MEM Devices For Drug Delivery

MEMS devices for drug delivery
Hyunjoo J. Lee, Nakwon Choi, Eui-Sung Yoon, Il-Joo Cho
PII: S0169-409X(17)30242-9
DOI: doi:10.1016/j.addr.2017.11.003
Reference: ADR 13210
To appear in: Advanced Drug Delivery Reviews
Received date: 20 May 2017

Revised date: 6 September 2017
Accepted date: 2 November 2017
Please cite this article as: Hyunjoo J. Lee, Nakwon Choi, Eui-Sung Yoon, Il-
Joo Cho, MEMS devices for drug delivery, Advanced Drug Delivery Reviews (2017),
doi:10.1016/j.addr.2017.11.003
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
ACCEPTED MANUSCRIPT
1
MEMS devices for drug delivery
T
Hyunjoo J. Leea, Nakwon Choib,c, Eui-Sung Yoonb, and Il-Joo Chob,c,*
P
RI
a
School of Electrical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141,
SC
Republic of Korea
b
Center for BioMicrosystems, Brain Science Institute, Korea Institute of Science and Technology (KIST),
NU
Seoul 02792, Republic of Korea
c
Division of Bio-Medical Science & Technology (Biomedical Engineering), KIST School, Korea University
MA
of Science and Technology (UST), Daejeon 34113, Republic of Korea
ED
*
Corresponding author: Tel.: +82 2 958 6754; Fax.: +82 2 958 6910; E-mail address: ijcho@kist.re.kr
PT
Abstract - Novel drug delivery systems based on microtechnology have advanced tremendously, but yet
CE
face some technological and societal hurdles to fully achieve their potential. The novel drug delivery systems
aim to deliver drugs in a spatiotemporal- and dosage-controlled manner with a goal to address the unmet
AC
medical needs from oral delivery and hypodermic injection. The unmet needs include effective delivery of
new types of drug candidates that are otherwise insoluble and unstable, targeted delivery to areas protected
by barriers (e.g. brain and posterior eye segment), localized delivery of potent drugs, and improved patient
compliance. After scrutinizing the design considerations and challenges associated with delivery to areas that
cannot be efficiently targeted through standard drug delivery (e.g. brain, posterior eye segment, and
gastrointestinal tract), this review provides a summary of recent advances that addressed these challenges and
summarizes yet unresolved problems in each target area. The opportunities for innovation in devising the
novel drug delivery systems are still high; with integration of advanced microtechnology, advanced
ACCEPTED MANUSCRIPT
2
fabrication of biomaterials, and biotechnology, the novel drug delivery is poised to be a promising alternative
to the oral administration and hypodermic injection for a large spectrum of drug candidates.
T
Keywords – brain infusion, blood-brain barrier (BBB) disruption, capsule endoscope, implantable
P
RI
drug delivery, microneedles, transdermal drug delivery
SC
1. Introduction
NU
2. Drug delivery to the brain
2.1. Direct brain infusion

MA
2.1.1. Design considerations, challenges, and opportunities
2.1.2. Recent advances and perspectives

ED
2.2. Drug delivery to the brain through blood-brain barrier (BBB) disruption

PT

CE
3. Ocular drug delivery
3.1. Design considerations, challenges, and opportunities

AC
3.2. Recent advances
3.2.1. Minimally invasive microneedles
3.2.2. Stimuli-responsive implants for on-demand drug delivery
3.2.3. Batteryless actuation
4. Gastrointestinal tract drug delivery – capsule endoscopy
4.1.1. Anchoring mechanism
4.1.2. Trade-off between drug volume and on-chip functionalities

ACCEPTED MANUSCRIPT
3
4.2.1. Legged mechanism
4.2.2. Other anchoring mechanisms
T
4.2.3. Remaining problems
P
RI
5. Transdermal drug delivery
5.1. Challenges and opportunities
SC
5.2. Stimuli-responsive microneedles
NU
6. Implantable subcutaneous drug delivery
6.1. Design considerations

MA
6.2.1. Biocompatibility and reliability

ED
6.2.2. Perspectives
7. Conclusions
PT
Acknowledgements
CE
References
AC
1. Introduction
With the rapid development in novel pharmaceutical compounds and intervention, there is an increasing
need for novel drug delivery systems that can address challenges associated with conventional drug delivery
systems. For example, modern drug candidates include a wide spectrum of molecules including large
biomolecules (e.g. peptides and proteins) with low bioavailability, small molecules with poor water solubility,
and potent drugs with narrow therapeutic windows. Due to this wide range of physiochemical and
pharmacokinetic properties of the modern drug candidates, conventional oral or intravenous administration
might not be the most suitable route of administration. Evaluation of drug candidates and optimization of
ACCEPTED MANUSCRIPT
4
drug developments are thus limited by a lack of adequate delivery systems. In addition, with advances in
diagnostic techniques, drug delivery is not limited only to wound healing and immunology but is applicable
to cancer treatment, gene delivery, and insulin delivery [1], which requires targeted drug delivery with
T
controlled release. There are also areas in our body such as the brain and the posterior eye segment that are
P
RI
significantly challenging sites to target through conventional intravenous administration due to the physical
barriers (i.e. BBB and blood-retinal barrier) that separate the organs from blood circulation. One method to
SC
overcome these difficulties is to formulate nanoscale delivery vehicles to enable site-specific targeted drug
NU
delivery with a goal for oral delivery of proteins, peptides, and even imaging nanoprobes [2-4].
Nanoparticle-based drug delivery enables targeted drug delivery to the desired regions but reliable
MA
encapsulation of drugs in the nanoparticle with desired release characteristics are challenging to achieve [5].
Microtechnology or Microelectromechanical Systems (MEMS) is another promising technology for

ED
developments of the novel drug delivery systems that overcome the current challenges and accommodate a
vast variety of drug delivery applications. By offering miniaturization [4-7], integrations of multiple
PT
functions [8, 9], and electromechanical control [10-12], microtechnology allows delivery of a wide range of
drugs with high therapeutic efficacy. Also, microtechnology enables localized drug delivery to challenging
CE
areas in our body by means of alternative routes of administration. For instance, microneedle technology for
AC
transdermal drug delivery is one of the successful applications of microtechnology. Microneedle technology
now in the third generation of development accommodates delivery of RNA and vaccine [13, 14] and strives
to achieve active control of drug release through smart triggering systems [8]. Using MEMS technology,
hundreds of thin microneedles can be precisely manufactured in a single array to deliver drugs without
incurring damage and pain. In addition, while the conventional drug delivery relies mostly on diffusion,
MEMS micropump technology allows active control over drug release such as release rates and infusion
volumes and provides means to continuously supply drugs through a reservoir [15]. Furthermore, the agile
interface between a microtechnology component to electronic components greatly expands the efficiency and
functionality of the novel drug delivery systems. Smart release through wireless transmission and accurate
ACCEPTED MANUSCRIPT
5
control of drug doses over multiple occasions are now possible [10]. Thus, advances in microfabrication
technology and biocompatible materials have expanded the capability of drug delivery systems in terms of
target sites, route of drug administration, patient compliance, a spectrum of deliverable drugs, and dosing
T
procedures [16].
P
RI
Not only to further advance existing drug delivery systems but also to accommodate the need for spatial-,
temporal- and dosage-controlled release, it is important to understand the current challenges in the field.
SC
However, these challenges differ greatly depending on the drug candidates, target areas, and routes of
NU
administration. For instance, while the current challenge in targeting the brain and the posterior eye segment
is intervention of the physical barriers, the recent challenge in developing advanced transdermal patch is less
MA
involved with overcoming stratum corneum (SC) barrier, but rather involves with advanced control of dosage
duration (e.g. intermittently, as-needed, or over a long period). Thus, in this review, we first discuss the
ED
current challenges in targeting different areas of the body (Table 1) and discuss recent works that have
addressed these problems (Fig. 1).

PT
2. Drug delivery to the brain

CE
With a rapidly prevailing population ageing, there is an increasing need for effective treatments of
neurodegenerative diseases. As an alternative to surgical resection, localized drug delivery to the brain is one
AC
of the important therapeutic means to treat brain diseases such as brain tumors and Alzheimer’s diseases.
However, unlike delivering drugs to most parts of our body, delivering drugs to the brain is not
straightforward because of the existence of blood-brain barrier (BBB). BBB, the epithelial-like tight
junctions within the brain capillary endothelia, serves as a physical and biochemical barrier to most
molecules from entering the brain. Only a small fraction of small-molecule drugs (i.e. small molecules with
the molecular weight below 400~500 Da and with high lipid solubility) can penetrate BBB in a
pharmacologically significant amount [17]. Thus, the targetable brain diseases are limited in number. In
addition, because of the high lipid solubility, these small molecules can penetrate through all biological
ACCEPTED MANUSCRIPT
6
membranes which consequently affects target specificity, increases the risk of side effects, and limits
therapeutic efficacy. Therefore, various strategies spanning from direct injection to non-invasive BBB
disruption [11, 18-20], endogenous BBB transporter-mediated delivery [17, 21], and transnasal route of
T
administration [22, 23] have been explored to overcome or bypass BBB (Fig. 1). In this review, we focus on
P
RI
two systems for drug delivery to the brain that benefit from microtechnology: transcranial direct brain
infusion and BBB disruption using focused ultrasound.
SC
NU
2.1. Direct brain infusion

MA
2.1.1.1. Convection-enhanced diffusion. Direct brain infusion is invasive but is the most effective means
to deliver a known concentration of therapeutic agents to a specific location in the brain. There are mainly
ED
three neurosurgical methods for human transcranial brain drug delivery: intracerebral implantation,
intracerebroventricular (ICV) infusion, and convection-enhanced diffusion (CED) [24]. There are several
PT
factors that need to be considered in choosing the delivery method: desired infusion area, infusion speed,
CE
distribution of delivered drugs, area of tissue damage, and sensitivity to drug reflux. While intracerebral
implantation and ICV infusion rely on diffusion of drugs from a concentrated source at the implanted sites
AC
(e.g. diffusion-based eluting polymer), CED uses external forces to push bulk flow of drugs at constant flow
rate into the brain through a hollow cannula or needle [25]. Owing to the convective flow at the infusion site,
CED allows for a homogeneous distribution of drugs over a longer distance (~cm) regardless of the
molecular size and the refluxed drugs are within the target volume. The minimum dimension of the cannula is
limited by several factors such as fabrication technology and desired flow rate which is a function of viscosity
and density of drug.
For small animal experiments, CED is also the most dominant delivery method. A commercially available
hypodermic needle is typically used to deliver agents such as genes, drugs, and neurotransmitters to a target
region of the brain. Hypodermic needles with gauge numbers as small as 30 and 31 are commercially
ACCEPTED MANUSCRIPT
7
available if specially ordered which have the outer diameter of 311 µm and 260 µm, respectively. However,
the size of the mouse brain is approximately 4 mm in depth (in the smallest dimension) and some brain
regions of the mouse brain are only a few hundreds of micrometers in one dimension, which requires further
T
miniaturization of the cannulae. Thus, microneedles [26, 27] or neural probes with an integrated microfluidic
P
RI
channel [9, 28] based on MEMS technology have been proposed for direct brain infusion for small animal
experiments (Fig. 1). The first MEMS-based silicon microneedle for brain infusion was reported in 1997
SC
where a boron-doped mask layer was used to fabricate a 15-µm-thick 58-µm-wide microneedle [27]. Various
NU
techniques to integrate microfluidic channels without increasing the microneedle dimensions, such as buried
channel technology [29] and glass cover on silicon technology [26], have been developed to minimize the
MA
dimension and thus the damage in the brain tissue. The devices for direct brain infusion have been used for
the experiments with animals in the preclinical stage.

