FEATURE ARTICLE

Drug Delivery www.afm-journal.de

Microfabricated Drug Delivery Devices: Design, Fabrication,

and Applications
Hongbin Zhang,* John K. Jackson, and Mu Chiao*
uniformity of the drug dose. Uncontrolled
Microfabrication technology has enabled the development of novel con- drug release patterns may pose a risk of
trolled-release devices that possess an integration of structural, mechanical, undesirable toxicity and related complica-
and perhaps electronic features, which may address challenges associated tions due to the initial concentration peaks
with conventional delivery systems. In this feature article, microfabricated arising from burst release and low efficacy
because of subsequent rapid drug con-
devices are described in terms of materials, mechanical design, working prin-
centration decline below the therapeutic
ciples, and fabrication methods, all of which are key features for production range.[2]
of multifunctional, highly effective drug delivery systems. In addition, the cur- In the 1960s, the concept of sustained
rent status and future prospects of different types of microfabricated devices release came up for achieving zero-
for controlled drug delivery are summarized and analyzed with an emphasis order release kinetics.[3] Thereafter, some
on various routes of administration including ocular, oral, transdermal, and polymer-based matrices and membrane-
controlled vehicles have been developed
implantable systems. It is likely that microfabrication technology will continue
to realize a constant release rate. Although
to offer new, alternative solutions to design advanced and sophisticated drug sustained release systems, to some extent,
delivery devices that promise to significantly improve medical care. reduce the risk of toxic effects by attenu-
ating the peaks and valleys of plasma drug
concentration, most of them release drugs
1. Introduction over a limited time period (less than a day) and their release
rates may be influenced by environmental conditions, such
Drug delivery, the method by which therapeutic agents are intro- as pH, temperature, and ionic strength, which lead to unde-
duced into the body, plays a crucial role in achieving optimal sired variation in efficacy.[4–6] On the other hand, many clinical
treatment efficacy of medications and provides improvements situations actually need more than a zero-order drug release,
for drug safety, convenience, and patient compliance. With an requiring an on-demand control of drugs which may vary with
increasing awareness of the significance of pharmacokinetics time or patients’ conditions. Moreover, the emergence of biop-
and biodistribution for the successful therapeutic effect of a harmaceuticals including proteins, peptides, vaccines, etc., also
drug, the optimal application of drug delivery technologies has calls for new delivery strategies due to their low bioavailability
evolved substantially over time.[1] and poor stability in the gastrointestinal tract, making them not
Primitive methods of delivering drugs were mainly through suitable to be delivered by oral methods.[4,7]
physical digestion of chewed medical plants, soot inhala- Therefore, new advanced delivery systems capable of targeted
tion from the burning of medical substances, or application dosing with an adjustable rate for a definite time period are
of mashed herbs on skin. When the effective ingredients of needed. To date, with advances in materials science, chemi­cal
such materials could be synthesized or extracted from plants engineering and manufacturing technology, numerous novel
sources, a variety of pharmaceutical formulations were pro- controlled release systems such as nano-/microcarriers,
duced using different excipients which include tablets, cap- poly­mer/hydrogel matrices, and microfabricated devices/
sules, syrups, emulsions, ointments, solutions, and so on.[2] implants, have sprung up.[1,8,9] The existing drug delivery sys-
Drug delivery was extended to include intravenous and intra- tems can roughly be categorized into two types: nonstimulated
muscular injections, eye drops, implants, suppositories, etc. release such as diffusion from polymers or stimulated release
However, these traditional delivery systems are simple and usu- such as from mechanical devices. The nonstimulated group is
ally follow first-order release kinetics, lacking consistency and mainly based on the development of new materials by chemical
synthesis and biological techniques. In these systems, materials
act as drug depots from which the drug release depends on the
Dr. H. Zhang, Prof. M. Chiao
Department of Mechanical Engineering
material’s chemical/physical properties and structures.[10–12]
The University of British Columbia For example, drug release from polymeric materials generally
Vancouver, BC V6T 1Z4, Canada is controlled by mechanisms of diffusion, chemical reaction-
E-mail: izhanghongbin@gmail.com; muchiao@mech.ubc.ca related polymer degradation or chemical bond cleavage of
J. K. Jackson the drug from polymer chains, and solvent activation such as
Department of Pharmaceutical Sciences swelling or osmotic effects.[13,14] Nanomaterials usually control
The University of British Columbia
Vancouver, BC V6T 1Z3, Canada release drugs by physically or chemically responsive disintegra-
tion, and targeting delivery via the incorporation of biological
DOI: 10.1002/adfm.201703606 agents.[15] The stimulated group of delivery systems includes

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controlled release devices that involve materials, mechanical

