitoring devices.
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building up one layer at a time until completion, e.g., DeMuth [2] T. Waghule, G. Singhvi, S. K. Dubey, M. M. Pandey, G. Gupta,
et al.[107] demonstrated the use of layered MN’s for DNA vaccine M. Singh, K. Dua, Biomed. Pharmacother. 2019, 109, 1249.
by forming biodegradable poly(lactide-co-glucolide) (PLGA) [3] Y. Hao, W. Li, X. Zhou, F. Yang, Z. Qian, J. Biomed. Nanotechnol.
MNs. They used spray deposition to deposit a photo- and pH- 2017, 13, 1581.
responsive polymer layer on top of the PLGA, along with other [4] K. Cheung, D. B. Das, Drug Delivery 2016, 23, 2338.
[5] H. Chang, M. Zheng, S. W. T. Chew, C. Xu, Adv. Mater. Technol.
layers, to complete their MNs. The ability to add additional
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Joseph G. Turner is a Ph.D. student in the Material for Heath Lab and Centre for Biosensors,
Bioelectronics and Biodevices (C3Bio) at the University of Bath. He obtained his M.Eng. in
Biomedical Engineering (2019). His research focuses on the development of polymeric responsive
microneedle-based skin patches for the detection of bacterial infections.
Leah R. White is working toward her M.Eng. in Chemical Engineering at the University of Bath
and is due to graduate in 2022. Her master’s research project focused on the development of
hydrogel-forming microneedles for the delivery of antibiotics.
Pedro Estrela is the Director of the Centre for Biosensors, Bioelectronics and Biodevices (C3Bio)
and associate professor in the Department of Electronic and Electrical Engineering at the
University of Bath. He has 20 years research experience in the area of biosensors. His research
focuses on the development of label-free electrical, electrochemical and plasmonic biosensors as
well as microfluidic sample processing and biodevice integration for a wide range of applications
such as medical diagnostics and environmental monitoring.
Hannah S. Leese is an assistant professor in the Department of Chemical Engineering at the

University of Bath and leading the Materials for Health Lab. She received her Ph.D. in Chemical
Engineering from the University of Bath and was post-doctoral research associate at Imperial
College London (2013–2017) and the University of Manchester (2017–2018). Hannah’s current
research focus includes responsive hydrogel microneedle biosensors, molecularly imprinted poly-
mers, and therapeutic textiles.

Microneedle Polimerization Metode

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Review

Hydrogel-Forming Microneedles: Current Advancements

reported and can be found in highly detailed

Table 2. Summary of fabrication methods used for polymeric MNs.

Fabrication method Description of method Positives Negatives

Table 3. Summary of materials used for HFMs.

Primary polymer Positives Negatives Reference(s)

MN array coated with alginate polymers functionalized with

HFMs have shown to overcome limitations of other MN

Hannah S. Leese is an assistant professor in the Department of Chemical Engineering at the

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