ED
2.1.1.2. Biocompatibility and systematic errors. Despite the advances in the fabrication techniques, there
PT
are still critical challenges that need to be resolved such as biocompatibility and systematic complications
such as clogging, reflux, and leakage. During the insertion of a microneedle, there are initial bleeding, death
CE
of neurons along the insertion path, and a microglial response, followed by an astrogliotic reaction during the
AC
period of implantation. In addition, due to the brain micromotion and the mechanical mismatch between the
implant and the brain, there is a persistent friction. Thus, over the past decade, new materials such as SU-8
and parylene have been exploited as flexible substrates of the microneedles to minimize the chronic
inflammation [30, 31]. However, microneedles based on these relatively soft materials are often thicker than
rigid silicon microneedles to ensure insertion without buckling; thus, initial damage incurred during the
insertion still remains a problem. In addition to the biocompatibility, the current systems are also susceptible
to systematic errors associated with delivering drugs through a cannula. Some of these errors are more prone
for miniaturized cannulae; due to the small dimensions of the microfluidic channels and outlet ports,
microneedles are more susceptible to clogging, which often requires much more endeavor for removal,
ACCEPTED MANUSCRIPT
8
cleaning, and re-insertion, and leads to irreversible deterioration.
2.1.1.3. Perspective for additional functionalities. There are also additional features or functions that are
T
desired to achieve more efficient and powerful drug delivery to the brain, such as active control of drug
P
RI
release, sampling, and delivery of multiple drugs in situ [32, 33]. The current CED-based system is more
suitable for acute drug delivery because the implanted cannula must be connected to the external fluidic
SC
driving system via tubing. Thus, temporal control of drug delivery is restricted. Another problem is the
NU
difficulty of predicting the exact dosage delivered to the target site due to dead volume; dead volume arises
due to the presence of a reservoir, adsorption of the drugs to channel walls, and leakage at an outlet along the
MA
insertion path [26]. Thus, simply monitoring the decrease in the drug volume at an input reservoir does not
necessarily indicate actually delivered volume to the target site. Lastly, with the current delivery system, it is
ED
challenging to deliver multiple drugs or different concentrations of drugs in situ through single implantation
because the tubing must be changed without introducing any air bubbles [32].
PT
These aforementioned problems and additional features associated with direct brain infusion are not only
restricted to small animal experiments but also map directly to large primates and humans. For example,
CE
demyelination and loss of cells were observed in the primate brain during the autopsy [24], which raised
AC
concern about long-term effects of direct brain infusion for humans. Therefore, it is highly required to discuss
the challenges and improvements in microneedle technology to apply the direct infusion to therapeutic
applications as well as animal experiments.
2.1.2.1. Recent advances. Recent works focused on the active control of drug release in the brain. For
example, one method of functional brain mapping is to trace responses of injected neuronal tracer such as
Mn2+ ions upon electrical stimulation using manganese-enhanced MRI, which requires a timed release of a
small volume of Mn2+ synchronized with the electrical stimulation. Recently, Huang, et al. reported a
ACCEPTED MANUSCRIPT
9
conductive nanogel-based neural interface that achieved both temporal and spatial controlled release of Mn2+
[34]. Mn2+-encapsulated conductive nanostructural networks were coated on a neural probe with multiple
gold microelectrodes; by applying biphasic pulse on the microelectrodes, both the electrical stimulation for
T
activation of neural circuits and the release of Mn2+ for tracing the circuit were achieved. The authors
P
reported an increase in both released concentration of Mn2+ and diffusion volume by adjusting frequencies of
RI
the biphasic pulse from 20 Hz to 120 Hz. As a similar application of the neuronal tracing, Fekete, et al. have
SC
reported a hybrid drug-delivery system where a neuronal tracer was injected through a microfluidic channel
NU
but drug delivery was actuated through iontophoresis rather than by pressure [35]. The iontophoresis, which
ejects charged molecules by generating voltage gradients, was achieved by placing an electrode near an outlet
MA
of the microfluidic channel and another electrode outside of brain tissue. In contrast to diffusion-based
delivery where no current was applied, the authors reported successful delivery of neuronal tracers at various
ED
current levels and injection times. In both reports, no neuronal damage due to the application of electrical
currents were observed.

PT
Since the current delivery systems are mostly limited to delivery of a single drug, there are on-going efforts
to design a drug delivery system that allows infusion of multiple drugs. McCall, et al. have reported a system
CE
which consisted of four fluidic reservoirs connected to four separate microfluidic channels [33]. Different
AC
drugs could be loaded using a blunt syringe into a reservoir (Fig. 2(c1)). In addition, since the drugs were
delivered through thermally actuated pumps via the metal electrodes located at the bottom of a reservoir, this
system was operational without a bulky tubing and an external driving module. In contrast, Shin, et al. have
integrated a microfluidic mixer to accommodate three different drugs [32]. Since three inputs were combined
through the mixer that was merged into a single microfluidic channel, this system enabled delivery of drugs
at different concentrations in situ at a single implantation (Fig. 2(c2)).
2.1.2.2. Perspectives. There are few additional functionalities such as sampling and enhancement of
biocompatibility which would further improve the current drug delivery systems. For example, accurate
ACCEPTED MANUSCRIPT
10
sampling of fluids around the cannula would be an approach to confirm successful delivery of drugs and
monitor a dosage as well as to monitor changes in neurochemical concentrations affected by the delivered
drugs or the brain functions. There are largely two methods for sampling cerebrospinal fluid (CSF):
T
microdialysis and push-pull. Microdialysis uses semi-permeable membranes at the target site to deliver drugs
P
RI
and to retrieve fluids; due to the small size of pores (typically sub nm), microdialysis relies only on
concentration gradients of the small molecules at the interfacial membrane between brain tissue and a
SC
sampling buffer and consequently is diffusion-limited. In contrast, push-pull uses two separate cannulae with
NU
an open gap in between. Principle of push-pull perfusion relies on the exchange of constituents between
perfusate and brain at the tip; At the same time a perfusate is pumped into the inflow (or push) cannula, the
MA
purfusate now mixed with constituents in the brain is immediately withdrawn at the same flow rate through
the outflow (or pull) cannula. Thus, push-pull perfusion is applicable for charged and larger molecules and is
ED
free of the diffusion limit.
Both microdialysis and push-pull microneedles have recently been developed to sample CSF and analyze
PT
neurochemicals quantitatively [36, 37]. While Lee, et al. have utilized deep reactive ion etching (DRIE)
through a porous aluminum oxide layer to fabricate a nanoporous membrane for microdialysis (Fig. 2(b1)),
CE
Chae, et al. have fabricated two parallel microfluidic channels for the push-pull operations (Fig. 2(b2)).
AC
Recently, Petit-Pierre, et al. have proposed an interesting idea of applying droplet microfluidic technology to
the push-pull method for sampling CSF [38]. The CSF that was retrieved through a pull microchannel was
immediately segmented in nanoliter droplets by a perfluoromethyldecaline carrier phase (Fig. 2(b3)). Due to
this isolation of the retrieved solution immediately after the push-pull operation, the sampled liquid was
affected by neither the diffusion through a membrane nor the Taylor dispersion in the sampling tube.
Therefore, a high temporal resolution of 170 ms for sampling was reported. The capability to deliver drugs
and to acquire samples simultaneously at an identical site serves as an important function for next generation
drug delivery systems because a closed-loop control of drug release which depends on the concentration of
neurotransmitters in the brain is now possible.

ACCEPTED MANUSCRIPT
11
In addition, there are largely two groups of efforts to minimize the immune response of the implanted
microneedles: physical and biochemical approaches. Physical efforts involve an adjustment of mechanical
structures and properties by using soft materials [28] that have Young’s modulus closer to that of the brain
T
(~a few kPa) [39]. Recently, Liu, et al. have modified both the mechanical structure and properties of
P
RI
microneedles to enhance biocompatibility [40]. The body and the sharp tip of the microneedles were
composed of silicon which were connected through a 250-µm-long parylene structure with opening gaps (Fig.
SC
2(a)); the silicon-parylene hybrid structure provided a flexible section between the implant and the brain
NU
while the openings in the structure allowed for the regrowth of surrounding neural tissue. The authors
demonstrated a reduced reactivity of both astrocytes and microglial around the implant. Another approach to
MA
enhance biocompatibility is to deliver anti-inflammatory drugs either through a microfluidic channel or
active sites along the microneedle [40, 41]. The same authors who fabricated the aforementioned hybrid
ED
structure also delivered minocycline, which is known to suppress the microglia activation, through the
openings and reported a reduced microglial activity. Another recent work by Boehler, et al. designed an
PT
actively controlled release system for chronic applications which released an anti-inflammatory drug (i.e.
dexamethasone) to actively intervene with the foreign body reaction [41]. The drug was loaded on a layer of
CE
a conducting polymer coated selectively on electrodes. By releasing the drug through cyclic voltammetry
AC
(CV) on a weekly basis, the authors observed reduced inflammation with a larger neuronal population near
the implant over 12 weeks of implantation. Through the 12-week study, the authors have also verified their
hypothesis that the anti-inflammatory treatment beyond an initial healing phase of 6 weeks was still effective
in enhancing the biocompatibility.
2.2. Drug delivery to the brain through BBB disruption
There are increasing efforts towards delivering drugs to the brain via blood stream by overcoming BBB.
One promising strategy is to use focused ultrasound (FUS) to transiently disrupt or breach BBB by applying
a concentrated acoustical energy to a focal spot in the brain. Upon sonication, the induced BBB disruption
ACCEPTED MANUSCRIPT
12
lasts for several hours, after which the BBB disruption recovers to the baseline [42]. Thus, when a drug along
with an ultrasound contrast agent (i.e. microbubble) is administrated through intervascular injection, the drug
circulating in the blood stream enters the brain only at the location where BBB is disrupted by sonication. The
T
clinical need for this technology is expected to be tremendous because not only the FUS technology enables
P
RI
spatial- and temporal-controlled delivery to the brain, but also this technology is non-invasive and applicable
to a wide spectrum of drugs including DNAs [43], genes [44], small molecules [45], hydrophilic molecules
SC
[46], drug-loaded microbeads [47], and macromolecules [48]. Moreover, early studies on the BBB disruption
NU
using ultrasound demonstrated that no apparent damages on surrounding parenchyma were induced [49-51].
In addition to targeting the brain, the FUS technology has been applied for drug delivery to other parts of the
MA
body through transdermal [52, 53], transcorneal [54], and gastrointestinal [55] routes of administration.
ED
2.2.1.1. BBB disruption. The effect of ultrasound on BBB has been reported as early as 1956 but the idea
PT
of delivering drugs through BBB disruption was not technologically possible. Because ultrasound attenuates
CE
greatly in the skull due to its high mechanical impedance, delivering focused acoustic energy through skull
was challenging. With the advancement in the ultrasound transducer technology, non-invasive BBB
AC
disruption through intact skull became possible. By combining the ultrasound contrast agents with FUS, BBB
disruption became more effective and repeatable. Thus, the threshold for BBB disruption was lowered which
resulted in less risk of overheating in the skull and higher spatial selectivity. As a result, the FUS-mediated
drug delivery is now ready for clinical trials. The first clinical trial for delivering chemotherapy to patients
with brain tumors started in 2015 at Sunnybrook Health Sciences Center in Toronto, Canada. For more
in-depth historical developments and pre-clinical achievements, readers are referred to the following
comprehensive reviews by Vykhodtseva, et al. [19], Arayl, et al. [11], and Dasgupta, et al. [20].
2.2.1.2. Sonication parameters and microbubble properties. For a specific target drug, there are two sets
ACCEPTED MANUSCRIPT
13
of parameters that can be adjusted in the FUS-mediated drug delivery: sonication parameters (e.g. frequency,
intensity, pulse repetition frequency (PRF), burst length, and duration) and microbubbles properties (e.g. size,
concentration, and composition). Over the years, a large range of parameters has been reported for successful
T
disruption of BBB. For example, the reported center frequency and burst length span over several orders of
P
RI
magnitude: 28 kHz ~ 8.9 MHz and a few periods ~ 100 ms, respectively. The threshold for BBB disruption
tends to decrease with larger pressure amplitude, lower frequency, longer duration, and larger microbubbles
SC
while mixed trends were observed for burst length, PRF, and concentration of the contrast agent [11].
NU
One of the reasons for the difficulty in finding an optimal set of parameters is because the exact
mechanism is still unknown; modeling the behavior of microbubbles in an acoustic field is complex,
MA
especially in a capillary [20]. Among the known bioeffects induced by FUS, heating and inertial cavitation
due to the collapse of microbubbles leading to the rapid opening of BBB (i.e. sonoporation) have been
ED
dismissed through experimental studies. No measurable increase in temperature and no wideband acoustic
emission due to inertial cavitation were observed. Also, the effects of sonication were not transient but rather
PT
lasted for over several hours. Thus, the only remaining known bioeffect seems to be stable cavitation, which
can stimulate brain endothelial cells via three potential means: radiation force acting on the bubble,
CE
oscillation of microbubbles in the acoustic field, and microstreaming of fluid around the bubbles. However,
AC
the difference in the threshold for BBB opening and inertial cavitation has been reported to be small. Due to
this small margin, studies have reported the observation of both stable and inertial cavitation which
accompanied mild capillary and erythrocyte extravasation. Thus, recently there have been efforts in
designing microbubbles that would favor stable cavitation and also in integrating drugs into the microbubble
for more efficient delivery of drugs to target regions [56].
2.2.1.3. Unmet needs. Since the FUS-mediated drug delivery systems are still in the early clinical stage,
there is still a large number of challenges and thus opportunities for technological innovations, especially for
researchers in the field of microtechnology. Currently, commercially available ultrasound transducers based
ACCEPTED MANUSCRIPT
14
on piezoelectric materials are used for BBB disruption, which are fixed in terms of frequency, radius of
curvature, and aperture [11, 20]. Thus, customized or adaptive adjustments of the level of disruption for
different patients and different target drugs are currently not possible, which limits full exploration of large
T
parameter space of sonication. Since there is a natural trade-off between the frequency, attenuation, and focal
P
RI
spot size, operators are often limited to one frequency with a fixed focal spot size [47, 48]. For example, for a
low-frequency transducer, the focal spot size might not be spatially specific enough. In addition, the
SC
commercially available transducers are suitable for human cases but are often too bulky for animal
NU
experiments.
Because use of ultrasound for drug delivery is relatively new, there is still an increasing need for
MA
miniaturized transducers for small animal experiments [57-59]. For example, pre-clinical screening of newly
developed drugs using animal models are still required and the safety of long-term exposure still needs to be
ED
validated. Another important issue in the FUS-mediated drug delivery is that the ultrasound beam inside the
brain cannot be visualized and thus requires usage of an imaging system such as magnetic resonance imaging
PT
(MRI) [46]. However, since drug administration would often require multiple sessions and MRI is bulky and
costly, a better solution is to develop an MRI-free system that still accurately predicts the location of the
CE
sonication. Lastly, the exact mechanism of BBB disruption by ultrasound should be continuously researched
AC
to provide insights into the optimal ultrasound parameters and microbubble properties.
Medical ultrasound imaging is the major application for the ultrasound transducers which require both
transmit and receive modes. Although small in number, recently, there have been early research works on
developing miniaturized ultrasound transducer arrays using MEMS technology for sonication only. Another
impetus for these efforts is applications of FUS technology in non-invasive neuromodulation [60, 61] and cell
ablation using high-intensity FUS (HIFU) [62]. Recently, Goldwirt, et al. have demonstrated a successful
drug delivery in a primate model where a custom-built implantable air-backed 1 MHz transducer was used
ACCEPTED MANUSCRIPT
15
[57] (Fig. 3(a)). Although the transducer was less bulky than the commercially available transducers with a
size of 10-mm in diameter, the transducer was a flat single element without any mechanical focusing which
resulted in unfocused ultrasound with a large focal spot. Another work on devising a customized ultrasound
T
transducer array was the development of a light-weight PZT-based transducer array designed for portable
P
RI
transdermal drug delivery systems [58, 59]. A 12.7-mm-diameter PZT-4 disk was encapsulated in
cymbal-shaped capping to amplify the displacement by a factor of 40, which was packed in a 6-cm-wide
SC
3-by-3 array.
NU
Another interesting application of bioMEMS technology for FUS-mediated brain sonication is in vitro
investigation of the effects of ultrasound. Recently, Ko, et al. have reported an in vitro system that resolved
MA
both of these problems [63]. A 781-kHz piezoelectric micromachined ultrasonic transducer (pMUT) array
was custom-designed and fabricated, which contained 16 elements placed in a linear fashion. By directly
ED
placing cultured cells on the backside of the pMUT array, sonication of the cultured cells at multiple locations
at the same time was possible (Fig. 3(b)). This MEMS-based in vitro system could provide a means to
PT
investigate the effects of ultrasound in cell levels. This work is an example of excellent interdisciplinary
research where the application of microtechnology has advanced the overall system to a great extent.
CE
Because the FUS-mediated drug delivery system is still at the clinical stage, there is a large room for
AC
technological advancements in terms of transducers and interfacial circuits. For example, capacitive
micromachined ultrasound transducer (CMUT) arrays which has an advantage of design freedom in terms of
frequency and array shapes are excellent candidates for future ultrasound-mediated drug delivery systems
[64]. The integration of these custom-built transducers with low-power, compact integrated circuits (ICs) and
an advanced control system for locating the target region could one day allow a fully portable drug-delivery
system. Patients can receive sonication for drug delivery at home simply by wearing a sonication headset and
swallowing a pill. Thus, with miniaturization of the sonication system, we can anticipate a completely
non-invasive wearable system that will allow on-demand drug delivery.

ACCEPTED MANUSCRIPT
16
3. Ocular drug delivery
The eye is an interesting yet complex organ for drug delivery; the anterior segment is exposed and thus
accessible externally through a thin layer of the cornea while the posterior segment interfaces with the
P T
internal vascular network through inner and outer blood-retinal barriers (Fig. 1). Possible routes of
RI
administration for intraocular drug delivery include topical, systemic, intravitreal, and periocular routes; the
SC
topical route using eye drops and ointments is currently the most common for treating ocular diseases in the
anterior eye segment. However, because of a continuous turnover of tears, clearance through nasolacrimal
NU
ducts, and low permeability of the corneal layer, less than 5% of a dose is absorbed into the eye [65]. Thus,
the frequency of instilment or the concentration of drugs must be increased to reach the therapeutically
MA
effective dosage. Thus, despite the accessibility, targeting the anterior segment is still challenging. In
addition, it is even harder to target the posterior segment because of the physiological blood-retinal barrier
ED
and anatomical inaccessibility and most ocular diseases that lead to visual impairments occur in the posterior
segment. Therefore, implantable drug delivery systems are attractive alternatives in targeting diseases in the
PT
posterior segment. Intraocular implants bypass or penetrate the barriers to increase the efficiency of drug
CE
delivery and there are a large number of potential implantable sites: vitreous space, pars plana, peribulbar,
and intrascleral space. Implantable intraocular drug delivery systems are especially useful for ocular diseases
AC
such as cytomegalovirus (CMV) retinitis and proliferative vitreoretinopathy (PVR) which require repeated
drug injections and surgeries. In addition, these systems are suitable for treatments of chronic diseases with
no other effective treatments, such as age-related macular degeneration (AMD), macular edema, and retinitis
pigmentosa [66]. Lastly, through localized delivery, implantable intraocular drug delivery systems allow
administration of a large spectrum of drugs including potent antiangiogenic agents and biomolecules. For
general details on ocular drug delivery, readers are referred to [66-72]. These implantable systems have been
tested with animals in the preclinical stage.
3.1. Design considerations, challenges and opportunities

ACCEPTED MANUSCRIPT
17
Since the introduction of the first polymeric insert developed for sustained drug release in the 1800s, a
large number of polymeric implants such as vitreal implants, intrascleral discs, and scleral plugs was
T
developed and commercialized [66]. For example, Vitrasert (Bausch & Lomb, USA) was developed in the
P
1990s to treat opportunistic viral retinitis in human immunodeficiency virus infection and acquired immune
RI
deficiency syndrome (HIV/AIDS) patients over 8 months. While the surgery for these implants is not
SC
complex, there is always a risk of complication accompanied with the surgery. Thus, soft contact lenses that
satisfy both medication needs and refraction correction were explored as an alternative non-invasive means.
NU
Various methods of incorporating drugs into contact lenses without compromising transparency were
explored including soak and absorption, surface immobilization of drugs, and molecular imprinting [73].
MA
Bandage contact lenses that deliver antibiotic and anti-inflammatory medication have been commercialized
for effective managements of ocular trauma and post-surgery conditions. Few examples include Pure Vision
ED
(balafilcon A, Bausch+Lomb), Acuvue 2 (etafilcon A, Vistakon Inc.), Acuvue Oasys (senofilcon A, Vistakon
Inc.), and Air Optix Night & Day (lotrafilcon A, Alcon) [73]. However, due to the concerns over diffusion of
PT
preservative (e.g. benzalkonium chloride) on the ocular surface, pharmacokinetics and stability of the drug,
CE
and safety issues on the cornea, commercialization of drug-loaded contact lenses were not as successful as
initially anticipated.
AC
The ultimate objective of intraocular drug delivery is to deliver drugs more than two years with improved
ocular drug bioavailability, minimal complications, and maximal patient compliance [74]. These unmet
needs can be fulfilled by microtechnology which enables miniaturization of biocompatible materials and
integration of active control components. Thus, microtechnology-based intraocular drug delivery systems,
such as minimally invasive microneedle systems, MEMS-based drug delivery systems with on-demand drug
release, and advanced bioresponsive polymeric devices for self-regulated drug delivery, are actively
researched. Design factors for intraocular drug delivery systems include volume of the implants, site of
implantation, materials (biodegradability), and actuation methods (passive or active), and reliability.
As for any implantable systems, there is a trade-off between the amount of a drug that can be loaded and
ACCEPTED MANUSCRIPT
18
size of the implants. The size of the implant is typically designed to be less than a few millimeters in order to
enhance patient comfort level and minimize the complexity of surgery. However, the volume of loadable
drug also decreases. Since the therapeutic effective drug concentration is fixed, the frequency of
T
replacements or refills of the reservoir would increase. However, this implies an increase in the implant size
P
RI
and therefore reduces patient compliance. The material of the implant is also an important parameter which
affects release characteristics. For instance, degradable polymeric devices that release a drug through
SC
dissolution do not require additional surgical removal, but suffer from an initial burst of the drug, which
NU
results in an overdose of the drug in the eye over a short period of time. Biocompatibility and reliability are
categorized into another important set of problems; complications such as vitreous hemorrhage and
MA
rhegmatogenous retinal detachment were observed in 13 out of 110 eyes after implantation [75]. Thus, the
site of implantation is another design factor as the degree of invasiveness and the associated risks of
ED
complications differ.
PT

CE
3.2.1. Minimally invasive microneedles
Because of minimally invasive nature of microneedles that penetrate through only a thin layer of physical
AC
barrier, various microneedles such as drug-coated microneedles and hollow microneedles were fabricated
and tested for intrascleral and suprachoroidal drug delivery [76-78]. Recently, Valdés-Ramírez, et al.
reported a multiplexed, switchable microneedle-based intraocular drug delivery system [79]; the system
consisted of an actuator composed of a conductive polymer, a PDMS drug reservoir, and an electrode array to
control actuation. Application of suitable redox potentials induced a reversible volume change of the
conductive polymer which led to expulsion of drugs from the reservoir. Individually addressable two
channels allowed delivery of multiple drugs at single implantation (Fig. 4(a1)). However, the system required
a separate reservoir and a delivery cannula for each drug and thus fluidic interfaces were not optimal for
multiplexed delivery of a larger number of drugs. There is also a movement towards fabricating a dissolvable
ACCEPTED MANUSCRIPT
19
microneedle array. Thakur, et al. developed a dissolving polymeric microneedle based on a
polyvinylpyrrolidone (PVP)/hydrogel formulation [80] (Fig. 4(a2)). Drug-loaded PVP rapidly dissolved in
biological tissues due to its high water solubility. In addition to the fact that no additional surgery is required
T
for the dissolvable system, dissolvable polymeric microneedle systems offer an advantage of enhanced safety;
P
RI
a broken small part of the rigid microneedles during implantation could lead to a serious complication.
SC
3.2.2. Stimuli-responsive implants for on-demand drug delivery
NU
Intraocular drug delivery systems with active control enable on-demand drug delivery which is controlled
internally through either physiological signals or external stimuli, such as temperature, electrical field,
MA
magnetic field, and osmotic pressure [15]. The first on-demand MEMS-based intraocular drug delivery
system was reported by Lo, et al. which consisted of a refillable PDMS reservoir, suture tabs, and cannula
ED
with a one-way check valve [81]. The reliability of the refillable PDMS reservoir was limited to 12 times
after which a leakage was observed through an injection port. The same authors demonstrated the chronic
PT
usage of this system where no blockage of the cannula due to biofouling was observed for over 6 months after
implantation [82] (Fig. 4(b1)). However, because the drug delivery was actuated manually, this system
CE
suffered from imprecise control over infused volumes. This problem was overcome by devising a mini drug
AC
pump that was actuated by hydrolysis [83]. With low power consumption and precise control over the
infusion volume, the proposed intraocular drug delivery system was more practical for clinical applications.
Now, there is also a commercially available minipump (MicroPumpTM System, Replenish) which is designed
for clinical use with a lifetime of up to five years. This system contained a fluidic flow sensor, bi-directional
telemetry for wireless programming, and a refillable reservoir using a proprietary 31-guage needle [84].
Zhang, et al. demonstrated a flexible ocular iontophoretic drug delivery device that was implanted under an
eyelid [85]. Placement of this device under the eyelid offered several advantages including simplified surgery
and stable, conformal contact to the target region using a planar electrode. Moreover, the device consisted of
a simple PDMS cup with poly-3,4-ehtylenedioxy-thiophene (PEDOT) electrodes for actuation which was
ACCEPTED MANUSCRIPT
20
simple and batch-fabricated. Since iontophoresis can increase the temperature near the electrodes, thermal
effects were also monitored in vivo where 37.8°C was determined by the authors as the maximum safe
temperature. However, this system did not contain drugs and thus required an external application of a liquid
T
drug; once the drug was administrated under the eyelid, iontophoresis drove the drugs into vitreous space.
P
RI
Furthermore, because of the wiring to provide an electrical interface to the PEDOT electrodes, this system
was not completely implantable. Another interesting area for ocular drug delivery where the MEMS
SC
technology could contribute is polymeric implants composed of various biocompatible materials such as
NU
hydrogel. For more details, readers are referred to the following recent work [86-88].
MA
3.2.3. Batteryless actuation
If there are no reliability issues in the implant, lifetime of the implant is limited by either the total volume of
ED
drugs or capacity of small size batteries. Implantable batteries not only increase the footprint of the implant
but also require frequent removal of the implant due to the limited energy capacity. There are currently two
PT
research fronts that aim to resolve this battery problem: wireless power transmission (or actuation) and
energy harvesting. Energy harvesting from physiological, mechanical, electrical and thermal processes in the
CE
human body is possible but has not been applied for drug delivery systems. Song, et al. developed a
AC
triboelectric nanogenerator which harvested energy from human body movements and interfaced the
nanogenerator to an electrochemical pressure pump embedded in an implantable intraocular drug delivery
system (Fig. 4(c1)) [89]. A PDMS microtube was implanted at the sclera and allowed for successful delivery
of 50 µL of microparticles to the anterior segment of porcine eyes ex vivo. However, because the
self-powered triboelectric nanogenerator must be attached to the body with largest movements and because it
does not generate high enough power for wireless transmission, this unit was connected to the implant
through long wiring. For clinical applications, a more practical solution for the connection should be
proposed.
Pirmoradi, et al. demonstrated an intraocular drug delivery system without a battery by actuating a pump
ACCEPTED MANUSCRIPT
21
magnetically [90]. A PDMS chamber was fabricated with a top membrane containing iron oxide
nanoparticles with a 100 x 100 µm2 aperture for drug release (Fig. 4(c2)). A 64-fold increase in the infused
volume was observed in the presence of 213mT magnetic field when compared with the spontaneous release
T
through the aperture without the magnetic actuation. The limitation of this system is rapid depletion of the
P
RI
magnetic response of the small magnets and thus chronic functionality must be further investigated. In
addition, magnetic actuation is not compatible with two major medical imaging modalities: computerized
SC
tomography (CT) and MRI.
NU
4. Gastrointestinal tract drug delivery – capsule endoscopy
MA
Unlike other parts of the body that require surgery for implantation, drug delivery to a specific location of
the gastrointestinal (GI) tract can be achieved non-invasively by oral intake of drugs. However,
ED
gastrointestinal absorption along the GI tract depends greatly on many physiological, pathological, and
PT
pharmacological factors, such as regions, gastric emptying time, intestinal motility, and drug formulations
[91, 92]. Thus, targeted and efficient drug delivery using passive oral medication is challenging. Another
CE
possible means to deliver drugs in the GI tract is through the use of traditional endoscopes. However, the
endoscope that enters either through the oral cavity or the anus does not provide access to the full GI tract. In
AC
addition, the traditional endoscope has low patient compliance. In contrary, the swallowable capsule
endoscope is highly patient compliant and provides access to the entire GI tract [93].
With the first introduction of a commercially available capsule endoscope in 2001, three small bowel
capsules and one esophageal capsule have been approved by U.S. Food and Drug Administration (FDA)
while one colonic capsule is now available in Europe and Japan [10]. By integrating the drug delivery
function to the capsule endoscope, spatial-, temporal-, and dosage-controlled drug delivery in the GI tract can
be achieved. This targeted on-demand drug release not only enables direct treatments of GI diseases but also
provides an efficient route of administration by targeting the regions with the highest drug absorption. For
ACCEPTED MANUSCRIPT
22
example, the small intestine is an attractive site for drug administration because of its high drug absorption
ascribed to large surface area. Moreover, drug delivery to different regions of the GI tract is an important
field of study for the pharmaceutical industry because understanding the different absorption rates across the
T
GI tract provides useful information in determining the dosage form of a drug for sustained release [94].
P
RI
Some of the passive devices have been utilized in human studies for colon targeting [95]. Since the intubation
process can disturb the normal physiological function of the GI tract, the swallowable capsules can be
SC
utilized as an evaluation tool to study absorption characteristics for drug developments. In addition to the
NU
capsule endoscope, there is an increasing number of works on developing GI patches which are completely
passive systems that rely on various matrices of polymeric layers to achieve timed release in the GI tract. For
MA
details on the GI patches, the readers are referred to a comprehensive review on this topic [96].
ED
4.1.1. Anchoring mechanisms

PT
The environment of the GI tract has been a major limitation factor in the design of the capsule endoscopes.
CE
Firstly, the small capsule size, which is typically ~11 mm in diameter and ~26 mm in length with a volume of
3 cm3, is determined by the minimum diameter of the GI tract (2~3 cm) and comfortable swallowable size.
AC
The second design factor is the control mechanism of the capsule movement: passive or active. Without
active control, the capsule moves by the natural peristaltic movement of the GI tract and thus does not require
additional space in the capsule for an on-chip battery. However, accurate control of the capsule position over
time is not plausible with the passive movement and thus certain areas could be overlooked during diagnostic
examinations. Therefore, the active control of the capsule movement back and forth along the GI tract has
been recently explored.
As capsule endoscope technology has reached its mature stage of development, recent research has focused
on integrating additional functionality to the capsule endoscope, such as biopsy, surgical interventions, and
drug delivery [10]. The drug delivery functionality requires additional considerations in terms of a capsule
ACCEPTED MANUSCRIPT
23
design such as anchoring mechanism, volume of a loaded drug, and release parameters including release rates
and the frequency of dosage. Anchoring is often achieved through the thin mechanical legs that protrude from
the capsule. The anchoring allows not only the navigation of the capsule against the natural peristaltic
T
movement of the GI tract but also localized delivery. The delicate walls of the GI tract, the different sizes of
P
RI
organs along the GI tract (i.e. stomach vs. small intestine), and limited size of the capsule, however, impose
challenges in the leg design such as length, shape, and actuation mechanisms of the legs.
SC
NU
4.1.2. Trade-off between drug volume and on-chip functionalities
Therapeutically effective drug dosage and the formulation of drugs (powder vs. liquids) are another
MA
important design factors in the capsule endoscope because of the limited capsule size. Due to the electronic
components such as battery, antenna, and integrated circuits, typically only 20-30% of the volume is
ED
available for drug loading. The storage size and formulation will determine the number of dosage and
capability to provide multi-site delivery. The volumetric ratio between a drug reservoir and the capsule (Rdc)
PT
is thus an important parameter that imposes trade-off in the capsule design.

CE
Another design consideration is the actuation mechanism of drug release. Since there are many factors that
affect rates of GI absorption such as gastric emptying rate, formulation of drugs, intestinal motility and
AC
metabolism [91], full control over the dosage, time of delivery, total amount of drug, and release rates is often
desired. The actuation of the drug release can be implemented in an either passive or active manner. Passive
drug release driven by diffusion is prone to leakage, retention of drugs, and low release rates. In addition, due
to a lack of an external driving force, the passive drug release relies largely on the dynamic environmental
conditions at target locations such as fluid availability. However, with the passive system, a high Rdc (~35%)
can be achieved due to a small number of active circuit components. Conversely, the active system provides
a wide range of control over the drug release but suffers from low Rdc. The active release system often
utilizes mechanical actuation by pistons and stretchable films to expel the drug. To overcome the low Rdc
issue, other activation mechanisms such as wireless power transfer [97, 98] and non-mechanical actuation
ACCEPTED MANUSCRIPT
24
such as chemically triggered release [99] and magnetic actuation through external magnets [100, 101] have
been reported.
T
P
RI
4.2.1. Legged mechanism
SC
MEMS technology plays a pivotal role in capsule endoscope integrated with the drug delivery capability,
especially in the propulsion and anchoring functions. Various mechanical systems have been proposed that
NU
achieve efficient and safe propulsion and anchoring through the usage of multiple legs [102-104],
inchworm-like locomotion [105, 106], and micropatterned wheels [107]. Followed by the first work in 2004
MA
on the use of mini-legs actuated by shape memory alloy (SMA) actuators [104], Quirini, et al. demonstrated
a 40-mm-length four-legged system which allowed propulsion of the capsule through the GI tract [103]. By
ED
designing the anchors with a C-shape, damage of the anchors to the delicate wall was minimized. However,
this system suffered from three limitations: high power consumption due to the usage of a micromotor,
PT
relatively short length of the legs (40 mm), and potential collision of the capsule into the wall. To minimize
CE
the impact of the collision, Valdastri, et al. proposed a system with twelve legs which were evenly distributed
along the capsule body [102]. These legs not only provided higher control over the propulsion but also
AC
prevented the capsule from impacting the wall of the GI tract. However, the length of the legs was still limited
to 30-35 mm since it was challenging to construct a long thin leg with high stability and controllability. To
overcome this limitation, Woods, et al. have proposed bow-shaped legs that could extend as far as 71.25 mm
stably through an extra support near the capsule body [108] (Fig. 5(a)).
4.2.2. Other anchoring mechanisms
Similar to the legged mechanism, earth-worm like locomotive mechanism has also been explored using
anchor-and-pull motion based on an SMA actuator [105] and a piezo actuator [106]. Chen, et al. have
recently demonstrated a capsule that combined both the legged and locomotion mechanisms; the earth-worm
ACCEPTED MANUSCRIPT
25
like locomotion was used for propulsion and the eight spiral-legs were used for anchoring [109] to benefit
from the both systems (Fig. 5(b)). Another proposed mechanism that provided movements along the GI tract
was based on contact locomotion through the use of wheels to produce tank-like motion [107] (Fig. 5(c)). By
T
patterning a few-hundreds-µm-wide PDMS micro-treads with an aspect ratio of 1:2 on the surface of the
P
RI
wheel, sufficient traction was achieved on various types of tissues such as the stomach and liver tissues in
vivo. In addition, active drug release also requires a means to expel the drugs from a reservoir in the capsule.
SC
MEMS technology has been also utilized in pushing drugs by microthrust [110], piezoactuation [111],
NU
pneumatic control [112], and stretchable piston membrane [113].
MA
4.2.3. Remaining problems
Unfortunately, because of the mechanical complexity and high power requirement, none of the reported
ED
capsule endoscopes equipped with the mechanical systems are in the clinical stage. Nevertheless, there have
been continuous efforts towards minimizing the volume required for anchoring and release activation by
PT
moving the control unit outside the capsule such as magnetic actuation through the use of external magnets
CE
[100, 114]. In addition, developments of a thin-film battery [115] for the implant and exploration of energy
harvesting strategies [116] provide a good prospect for drug delivery using capsule endoscopes. Moreover,
AC
components to actuate the drug release such as microheaters and mechanical parts could benefit from MEMS
technology [93].
5. Transdermal drug delivery
Drug administration through the skin is an attractive alternative to oral delivery and hypodermic injection
because of several distinctive advantages. Firstly, a transdermally delivered drug distributes systemically
through rich vascular networks in the dermis and is not subject to the first-pass metabolism in the liver as in
the case of oral delivery. In addition, transdermal drug delivery allows long-term drug administration through
the use of biocompatible patches. Nicotine patches and analgesia-loaded microneedles are a few examples
ACCEPTED MANUSCRIPT
26
where administration over an extended period of time (e.g. at least one day) is preferred. Intravenous (IV)
injection can deliver larger volumes of drugs but the mobility of patients is heavily restricted in comparison
to transdermal patches. Among the novel drug delivery systems, transdermal drug delivery is perhaps most
T
widely researched, developed, and accepted due to low patient compliance. Not only several transdermal
P
RI
drugs have received the US FDA approval [117], but also a number of transdermal delivery systems are
available in the market [118]. From a historical perspective, transdermal drug delivery had evolved over three
SC
generations of developments with hallmark achievements in each generation: 1) selection of transdermal
NU
drugs, 2) enhancements of skin permeability and transdermal transport, and 3) direct targeting of stratum
corneum using microneedles, thermal ablation, microdermabrasion, and ultrasound [117].

MA
5.1. Challenges and opportunities

ED
Although the history of microneedle technology is relatively long compared with that of other novel drug
delivery systems, there are still unresolved challenges and desired features that require technological
PT
innovations. Transdermal microneedles are designed to penetrate stratum corneum but not deeply enough to
reach nerve endings. Thus, secure positioning of the microneedles on the skin is important especially
CE
regarding drug administration over an extended period of time. Therefore, there is still a continuous effort to
AC
optimize structures of microneedles such as tip shape, length, and spacing. For instance, Seong, et al. have
recently reported a bullet-shape microneedle array with water-swellable tips; upon insertion, the tips swell
due to an uptake of biofluid and provide a strong mechanical interlock to the neighboring soft tissues [119].
Completely dissolvable microneedle arrays serve as another important area of interest in the transdermal drug
delivery especially for vaccine delivery [120, 121]. With the advancement in the polymeric fabrication and
biotechnology, delivery of a wide range of drug candidates including proteins, DNAs, and virus-based
vaccines is now also actively investigated [30, 122].
During the early stage of development, the infused drugs by microneedles were diffusion-limited because
of passive drug release. In order to enhance drug penetration and release rates, external forces were applied
ACCEPTED MANUSCRIPT
27
such as electric field, ultrasound, and mechanical forces. These external forces can also be used as external
stimuli for on-demand drug release [123]. If the stimuli are internally-generated physiological signals, a
closed-loop or self-regulated drug delivery can be achieved; activation of drug release is determined by
T
changes in the physiological signals through the use of bioresponsive vesicles [124]. This smart closed-loop
P
RI
approach would become useful for diabetes patients as well as patients who require on-demand
administration of analgesia over an extended period of time. Possible internal physiological signals include
SC
temperature, pH, glucose level, and enzyme concentrations. Design considerations for these systems include
NU
response rates of the closed-loop system, sensitivity to physiological signals, resolutions of the detectable
signals, on/off ratios, local and systemic side effects due to biocompatibility, and the volume of drugs
MA
required to match long-term dosage of specific therapeutics.
5.2. Stimuli-responsive microneedles

ED
There is an increasing number of works on developing stimuli-responsive microneedles that apply either
internal or external stimuli to achieve on-demand and self-regulatory drug delivery. Teodorescu, et al. have
PT
recently developed a flexible transdermal patch that was photo-thermally triggered; by applying
CE
continuous-wave near-infrared (NIR), an increase in temperature was induced which release drugs loaded in
microneedles through dissolution [125]. Photo-controlled delivery has an advantage of high spatial and
AC
temporal resolutions. However, thermal damage to the skin must be carefully designed. Thus, the authors
conducted immunohistology of skin tissues at the implant site to empirically determine the maximum light
intensity allowed for drug release. Another work by Chen, et al. reported a patient-controlled transdermal
analgesia system which was also triggered by NIR [8] (Fig. 6(a)). Exposure to NIR resulted in an increase in
temperature up to 50ºC at which lidocaine-loaded microneedles started dissolving. Programmed drug release
was demonstrated by controlling the on/off cycles of the NIR laser. Gulati, et al. also implemented a
switchable nicotine patch which used a carbon nanotube (CNT) membrane as a switching layer [126]. The
permeability of the CNT membrane was changed when DC bias (~600mV) was applied. However, because
the system relied on diffusion, the on/off ratio was low and the response time was in an order of hours. Di, et
ACCEPTED MANUSCRIPT
28
al. have also proposed a wearable, tensile strain-triggered drug delivery system which consisted of a
stretchable elastomer and microgel depots containing drug-loaded nanoparticles [127]. In this
stretch-triggered system, a tensile stress activated the drug release by increasing the surface area for
T
diffusion.
P
RI
Self-regulated drug release delivers therapeutic agents based on the physiological signals sensed through
biofunctional materials of the microneedle platform itself. The idea of closed-loop drug release was first
SC
demonstrated by Huang, et al. [128] where real-time measurements of glucose level in a PDMS microfluidic
NU
chip controlled the release of insulin. While this closed-loop system used separate sensing and drug release
units which were connected through an external circuitry, sensing and actuation units can be integrated in a
MA
single microneedle tip without any external circuitry by using bioresponsive vesicles. For example, in
recently proposed smart insulin delivery systems for diabetic patients, a change in glucose level within
ED
vascular and lymph capillaries triggered the release of insulin by use of glucose-responsive vesicles [129],
H2O2-sensitive polymersomes [130], and antibody-loaded pH-sensitive dextran nanoparticles [131]. Hu, et al.
PT
designed H2O2-responsive vesicles that facilitated oxidation of glucose to gluconic acid and generated H2O2
which in turn dissociated vesicles to allow for the release of insulin (Fig. 6(b)) [130]. Although the released
CE
amount of insulin was not constant at each pulsation, the response time was fast enough for the insulin
AC
concentration to follow a 10-min-period cyclic change in glucose concentrations. Since the closed-loop
systems are in the early stage of development, there are many areas for innovation in terms of increasing
sensitivity to physiological signals, improving repeatability of released drug dosage, and maximizing the
capacity to load therapeutically effective dosage enough for long-term administration.
6. Implantable subcutaneous drug delivery
Microfabrication plays an essential role in implementing microdevices for transdermal drug delivery and
subcutaneous implants, such as microneedles, micropumps, reservoirs, and encapsulation [132]. While
transdermal drug delivery is minimally invasive, self-administrable, inexpensive, and highly patient
ACCEPTED MANUSCRIPT
29
compliant, subcutaneous implants are invasive with low patient compliance but provide long-term
administration in an order of years. Because of the difference in the nature of invasiveness, these two systems
face different technological challenges and thus are discussed separately in this review.
T
Although implantation under the skin is subject to the issue of patients’ compliance and acceptance, there is
P
RI
still a need for implantable subcutaneous drug delivery to administrate drugs over an extended period of time
such as insulin injection and cancer therapy. Long-term administration reduces the need for frequent needle
SC
injections and thus dramatically improves the long-term patient comfort of patients. The first report on the
NU
multiwell silicon-based drug-release device in 1999 [133] was followed by another diffusion-based system, a
leuprolide acetate implant, which was evaluated over a period of 12 months by Alza Corporation [134].
MA
Although small in number, there has been a steady number of reports on the subcutaneous drug delivery
systems [135, 136] (Fig. 7(a)). For details on the individual components of the implantable systems such as
ED
micropumps and reservoir designs, readers are referred to [12, 132].
6.1. Design considerations

PT
Similar to the design of implants for the posterior segments of eyes and the capsule endoscopes, the volume
CE
of the implant is the most important design criterion for subcutaneous implants. The size of the implant is
directly related to patients’ compliance and comfort, complexity of surgery, capacity for drug loading, and
AC
available areas for active circuit components. The volume of loaded drug is an imperative design parameter
since it determines a maximum number of deliverable dosage and thus the duration of implantation.
Implementation of refillable reservoirs is another option to increase the number of dosages but is potentially
subject to clogging and infection. Similar to the capsule endoscope and eye implants, active actuation of drug
release is possible through magnetic, piezoelectric pumping, and electrothermal activation [136]. In addition,
diffusion-based passive drug release was also explored in terms of various regulating means such as
membranes, polymer matrices, microchannel implants, and osmotic pumps. Moreover, there is a continuous
effort in applying wireless technology to minimize the active components in the implant to secure space for
drug storage [137-139].

ACCEPTED MANUSCRIPT
30
Similar to the drug delivery implants for the posterior segment of eyes, long-term biocompatibility and
robustness are the major challenges for subcutaneous implants. Studies conducted by van Dijk, et al. on
complications of implantable pumps for intraperitoneal insulin infusion showed 10-17% of people reported
T
haematoma, cutaneous erosion, pain or infection at surgical sites [140]. Moreover, 5-17% of patients reported
P
RI
the need for replacements due to technical failure of the implantable pumps. A recent study on the
implantable pump for subcutaneous insulin delivery in healthy cats showed that one out of nine implantable
SC
pumps malfunctioned immediately after the implantation and only 50% of pumps delivered the correct
NU
amount of drugs during the four consecutive boluses [141]. Faulty parts in an implant imply surgical removal
and thus it is critical to ensure biocompatibility of the implants and to improve the reliability of the driving
MA
components in the subcutaneous implants.
ED
6.2.1. Biocompatibility and reliability. There are continuously evolving reports on new implantable
PT
subcutaneous microdevices [142-144] with movements towards wireless actuation [137-139]. Liu, et al.
devised a refillable MEMS drug delivery device which consisted of electrodes for actuation, a drug reservoir,
CE
and a cannula [143]. Metal electrodes for the actuation were fabricated on a silicon wafer while the
AC
10-mm-long, 10-mm-wide, and 2-mm-thick drug reservoir was fabricated using an SU-8 photoresist.
Successful delivery of 50 µL of adrenaline formulation was observed through an increase in blood pressure
after an injection in six mice, respectively. The long-term biocompatibility associated with drug delivery was
investigated on ten microdevices through in vivo mice experiments. After 28 days of implantation, the
devices were fully encapsulated with fibrous tissue (Fig. 7(b)).
Chin, et al. have recently demonstrated an implantable MEMS (iMEMS) drug delivery system that ensured
biocompatibility and improved reliability [144]. By fabricating a set of versatile three-dimensional
multilayers for biocompatible hydrogel devices, multilayered moving parts such as multi-reservoir single
gear, gate valves, and toothed rotors were all integrated in hydrogels (Fig. 7(c)). Poly(ethylene glycol)
ACCEPTED MANUSCRIPT
31
(PEG)-based hydrogel used in this work offered several distinctive advantages such as biocompatibility, a
non-fouling property, and flexibility for conformal contact and less damage. The versatile fabrication also
enabled embedment of iron nanoparticles in precise locations to achieve remote magnetic actuation of the
T
mechanical components. Authors demonstrated successful in vivo delivery of doxorubicin in mice for over
P
RI
10 days. The presented additive manufacturing of biocompatible materials is a promising enabling
microtechnology for the next-generation subcutaneous drug delivery systems.
SC
NU
6.2.2. Perspective. In order to accommodate a vast range of drug candidates such as macromolecules,
genes, and vaccines, there is a trend towards developing a system that can accommodate drugs with low
MA
bioavailability. Recently, Lathuiliere, et al. have developed a bioactive cellular implant that delivered
recombinant anti-amyloid-β antibodies in the subcutaneous tissue as immunotherapy against Alzheimer’s

ED
disease [142]. The implantation of genetically engineered cells allowed for continuous production of
monoclonal antibodies, and the implanted cells secreted sustained level of the therapeutic antibodies in the
PT
plasma (Fig. 7(d)). Long-term survival of myogenic cells in the encapsulated subcutaneous implant for over
10 months was demonstrated in two mouse models of Alzheimer’s disease. Combining this encapsulated cell
CE
technology with novel drug delivery systems is a promising alternative technology for treatments of diseases
AC
with no satisfactory therapies.
7. CONCLUSIONS
This review provides a comprehensive outlook of current challenges in novel drug delivery systems that
are enabled by microtechnology and a summary of recent advances in drug delivery systems that have
attempted to overcome these challenges. As each organ imposes different anatomical and physiological
challenges, these challenges and recent advancements have been discussed in terms of target areas (Table 1).
Through miniaturization, integration of multiple functions, and electromechanical actuation, MEMS
technology has served as the emerging technology to achieve spatiotemporal- and dosage-controlled drug
ACCEPTED MANUSCRIPT
32
delivery for a wide range of target areas. Thin microneedles or neural probes have enabled localized drug
delivery to various regions of the brain with a high spatial resolution while microneedle arrays have been
widely used for intraocular and transdermal drug delivery. Implantable systems that provide on-demand or
T
self-regulated drug delivery are now possible through the use of internal and external stimuli for intraocular,
P
RI
gastrointestinal, and subcutaneous drug delivery. For implantable systems, gaining patients’ compliance and
comfort through implementation of highly robust system is the most challenging hurdle. Regardless of the
SC
areas, there are common issues associated with the implant devices, such as total volume of drug loaded in a
NU
reservoir, frequency of reimplantation, passive or active activation and power transfer. With further
technological innovations in each of the drug delivery systems and matching the appropriate techniques with
MA
a wide spectrum of novel drug candidates, the prospect for novel drug delivery systems enabled by MEMS or
microtechnology is apparently high for clinical translation.

ED
ACKNOWLEDGEMENTS
PT
This work was supported by the Brain Research Program through the National Research Foundation of
CE
Korea (NRF) funded by Ministry of Science and ICT (NRF-2017M3C7A1028854) and was supported by the
Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry
AC
of Science and ICT (NRF-2016M3C7A1904343).
REFERENCES
[1] A.C. Hunter, S.M. Moghimi, Smart polymers in drug delivery: a biological perspective, Polymer Chemistry, 8 (2017) 41-51.
[2] B. Mishra, B.B. Patel, S. Tiwari, Colloidal nanocarriers: a review on formulation technology, types and applications toward
targeted drug delivery, Nanomedicine: Nanotechnology, biology and medicine, 6 (2010) 9-24.
[3] J. Shi, A.R. Votruba, O.C. Farokhzad, R. Langer, Nanotechnology in drug delivery and tissue engineering: from discovery to
applications, Nano letters, 10 (2010) 3223-3230.
[4] R. Fernandes, D.H. Gracias, Self-folding polymeric containers for encapsulation and delivery of drugs, Advanced drug delivery
reviews, 64 (2012) 1579-1589.
[5] J. Shi, A.R. Votruba, O.C. Farokhzad, R. Langer, Nanotechnology in drug delivery and tissue engineering: from discovery to
applications, Nano letters, 10 (2010) 3223.
ACCEPTED MANUSCRIPT
33
[6] Y.-C. Kim, J.-H. Park, M.R. Prausnitz, Microneedles for drug and vaccine delivery, Advanced drug delivery reviews, 64 (2012)
1547-1568.
[7] G. Kook, S.W. Lee, H.C. Lee, I.-J. Cho, H.J. Lee, Neural probes for chronic applications, Micromachines, 7 (2016) 179.
[8] M.-C. Chen, H.-A. Chan, M.-H. Ling, L.-C. Su, Implantable polymeric microneedles with phototriggerable properties as a
T
patient-controlled transdermal analgesia system, Journal of Materials Chemistry B, (2017).
[9] H.J. Lee, Y. Son, J. Kim, C.J. Lee, E.-S. Yoon, I.-J. Cho, A multichannel neural probe with embedded microfluidic channels for
P
simultaneous in vivo neural recording and drug delivery, Lab on a Chip, 15 (2015) 1590-1597.
RI
[10] F. Munoz, G. Alici, W. Li, A review of drug delivery systems for capsule endoscopy, Advanced drug delivery reviews, 71
(2014) 77-85.
SC
[11] M. Aryal, C.D. Arvanitis, P.M. Alexander, N. McDannold, Ultrasound-mediated blood–brain barrier disruption for targeted
drug delivery in the central nervous system, Advanced drug delivery reviews, 72 (2014) 94-109.
[12] A. Nisar, N. Afzulpurkar, B. Mahaisavariya, A. Tuantranont, MEMS-based micropumps in drug delivery and biomedical
NU
applications, Sensors and Actuators B: Chemical, 130 (2008) 917-942.
[13] K. van der Maaden, W. Jiskoot, J. Bouwstra, Microneedle technologies for (trans) dermal drug and vaccine delivery, Journal
MA
of controlled release, 161 (2012) 645-655.
[14] K. Ita, Dermal/transdermal delivery of small interfering RNA and antisense oligonucleotides-advances and hurdles,
Biomedicine & Pharmacotherapy, 87 (2017) 311-320.
[15] M.N. Yasin, D. Svirskis, A. Seyfoddin, I.D. Rupenthal, Implants for drug delivery to the posterior segment of the eye: A focus
ED
on stimuli-responsive and tunable release systems, Journal of Controlled Release, 196 (2014) 208-221.
[16] H. Li, Y. Yu, S. Faraji Dana, B. Li, C.-Y. Lee, L. Kang, Novel engineered systems for oral, mucosal and transdermal drug
delivery, Journal of drug targeting, 21 (2013) 611-629.
PT
[17] W.M. Pardridge, Drug transport across the blood–brain barrier, Journal of Cerebral Blood Flow & Metabolism, 32 (2012)
1959-1972.
CE
[18] S. Mitragotri, Healing sound: the use of ultrasound in drug delivery and other therapeutic applications, Nature Reviews Drug
Discovery, 4 (2005) 255-260.
[19] N. Vykhodtseva, N. McDannold, K. Hynynen, Progress and problems in the application of focused ultrasound for blood–brain
AC
barrier disruption, Ultrasonics, 48 (2008) 279-296.

[20] A. Dasgupta, M. Liu, T. Ojha, G. Storm, F. Kiessling, T. Lammers, Ultrasound-mediated drug delivery to the brain: principles,
progress and prospects, Drug Discovery Today: Technologies, 20 (2016) 41-48.
[21] F. Fang, D. Zou, W. Wang, Y. Yin, T. Yin, S. Hao, B. Wang, G. Wang, Y. Wang, Non-invasive approaches for drug delivery
to the brain based on the receptor mediated transport, Materials Science and Engineering: C, (2017).
[22] L. Illum, Is nose‐to‐brain transport of drugs in man a reality?, Journal of Pharmacy and Pharmacology, 56 (2004) 3-17.
[23] Z.N. Warnken, H.D. Smyth, A.B. Watts, S. Weitman, J.G. Kuhn, R.O. Williams, Formulation and device design to increase
nose to brain drug delivery, Journal of Drug Delivery Science and Technology, 35 (2016) 213-222.
[24] W.M. Pardridge, The blood-brain barrier: bottleneck in brain drug development, NeuroRx, 2 (2005) 3-14.
[25] M.S. Fiandaca, M.S. Berger, K.S. Bankiewicz, The use of convection-enhanced delivery with liposomal toxins in
neurooncology, Toxins, 3 (2011) 369-397.
[26] H.J. Lee, Y. Son, D. Kim, Y.K. Kim, N. Choi, E.-S. Yoon, I.-J. Cho, A new thin silicon microneedle with an embedded
microchannel for deep brain drug infusion, Sensors and Actuators B: Chemical, 209 (2015) 413-422.
ACCEPTED MANUSCRIPT
34
[27] J. Chen, K.D. Wise, J.F. Hetke, S. Bledsoe, A multichannel neural probe for selective chemical delivery at the cellular level,
Biomedical Engineering, IEEE Transactions on, 44 (1997) 760-769.
[28] Z. Fekete, A. Pongrácz, Multifunctional soft implants to monitor and control neural activity in the central and peripheral
nervous system: a review, Sensors and Actuators B: Chemical, 243 (2017) 1214-1223.
T
[29] M.J. de Boer, R.W. Tjerkstra, J. Berenschot, H.V. Jansen, G. Burger, J. Gardeniers, M. Elwenspoek, A. van den Berg,
Micromachining of buried micro channels in silicon, Microelectromechanical Systems, Journal of, 9 (2000) 94-103.
P
[30] A. Altuna, E. Bellistri, E. Cid, P. Aivar, B. Gal, J. Berganzo, G. Gabriel, A. Guimerà, R. Villa, L.J. Fernández, SU-8 based
RI
microprobes for simultaneous neural depth recording and drug delivery in the brain, Lab on a Chip, 13 (2013) 1422-1430.
[31] N. Vasylieva, S. Marinesco, D. Barbier, A. Sabac, Silicon/SU8 multi-electrode micro-needle for in vivo neurochemical
SC
monitoring, Biosensors and Bioelectronics, 72 (2015) 148-155.
[32] H. Shin, H.J. Lee, U. Chae, H. Kim, J. Kim, N. Choi, J. Woo, Y. Cho, C.J. Lee, E.-S. Yoon, Neural probes with multi-drug
delivery capability, Lab on a Chip, 15 (2015) 3730-3737.
NU
[33] J.G. McCall, R. Qazi, G. Shin, S. Li, M.H. Ikram, K.-I. Jang, Y. Liu, R. Al-Hasani, M.R. Bruchas, J.-W. Jeong, Preparation
and implementation of optofluidic neural probes for in vivo wireless pharmacology and optogenetics, Nature Protocols, 12 (2017)
MA
219-237.
[34] W.-C. Huang, Y.-C. Lo, C.-Y. Chu, H.-Y. Lai, Y.-Y. Chen, S.-Y. Chen, Conductive nanogel-interfaced neural microelectrode
arrays with electrically controlled in-situ delivery of manganese ions enabling high-resolution MEMRI for synchronous neural
tracing with deep brain stimulation, Biomaterials, (2017).
ED
[35] Z. Fekete, E. Pálfi, G. Márton, M. Handbauer, Z. Bérces, I. Ulbert, A. Pongrácz, L. Négyessy, Combined in vivo recording of
neural signals and iontophoretic injection of pathway tracers using a hollow silicon microelectrode, Sensors and Actuators B:
Chemical, 236 (2016) 815-824.
PT
[36] W. Lee, T. Ngernsutivorakul, O.S. Mabrouk, J.-M.T. Wong, C.E. Dugan, S.S. Pappas, H.J. Yoon, R.T. Kennedy,
Microfabrication and in vivo performance of a microdialysis probe with embedded membrane, Analytical chemistry, 88 (2016)
CE
1230.
[37] U. Chae, H. Shin, H.J. Lee, J. Lee, N. Choi, Y.J. Lee, S.H. Lee, J. Woo, Y. Cho, E.-S. Yoon, A new MEMS neural probe
system integrated with push-pull microfluidic channels and biosensors for real-time monitoring of neurochemicals, Micro Electro
AC
Mechanical Systems (MEMS), 2016 IEEE 29th International Conference on, IEEE, 2016, pp. 329-332.
[38] G. Petit-Pierre, A. Bertsch, P. Renaud, Neural probe combining microelectrodes and a droplet-based microdialysis collection
system for high temporal resolution sampling, Lab on a Chip, 16 (2016) 917-924.
[39] M.A. Green, L.E. Bilston, R. Sinkus, In vivo brain viscoelastic properties measured by magnetic resonance elastography,
NMR in Biomedicine, 21 (2008) 755-764.
[40] B. Liu, E. Kim, A. Meggo, S. Gandhi, H. Luo, S. Kallakuri, Y. Xu, J. Zhang, Enhanced biocompatibility of neural probes by
integrating microstructures and delivering anti-inflammatory agents via microfluidic channels, Journal of Neural Engineering, 14
(2017) 026008.
[41] C. Boehler, C. Kleber, N. Martini, Y. Xie, I. Dryg, T. Stieglitz, U. Hofmann, M. Asplund, Actively controlled release of
Dexamethasone from neural microelectrodes in a chronic in vivo study, Biomaterials, 129 (2017) 176-187.
[42] F.-Y. Yang, Y.-S. Lin, K.-H. Kang, T.-K. Chao, Reversible blood–brain barrier disruption by repeated transcranial focused
ultrasound allows enhanced extravasation, Journal of controlled release, 150 (2011) 111-116.
ACCEPTED MANUSCRIPT
35
[43] Y. Negishi, M. Yamane, N. Kurihara, Y. Endo-Takahashi, S. Sashida, N. Takagi, R. Suzuki, K. Maruyama, Enhancement of
blood–brain barrier permeability and delivery of antisense oligonucleotides or plasmid DNA to the brain by the combination of
Bubble liposomes and high-intensity focused ultrasound, Pharmaceutics, 7 (2015) 344-362.
[44] S. Wang, T. Kugelman, A. Buch, M. Herman, Y. Han, M.E. Karakatsani, S.A. Hussaini, K. Duff, E.E. Konofagou,
T
Non-invasive, Focused Ultrasound-Facilitated Gene Delivery for Optogenetics, Scientific Reports, 7 (2017).
[45] R.D. Airan, R.A. Meyer, N.P. Ellens, K.R. Rhodes, K. Farahani, M.G. Pomper, S.D. Kadam, J.J. Green, Noninvasive targeted
P
transcranial neuromodulation via focused ultrasound gated drug release from nanoemulsions, Nano letters, 17 (2017) 652-659.
RI
[46] R.D. Airan, C.A. Foss, N.P. Ellens, Y. Wang, R.C. Mease, K. Farahani, M.G. Pomper, MR-Guided Delivery of Hydrophilic
Molecular Imaging Agents Across the Blood-Brain Barrier Through Focused Ultrasound, Molecular Imaging and Biology, 19
SC
(2017) 24-30.
[47] Z. Jin, Y. Choi, S.Y. Ko, J.O. Park, S. Park, Experimental and simulation studies on focused ultrasound triggered drug
delivery, Biotechnology and applied biochemistry, (2016).
NU
[48] Y. Chau, W.L.L. Suen, H.Y. Tse, H.S. Wong, Ultrasound-enhanced penetration through sclera depends on frequency of
sonication and size of macromolecules, European Journal of Pharmaceutical Sciences, 100 (2017) 273-279.
MA
[49] H. Ballantine Jr, E. Bell, J. Manlapaz, Progress and problems in the neurological applications of focused ultrasound, Journal of
neurosurgery, 17 (1960) 858-876.
[50] L. Bakay, T. Hueter, H. Ballantine, D. Sosa, Ultrasonically produced changes in the blood-brain barrier, AMA Archives of
Neurology & Psychiatry, 76 (1956) 457-467.
ED
[51] A.H. Mesiwala, L. Farrell, H.J. Wenzel, D.L. Silbergeld, L.A. Crum, H.R. Winn, P.D. Mourad, High-intensity focused
ultrasound selectively disrupts the blood-brain barrier in vivo, Ultrasound in medicine & biology, 28 (2002) 389-400.
[52] B.E. Polat, D. Hart, R. Langer, D. Blankschtein, Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and
PT
emerging trends, Journal of controlled release, 152 (2011) 330-348.

[53] C.M. Schoellhammer, B.E. Polat, J. Mendenhall, R. Maa, B. Jones, D.P. Hart, R. Langer, D. Blankschtein, Rapid skin
CE
permeabilization by the simultaneous application of dual-frequency, high-intensity ultrasound, Journal of controlled release, 163
(2012) 154-160.
[54] P. Hariharan, M. Nabili, A. Guan, V. Zderic, M. Myers, Model for Porosity Changes Occurring during Ultrasound-Enhanced
AC
Transcorneal Drug Delivery, Ultrasound in Medicine & Biology, (2017).

[55] C.M. Schoellhammer, A. Schroeder, R. Maa, G.Y. Lauwers, A. Swiston, M. Zervas, R. Barman, A.M. DiCiccio, W.R.
Brugge, D.G. Anderson, Ultrasound-mediated gastrointestinal drug delivery, Science translational medicine, 7 (2015)
310ra168-310ra168.
[56] C.-H. Fan, C.-Y. Ting, Y.-C. Chang, K.-C. Wei, H.-L. Liu, C.-K. Yeh, Drug-loaded bubbles with matched focused ultrasound
excitation for concurrent blood–brain barrier opening and brain-tumor drug delivery, Acta biomaterialia, 15 (2015) 89-101.
[57] L. Goldwirt, M. Canney, C. Horodyckid, J. Poupon, S. Mourah, A. Vignot, J.-Y. Chapelon, A. Carpentier, Enhanced brain
distribution of carboplatin in a primate model after blood–brain barrier disruption using an implantable ultrasound device, Cancer
chemotherapy and pharmacology, 77 (2016) 211-216.
[58] E. Park, J. Werner, N.B. Smith, Ultrasound mediated transdermal insulin delivery in pigs using a lightweight transducer,
Pharmaceutical research, 24 (2007) 1396-1401.
[59] E. Maione, K.K. Shung, R.J. Meyer, J.W. Hughes, R.E. Newnham, N.B. Smith, Transducer design for a portable ultrasound
enhanced transdermal drug-delivery system, IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, 49 (2002)
1430-1436.
ACCEPTED MANUSCRIPT
36
[60] Y. Tufail, A. Matyushov, N. Baldwin, M.L. Tauchmann, J. Georges, A. Yoshihiro, S.I.H. Tillery, W.J. Tyler, Transcranial
pulsed ultrasound stimulates intact brain circuits, Neuron, 66 (2010) 681-694.
[61] M. Fini, W.J. Tyler, Transcranial focused ultrasound: a new tool for non-invasive neuromodulation, International Review of
Psychiatry, (2017) 1-10.
T
[62] H.-S. Yoon, S. Vaithilingam, K.K. Park, A. Nikoozadeh, K. Firouzi, J.W. Choe, R.D. Watkins, H.K. Oguz, M. Kupnik, K.B.
Pauly, A 1-MHz 2-D CMUT array for HIFU thermal ablation, AIP Conference Proceedings, AIP Publishing, 2017, pp. 050003.
P
[63] K. Ko, J.-H. Lee, H.J. Lee, S.-J. Oh, Y.E. Chun, T.S. Kim, C.J. Lee, E.-S. Yoon, K.-S. Yun, I.-J. Cho, Micromachined
RI
ultrasound transducer array for cell stimulation with high spatial resolution, Micro Electro Mechanical Systems (MEMS), 2015
28th IEEE International Conference on, IEEE, 2015, pp. 651-654.
SC
[64] J. Chen, Capacitive micromachined ultrasonic transducer arrays for minimally invasive medical ultrasound, Journal of
Micromechanics and Microengineering, 20 (2010) 023001.
[65] E.M. Del Amo, A. Urtti, Current and future ophthalmic drug delivery systems: a shift to the posterior segment, Drug
NU
Discovery Today, 13 (2008) 135-143.
[66] T. Yasukawa, Y. Ogura, E. Sakurai, Y. Tabata, H. Kimura, Intraocular sustained drug delivery using implantable polymeric
MA
devices, Advanced drug delivery reviews, 57 (2005) 2033-2046.
[67] P. Bansal, S. Garg, Y. Sharma, P. Venkatesh, Posterior segment drug delivery devices: current and novel therapies in
development, Journal of Ocular Pharmacology and Therapeutics, 32 (2016) 135-144.
[68] R.R. Joseph, S.S. Venkatraman, Drug delivery to the eye: what benefits do nanocarriers offer?, Nanomedicine, 12 (2017)
ED
683-702.
[69] P.W. Morrison, V.V. Khutoryanskiy, Advances in ophthalmic drug delivery, Therapeutic delivery, 5 (2014) 1297-1315.
[70] N. Kuno, S. Fujii, Recent advances in ocular drug delivery systems, Polymers, 3 (2011) 193-221.
PT
[71] A. Guzman-Aranguez, B. Colligris, J. Pintor, Contact lenses: promising devices for ocular drug delivery, Journal of Ocular
Pharmacology and Therapeutics, 29 (2013) 189-199.
CE
[72] A. Patel, K. Cholkar, V. Agrahari, A.K. Mitra, Ocular drug delivery systems: an overview, World journal of pharmacology, 2
(2013) 47.
[73] H.P. Filipe, J. Henriques, P. Reis, P.C. Silva, M.J. Quadrado, A.P. Serro, Contact lenses as drug controlled release systems: a
AC
narrative review, Revista Brasileira de Oftalmologia, 75 (2016) 241-247.

[74] N. Haghjou, M. Soheilian, M.J. Abdekhodaie, Sustained release intraocular drug delivery devices for treatment of uveitis,
Journal of ophthalmic & vision research, 6 (2011) 317.
[75] J.I. Lim, R.A. Wolitz, A.H. Dowling, H.R. Bloom, A.R. Irvine, D.M. Schwartz, Visual and anatomic outcomes associated
with posterior segment complications after ganciclovir implant procedures in patients with AIDS and cytomegalovirus retinitis,
American journal of ophthalmology, 127 (1999) 288-293.
[76] J. Jiang, J.S. Moore, H.F. Edelhauser, M.R. Prausnitz, Intrascleral drug delivery to the eye using hollow microneedles,
Pharmaceutical research, 26 (2009) 395-403.
[77] J. Jiang, H.S. Gill, D. Ghate, B.E. McCarey, S.R. Patel, H.F. Edelhauser, M.R. Prausnitz, Coated microneedles for drug
delivery to the eye, Investigative ophthalmology & visual science, 48 (2007) 4038-4043.
[78] S.R. Patel, A.S. Lin, H.F. Edelhauser, M.R. Prausnitz, Suprachoroidal drug delivery to the back of the eye using hollow
microneedles, Pharmaceutical research, 28 (2011) 166-176.
ACCEPTED MANUSCRIPT
37
[79] G. Valdés-Ramírez, J.R. Windmiller, J.C. Claussen, A.G. Martinez, F. Kuralay, M. Zhou, N. Zhou, R. Polsky, P.R. Miller, R.
Narayan, Multiplexed and switchable release of distinct fluids from microneedle platforms via conducting polymer nanoactuators
for potential drug delivery, Sensors and Actuators B: Chemical, 161 (2012) 1018-1024.
[80] R.R.S. Thakur, I.A. Tekko, F. Al-Shammari, A.A. Ali, H. McCarthy, R.F. Donnelly, Rapidly dissolving polymeric
T
microneedles for minimally invasive intraocular drug delivery, Drug Delivery and Translational Research, 6 (2016) 800-815.
[81] R. Lo, P.-Y. Li, S. Saati, R. Agrawal, M.S. Humayun, E. Meng, A refillable microfabricated drug delivery device for treatment
P
of ocular diseases, Lab on a Chip, 8 (2008) 1027-1030.
RI
[82] R. Lo, P.-Y. Li, S. Saati, R.N. Agrawal, M.S. Humayun, E. Meng, A passive MEMS drug delivery pump for treatment of
ocular diseases, Biomedical microdevices, 11 (2009) 959.
SC
[83] P.-Y. Li, J. Shih, R. Lo, S. Saati, R. Agrawal, M.S. Humayun, Y.-C. Tai, E. Meng, An electrochemical intraocular drug
delivery device, Sensors and Actuators A: Physical, 143 (2008) 41-48.
[84] I.D. Rupenthal, Sector overview: ocular drug delivery technologies: exciting times ahead, ONdrugDelivery, 54 (2015) 7-11.
NU
[85] Y. Zhang, Y. Chen, X. Yu, Y. Qi, Y. Chen, Y. Liu, Y. Hu, Z. Li, A flexible device for ocular iontophoretic drug delivery,
Biomicrofluidics, 10 (2016) 011911.
MA
[86] Y. Shikamura, Y. Yamazaki, T. Matsunaga, T. Sato, A. Ohtori, K. Tojo, Hydrogel ring for topical drug delivery to the ocular
posterior segment, Current eye research, 41 (2016) 653-661.
[87] S. Yu, X. Zhang, G. Tan, L. Tian, D. Liu, Y. Liu, X. Yang, W. Pan, A novel pH-induced thermosensitive hydrogel composed
of carboxymethyl chitosan and poloxamer cross-linked by glutaraldehyde for ophthalmic drug delivery, Carbohydrate Polymers,
ED
155 (2017) 208-217.

[88] N. Nagai, H. Kaji, H. Onami, Y. Ishikawa, M. Nishizawa, N. Osumi, T. Nakazawa, T. Abe, A polymeric device for controlled
transscleral multi-drug delivery to the posterior segment of the eye, Acta biomaterialia, 10 (2014) 680-687.
PT
[89] P. Song, S. Kuang, N. Panwar, G. Yang, D.J.H. Tng, S.C. Tjin, W.J. Ng, M.B.A. Majid, G. Zhu, K.T. Yong, A Self‐Powered
Implantable Drug‐Delivery System Using Biokinetic Energy, Advanced Materials, (2017).
CE
[90] F.N. Pirmoradi, J.K. Jackson, H.M. Burt, M. Chiao, On-demand controlled release of docetaxel from a battery-less MEMS
drug delivery device, Lab on a Chip, 11 (2011) 2744-2752.
[91] C.R. Craig, R.E. Stitzel, Modern pharmacology with clinical applications, Lippincott Williams & Wilkins2004.
AC
[92] I.R. Wilding, Site-specific drug delivery in the gastrointestinal tract, Critical Reviews™ in Therapeutic Drug Carrier Systems,
17 (2000).
[93] C. Mc Caffrey, O. Chevalerias, C. O'Mathuna, K. Twomey, Swallowable-capsule technology, IEEE Pervasive Computing, 7
(2008).
[94] H.N. Stevens, C.G. Wilson, P.G. Welling, M. Bakhshaee, J.S. Binns, A.C. Perkins, M. Frier, E.P. Blackshaw, M.W. Frame,
D.J. Nichols, Evaluation of Pulsincap™ to provide regional delivery of dofetilide to the human GI tract, International journal of
pharmaceutics, 236 (2002) 27-34.
[95] J.M. Hebden, P.J. Gilchrist, A.C. Perkins, C.G. Wilson, R.C. Spiller, Stool water content and colonic drug absorption:
contrasting effects of lactulose and codeine, Pharmaceutical research, 16 (1999) 1254-1259.
[96] R.S. Shawgo, A.C.R. Grayson, Y. Li, M.J. Cima, BioMEMS for drug delivery, Current Opinion in Solid State and Materials
Science, 6 (2002) 329-334.
[97] Z. Jia, G. Yan, Y. Shi, B. Zhu, A wireless power transmission system for an active capsule endoscope for colon inspection,
Journal of medical engineering & technology, 36 (2012) 235-241.
ACCEPTED MANUSCRIPT
38
[98] A. Abid, J.M. O’Brien, T. Bensel, C. Cleveland, L. Booth, B.R. Smith, R. Langer, G. Traverso, Wireless Power Transfer to
Millimeter-Sized Gastrointestinal Electronics Validated in a Swine Model, Scientific Reports, 7 (2017).
[99] M.N. Antipina, G.B. Sukhorukov, Remote control over guidance and release properties of composite polyelectrolyte based
capsules, Advanced drug delivery reviews, 63 (2011) 716-729.
T
[100] S. Yim, M. Sitti, Design and rolling locomotion of a magnetically actuated soft capsule endoscope, IEEE Transactions on
Robotics, 28 (2012) 183-194.
P
[101] A.W. Mahoney, J.J. Abbott, 5-DOF Manipulation of an Untethered Magnetic Device in Fluid using a Single Permanent
RI
Magnet, Robotics: Science and Systems, Citeseer, 2014.
[102] P. Valdastri, R.J. Webster III, C. Quaglia, M. Quirini, A. Menciassi, P. Dario, A new mechanism for mesoscale legged
SC
locomotion in compliant tubular environments, IEEE Transactions on Robotics, 25 (2009) 1047-1057.
[103] M. Quirini, A. Menciassi, S. Scapellato, C. Stefanini, P. Dario, Design and fabrication of a motor legged capsule for the
active exploration of the gastrointestinal tract, IEEE/ASME Transactions on mechatronics, 13 (2008) 169-179.
NU
[104] A. Menciassi, C. Stefanini, S. Gorini, G. Pernorio, B. Kim, J. Park, P. Dario, Locomotion of a legged capsule in the
gastrointestinal tract: theoretical study and preliminary technological results, Engineering in Medicine and Biology Society, 2004.
MA
IEMBS'04. 26th Annual International Conference of the IEEE, IEEE, 2004, pp. 2767-2770.
[105] B. Kim, S. Lee, J.H. Park, J.-O. Park, Design and fabrication of a locomotive mechanism for capsule-type endoscopes using
shape memory alloys (SMAs), IEEE/ASME Transactions On Mechatronics, 10 (2005) 77-86.
[106] B. Kim, S. Park, C.Y. Jee, S.-J. Yoon, An earthworm-like locomotive mechanism for capsule endoscopes, Intelligent Robots
ED
and Systems, 2005.(IROS 2005). 2005 IEEE/RSJ International Conference on, IEEE, 2005, pp. 2997-3002.
[107] L.J. Sliker, X. Wang, J.A. Schoen, M.E. Rentschler, Micropatterned treads for in vivo robotic mobility, Journal of Medical
Devices, 4 (2010) 041006.
PT
[108] S.P. Woods, T.G. Constandinou, Wireless capsule endoscope for targeted drug delivery: mechanics and design
considerations, IEEE Transactions on Biomedical Engineering, 60 (2013) 945-953.
CE
[109] W. Chen, G. Yan, Z. Wang, P. Jiang, H. Liu, A wireless capsule robot with spiral legs for human intestine, The International
Journal of Medical Robotics and Computer Assisted Surgery, 10 (2014) 147-161.
[110] P. Xitian, L. Hongying, W. Kang, L. Yulin, Z. Xiaolin, W. Zhiyu, A novel remote controlled capsule for site-specific drug
AC
delivery in human GI tract, International journal of pharmaceutics, 382 (2009) 160-164.

[111] D. Sinha, Wireless actuation of piezoelectric coupled micromembrane using radio frequency magnetic field for biomedical
applications, Journal of Applied Physics, 121 (2017) 134501.
[112] H. Dehghani, C.R. Welch, A. Pourghodrat, C.A. Nelson, D. Oleynikov, P. Dasgupta, B.S. Terry, Design and preliminary
evaluation of a self-steering, pneumatically driven colonoscopy robot, Journal of Medical Engineering & Technology, 41 (2017)
223-236.
[113] J. Cui, X. Zheng, W. Hou, Y. Zhuang, X. Pi, J. Yang, The study of a remote-controlled gastrointestinal drug delivery and
sampling system, Telemedicine and e-Health, 14 (2008) 715-719.
[114] F. Munoz, G. Alici, W. Li, A magnetically actuated drug delivery system for robotic endoscopic capsules, Journal of Medical
Devices, 10 (2016) 011004.
[115] D. She, M. Tsang, J. Kim, M. Allen, Immobilized electrolyte biodegradable batteries for implantable MEMS, Solid-State
Sensors, Actuators and Microsystems (TRANSDUCERS), 2015 Transducers-2015 18th International Conference on, IEEE, 2015,
pp. 494-497.
ACCEPTED MANUSCRIPT
39
[116] P. Nadeau, D. El-Damak, D. Glettig, Y.L. Kong, S. Mo, C. Cleveland, L. Booth, N. Roxhed, R. Langer, A.P. Chandrakasan,
Prolonged energy harvesting for ingestible devices, Nature Biomedical Engineering, 1 (2017) 0022.
[117] M.R. Prausnitz, R. Langer, Transdermal drug delivery, Nature biotechnology, 26 (2008) 1261-1268.
[118] S.M. Bal, Z. Ding, E. van Riet, W. Jiskoot, J.A. Bouwstra, Advances in transcutaneous vaccine delivery: do all ways lead to
T
Rome?, Journal of controlled release, 148 (2010) 266-282.
[119] K.-Y. Seong, M.-S. Seo, D.Y. Hwang, E.D. O'Cearbhaill, S. Sreenan, J.M. Karp, S.Y. Yang, A self-adherent, bullet-shaped
P
microneedle patch for controlled transdermal delivery of insulin, Journal of Controlled Release, (2017).
RI
[120] K. Tsioris, W.K. Raja, E.M. Pritchard, B. Panilaitis, D.L. Kaplan, F.G. Omenetto, Fabrication of Silk Microneedles for
Controlled‐Release Drug Delivery, Advanced Functional Materials, 22 (2012) 330-335.
SC
[121] S.P. Sullivan, D.G. Koutsonanos, M. del Pilar Martin, J.W. Lee, V. Zarnitsyn, S.-O. Choi, N. Murthy, R.W. Compans, I.
Skountzou, M.R. Prausnitz, Dissolving polymer microneedle patches for influenza vaccination, Nature medicine, 16 (2010)
NU
915-920.
[122] P.C. DeMuth, Y. Min, B. Huang, J.A. Kramer, A.D. Miller, D.H. Barouch, P.T. Hammond, D.J. Irvine, Polymer multilayer
tattooing for enhanced DNA vaccination, Nature materials, 12 (2013) 367-376.
MA
[123] A. Alexander, S. Dwivedi, T.K. Giri, S. Saraf, S. Saraf, D.K. Tripathi, Approaches for breaking the barriers of drug
permeation through transdermal drug delivery, Journal of Controlled Release, 164 (2012) 26-40.
[124] J. Yu, Y. Zhang, A.R. Kahkoska, Z. Gu, Bioresponsive transcutaneous patches, Current Opinion in Biotechnology, 48 (2017)
28-32.
ED
[125] F. Teodorescu, G. Quéniat, C. Foulon, M. Lecoeur, A. Barras, S. Boulahneche, M.S. Medjram, T. Hubert, A. Abderrahmani,
R. Boukherroub, Transdermal skin patch based on reduced graphene oxide: A new approach for photothermal triggered permeation
PT
of ondansetron across porcine skin, Journal of Controlled Release, 245 (2017) 137-146.
[126] G.K. Gulati, T. Chen, B.J. Hinds, Programmable carbon nanotube membrane-based transdermal nicotine delivery with
microdialysis validation assay, Nanomedicine: Nanotechnology, Biology and Medicine, 13 (2017) 1-9.
CE
[127] J. Di, S. Yao, Y. Ye, Z. Cui, J. Yu, T.K. Ghosh, Y. Zhu, Z. Gu, Stretch-triggered drug delivery from wearable elastomer films
containing therapeutic depots, ACS nano, 9 (2015) 9407-9415.
[128] C.-J. Huang, Y.-H. Chen, C.-H. Wang, T.-C. Chou, G.-B. Lee, Integrated microfluidic systems for automatic glucose sensing
AC
and insulin injection, Sensors and Actuators B: Chemical, 122 (2007) 461-468.
[129] Y. Ye, J. Yu, C. Wang, N.Y. Nguyen, G.M. Walker, J.B. Buse, Z. Gu, Microneedles Integrated with Pancreatic Cells and
Synthetic Glucose‐Signal Amplifiers for Smart Insulin Delivery, Advanced Materials, (2016).
[130] X. Hu, J. Yu, C. Qian, Y. Lu, A.R. Kahkoska, Z. Xie, X. Jing, J.B. Buse, Z. Gu, H2O2-Responsive Vesicles Integrated with
Transcutaneous Patches for Glucose-Mediated Insulin Delivery, ACS Nano, (2017).
[131] C. Wang, Y. Ye, G.M. Hochu, H. Sadeghifar, Z. Gu, Enhanced cancer immunotherapy by microneedle patch-assisted
delivery of anti-PD1 antibody, Nano letters, 16 (2016) 2334-2340.
[132] C.L. Stevenson, J.T. Santini, R. Langer, Reservoir-based drug delivery systems utilizing microtechnology, Advanced drug
delivery reviews, 64 (2012) 1590-1602.
[133] J.T. Santini, M.J. Cima, R. Langer, A controlled-release microchip, Nature, 397 (1999) 335-338.
[134] J.C. Wright, S.T. Leonard, C.L. Stevenson, J.C. Beck, G. Chen, R.M. Jao, P.A. Johnson, J. Leonard, R.J. Skowronski, An in
vivo/in vitro comparison with a leuprolide osmotic implant for the treatment of prostate cancer, Journal of controlled release, 75
(2001) 1-10.
ACCEPTED MANUSCRIPT
40
[135] H. Gensler, R. Sheybani, P.-Y. Li, R. Lo, S. Zhu, K.-T. Yong, I. Roy, P.N. Prasad, R. Masood, U.K. Sinha, Implantable
MEMS drug delivery device for cancer radiation reduction, Micro Electro Mechanical Systems (MEMS), 2010 IEEE 23rd
International Conference on, IEEE, 2010, pp. 23-26.
[136] M. Ochoa, C. Mousoulis, B. Ziaie, Polymeric microdevices for transdermal and subcutaneous drug delivery, Advanced drug
T
delivery reviews, 64 (2012) 1603-1616.
[137] R. Jegadeesan, K. Agarwal, Y.-X. Guo, S.-C. Yen, N.V. Thakor, Wireless Power Delivery to Flexible Subcutaneous
P
Implants Using Capacitive Coupling, IEEE Transactions on Microwave Theory and Techniques, 65 (2017) 280-292.
RI
[138] A. Cobo, R. Sheybani, H. Tu, E. Meng, A wireless implantable micropump for chronic drug infusion against cancer, Sensors
and Actuators A: Physical, 239 (2016) 18-25.
SC
[139] W.-J. Jo, S.-K. Baek, J.-H. Park, A wireless actuating drug delivery system, Journal of Micromechanics and
Microengineering, 25 (2015) 045014.
[140] P.R. van Dijk, S.J. Logtenberg, K.H. Groenier, J.W. Haveman, N. Kleefstra, H.J. Bilo, Complications of continuous
NU
intraperitoneal insulin infusion with an implantable pump, World journal of diabetes, 3 (2012) 142.
[141] E. Zini, I. Padrutt, K. Macha, A. Riederer, M. Pesaresi, T. Lutz, C. Reusch, Use of an implantable pump for controlled
MA
subcutaneous insulin delivery in healthy cats, The Veterinary Journal, 219 (2017) 60-64.
[142] A. Lathuilière, V. Laversenne, A. Astolfo, E. Kopetzki, H. Jacobsen, M. Stampanoni, B. Bohrmann, B.L. Schneider, P.
Aebischer, A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau
pathologies, Brain, (2016) aww036.
ED
[143] Y. Liu, P. Song, J. Liu, D.J.H. Tng, R. Hu, H. Chen, Y. Hu, C.H. Tan, J. Wang, J. Liu, An in-vivo evaluation of a MEMS drug
delivery device using Kunming mice model, Biomedical microdevices, 17 (2015) 6.
[144] S.Y. Chin, Y.C. Poh, A.-C. Kohler, J.T. Compton, L.L. Hsu, K.M. Lau, S. Kim, B.W. Lee, F.Y. Lee, S.K. Sia, Additive
PT
manufacturing of hydrogel-based materials for next-generation implantable medical devices, Science Robotics, 2 (2017) eaah6451.
[145] A. Weltman, J. Yoo, E. Meng, Flexible, Penetrating Brain Probes Enabled by Advances in Polymer Microfabrication,
CE
Micromachines, 7 (2016) 180.

AC
ACCEPTED MANUSCRIPT
41
TP
RI
SC
Figure 1 NU
MA
ED
PT
CE
AC
ACCEPTED MANUSCRIPT
42
TP
RI
SC
NU
MA
ED
Figure 2
PT
CE
AC
ACCEPTED MANUSCRIPT
43
TP
RI
SC
NU
MA
ED
PT
CE
Figure 3
AC
ACCEPTED MANUSCRIPT
44
TP
RI
SC
NU
MA
ED
Figure 4
PT
CE
AC
ACCEPTED MANUSCRIPT
45
TP
RI
SC
NU
MA
Figure 5
ED
PT
CE
AC
ACCEPTED MANUSCRIPT
46
TP
RI
SC
Figure 6
NU
MA
ED
PT
CE
AC
ACCEPTED MANUSCRIPT
47
TP
RI
SC
NU
MA
ED
Figure 7
PT
CE
AC
ACCEPTED MANUSCRIPT
48
TP
RI
SC
Graphical abstract
NU
MA
ED
PT
CE
AC
ACCEPTED MANUSCRIPT
49
Figure Captions
Table 1. Summary of MEMS devices utilized in novel drug delivery systems and the associated remaining challenges
for systems targeting different body areas.
P T
RI
Fig. 1. Schematic diagrams of various target organs and their associated physical barriers and targeting strategies
using novel drug delivery systems enabled by microtechnology. The blood-brain barrier (BBB), stratum corneum, and
SC
retina-blood barrier are shown for brain, skin, and eye, respectively. All figures reprinted with permission [88, 108,
119, 142, 145]
NU
Fig. 2. Microneedles with integrated microfluidic channels for brain infusion: (a) silicon-parylene hybrid structure
MA
with openings at the tip for the regrowth of neural tissues to enhance biocompatibility [40], (b1) microneedle
integrated with U-shaped channels and nanopores at the tip for microdialysis [36], (b2) push-pull microneedle to
ED
sample neurotransmitters [37], (b3) droplet-based sampling microfluidics [38], (c1) fluidic channel integrated with a
refillable, multi-drug chamber (scale bar: 5 mm) [33], and (c2) neural probe integrated with microfluidic channel and
PT
interfaced with a PDMS chip which consists of 3 input channels, a micromixer, and 1 output channel [32]. All figures
reprinted with permission.

CE
Fig. 3. (a) MR image immediately after BBB disruption by pulsed ultrasound using the implanted ultrasound
AC
transducer (top) with a contrast-enhanced image (bottom) [57]. (b) the 16-element pMUT array with a resonant
frequency of 781 kHz developed for in vitro neuromodulation [63]. All figures reprinted with permission.
Fig. 4. Novel intraocular drug delivery systems: (a1) individually switchable two-channel microneedle arrays [79],
(a2) microneedle array that releases drug as it dissolves [80], (b1) MEMS implantable reservoir and cannula with a
check valve [82], (b2) multi-drug polymeric transscleral inserts developed for non-invasive ocular drug delivery [88],
(c1) self-powered drug delivery systems using a triboelectric nanogenerator [89], and (c2) magnetically actuated
drug-delivery system [90]. All figures reprinted with permission.

ACCEPTED MANUSCRIPT
50
Fig. 5. Micromotion and anchoring mechanisms for capsule endoscope: (a) microrobot based on legging mechanism
where the bow-shaped legs extend largely and resist peristaltic pressure along the GI tract [108], (b) schematic of
inchworm-like locomotion that enables capsule endoscope to crawl along the GI tract [109], and (c) wheel-based
T
movement [107]. All figures reprinted with permission.
P
RI
Fig. 6. Schematics of on-demand and self-regulated drug delivery using smart microneedles: (a) light-triggered drug
SC
delivery system using near-infrared (NIR) light [8]and (b) closed-loop insulin injection according to the glucose level
in the intravascular network [130]. All figures reprinted with permission.
NU
MA
Fig. 7. Subcutaneous implantable drug delivery systems: (a) photo of encapsulated electrolysis pump [135], (b) photo
of biological responses to the implanted device over 28 days [143], (c) MEMS mechanical components such as driving
ED
gears and rotors fabricated using soft hydrogel materials [144], and (d) a biocompatible implant to deliver in vivo
antibody delivery (scale bar: 750 µm) [142]. All figures reprinted with permission.
PT
CE
AC
ACCEPTED MANUSCRIPT
51
Table 1.
TARGET AREA MEMS DEVICES REMAINING CHALLENGES
BRAIN Implantable Neural probes / • Biocompatibility
T
Microneedles • Systematic errors
[9, 26, 27, 30-33, (leakage, clogging, biofouling)
P
36-38] • Multi-functionalities
RI
Noninvasive Ultrasound • Miniaturization
transducers • Higher control over ultrasound parameters
[57-59, 63, 64]
SC
EYE Implantable MEMS pumps, • Choric robustness
reservoir, polymeric • Drug volume
inserts • Removal
NU
[76-83, 85-90] • On-demand activation
Noninvasive Therapeutic contact • Interaction between drugs and contact lens
lens materials
MA
[73] • Preserving transparency
GI Oral Capsule endoscope • Reliable anchoring and actuation mechanism
[100-114] • Batteryless activation
SKIN Implantable Subcutaneous MEMS • Biocompatibility

ED
pumps, reservoir, • Drug volume

polymeric inserts • Removal
[137-144] • Self-administrated release
•
PT
Minimally Transdermal Closed-loop release

invasive microneedles • On-demand release
[8, 14, 125-127, 129] • Multi-functionalities
• Chronic uses (clogging, biofouling)
CE
AC

MEM Devices For Drug Delivery

Uploaded by

Copyright:

Available Formats

You might also like

MEM Devices For Drug Delivery

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

MEM Devices For Drug Delivery

Uploaded by

Copyright:

Available Formats

 

Hyunjoo J. Lee, Nakwon Choi, Eui-Sung Yoon, Il-Joo Cho

To appear in: Advanced Drug Delivery Reviews

Received date: 20 May 2017

MEMS devices for drug delivery

2.1. Direct brain infusion

2.1.2. Recent advances and perspectives

2.2.1. Design considerations, challenges, and opportunities

2.2.2. Recent advances and perspectives

3. Ocular drug delivery

3.1. Design considerations, challenges, and opportunities

3.2. Recent advances

3.2.1. Minimally invasive microneedles

3.2.2. Stimuli-responsive implants for on-demand drug delivery

3.2.3. Batteryless actuation

4. Gastrointestinal tract drug delivery – capsule endoscopy

4.1. Design considerations, challenges, and opportunities

4.1.1. Anchoring mechanism

4.1.2. Trade-off between drug volume and on-chip functionalities

4.2. Recent advances

4.2.1. Legged mechanism

4.2.2. Other anchoring mechanisms

5.1. Challenges and opportunities

6.1. Design considerations

6.2.1. Biocompatibility and reliability

Microtechnology or Microelectromechanical Systems (MEMS) is another promising technology for

addressed these problems (Fig. 1).

2. Drug delivery to the brain

infusion and BBB disruption using focused ultrasound.

2.1.1. Design considerations, challenges, and opportunities

and density of drug.

the experiments with animals in the preclinical stage.

cleaning, and re-insertion, and leads to irreversible deterioration.

applications as well as animal experiments.

2.1.2. Recent advances and perspectives

currents were observed.

at different concentrations in situ at a single implantation (Fig. 2(c2)).

free of the diffusion limit.

neurotransmitters in the brain is now possible.

in enhancing the biocompatibility.

2.2. Drug delivery to the brain through BBB disruption

2.2.1. Design considerations, challenges, and opportunities

for more efficient delivery of drugs to target regions [56].

2.2.2. Recent advances and perspectives

non-invasive wearable system that will allow on-demand drug delivery.

3. Ocular drug delivery

tested with animals in the preclinical stage.

3.1. Design considerations, challenges and opportunities

3.2. Recent advances

3.2.1. Minimally invasive microneedles

microneedle array. Thakur, et al. developed a dissolving polymeric microneedle based on a

nanogenerator to an electrochemical pressure pump embedded in an implantable intraocular drug delivery

4.1. Design considerations, challenges, and opportunities

4.1.1. Anchoring mechanisms

been recently explored.

is thus an important parameter that imposes trade-off in the capsule design.

4.2.2. Other anchoring mechanisms

5. Transdermal drug delivery