design, and fabrication techniques, such as micro-electrome- Hongbin Zhang is currently
chanical systems (MEMS) and nano-electromechanical systems a postdoctoral research
(NEMS)-based devices.[16–19] The devices consist of different fellow in the Department
functional components such as micropumps, microvalves, of Mechanical Engineering,
reservoirs, channels, etc., forming an integrated system for University of British Columbia
achieving more sophisticated and precise drug delivery.[17,20] (Canada). He received his
Although many types of devices are still in different stages of B.S. degree from the Sichuan
production and clinical evaluation, the development of the con- University (China) and Ph.D.
trolled release devices has shown great potential to offer new from the University of Science
ways of drug administration with effective therapeutic regi- and Technology Beijing
mens.[18] The fast evolution of the microfabricated drug delivery (China). His current research
devices is reflected in Figure 1A, where the number of relevant interests focus on soft mate-
publications per year from 2000 to 2016 is presented and the rials, controlled drug delivery systems, surface modifica-
proportion of publications has reached around one third in the tion and antifouling, and tissue engineering.
annual publications on drug delivery systems.
The purpose of this feature article is to provide a comprehen- John K. Jackson is a research
sive overview of the emerging controlled drug release microfab- scientist in the Faculty of
ricated devices. The devices are first discussed from the aspects Pharmaceutical Sciences
of materials, design principles, and manufacturing technolo- at the University of British
gies, followed by their respective reviews on the applications Columbia. He has worked on
according to their different features and various administration polymeric controlled release
routes for drug delivery. drug delivery systems for
over 25 years. His interests
include drug coating of
medical devices and he was
2. Microfabricated Drug Delivery Devices the first to coat implantable
Many types of devices have been designed and fabricated for stents with drugs such as
controlled drug delivery over the years. Unlike traditional drug paclitaxel.
delivery systems which mostly are composed of drugs together
Mu Chiao is a professor
with excipients or carrier materials, drug delivery devices are
in the Department of
fabricated through a combination way with different materials,
Mechanical Engineering at the
mechanical design, and specific manufacture technologies
University of British Columbia
(Figure 1B).[21] This provides variety in release mechanisms that
(Canada). He obtained his
are independent of material properties to achieve more accu-
B.S. degree from the National
rate and active control over drug delivery.
Taiwan University (Taiwan)
and Ph.D. from the University
of California–Berkeley (USA).
2.1. Materials
His research interests include
microelectromechanical
Material selection is the process of seeking the material with
systems (MEMS), BioMEMS/
appropriate properties to meet design requirements, serve
drug delivery, MEMS/protein interaction, and micro-optical
device performance goals, and minimize cost. Some aspects
scanner for biological applications.
to be considered include mechanical properties for processing
and use, stability when loaded with drugs both in storage and
in physiological environments, biosafety to avoid the genera- immersion in a chemical solution (wet etching) or by exposure
tion of toxic substances especially for implantable devices, etc. to chemically reactive plasma (dry etching). For example, fast
anisotropic etching of single-crystal silicon can be achieved
in strong base solutions, which allows fabrication of a large
2.1.1. Rigid Materials variety of silicon structures in a controllable and reproducible
manner. In addition, photolithography and chemical/physical
Silicon is one of the initially used materials in microfabricated vapor deposition can also be used for the silicon material in
devices because of its favorable electrical and mechanical prop- microfabrication.
erties and easy integration with conventional semiconductor Silicon is chemically and biologically stable, which is suit-
processing techniques.[22] This material could be a variety of able for drug loading and delivery. And importantly, silicon
thin single-crystal wafers (0.25–10 mm) with different crys- has shown to have biocompatibility and nonimmunogenicity
talline orientations. Various microstructure or micropatterns approximately equivalent to tissue culture polystyrene on
such as microchannels and micropores are able to be cre- either its flat or micro-/nanostructured surface.[22–26] These
ated by etching directly into the silicon substrate either by features make silicon a good material for making components

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Figure 1.  A) Microfabricated drug delivery device documents published
per year from 2000 to 2016 and its proportion in the annual publications
on drug delivery systems. The presented data collected from the Web of
Knowledge by using the key search keywords of “drug delivery,” “device,”
and “micro-,” or “drug delivery system.” B) Influencing factors of a micro-
fabricated device for controlled drug delivery.
of drug delivery systems. So far, silicon has been processed
into platforms with different microstructures in drug delivery
devices such as microneedles (MNs),[27,28] microreservoir-
based devices,[29,30] and nanoporous and nanochannel micro-
chips.[31,32] Microstructured silicon can be used as a template as
well for the formation of microneedles or microchannels from
other materials, with the patterns being transferred to the end
state material through methods such as micromolding.[33,34]
Great potential has been shown for silicon-based devices as
an essential platform for future diagnostics/therapeutics due
to the ability to integrate electronic components directly within
microfluidic and drug delivery systems.[35,36] Although expen-
sive microfabrication techniques and clean rooms are required
in the fabrication of silicon-based microsystems, much of the
added cost and complexity associated with silicon processing
can be compensated by the economics of scale associated with
miniaturization.
Glass is another common material which can be microma-
chined by lithography and etching.[22] Glass-based micronee-
dles,[37] fibers,[38–40] and tubes[41] are examples in the application
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of drug delivery. It can be used alone or be bonded to silicon
using anodic bonding or silicone rubbers to form complex sys-
tems with different microstructures (e.g., microfluidic chips)
for controlled drug delivery.[42–44] Porous inorganic materials
such as mesoporous silica[45,46] and zeolite[47] in different
shapes have attracted special attention in drug delivery micro-
devices due to the large surface area and pore volume.[48,49] In
addition, functionalization of the porous materials with mole­
cular, supramolecular, or polymer moieties enable fabrication
of new devices with great versatility in controlled drug delivery
utilizations including sustained release, targeted release, and
stimuli-responsive release.[50,51] Other rigid materials such as
metals,[52–54] ceramics,[55,56] silicon nitride,[57,58] and polycrystal-
line silicon[59,60] have also been used in developing various drug
delivery devices.
2.1.2. Polymers
Polymers have been used extensively in biomedical applications
including controlled drug delivery systems. Much of the con-
trolled-release technology relies on polymer properties such as
stimuli-responsive behavior, degradability, tissue-like mechan-
ical strength, controllable hydrophilicity and hydrophobicity,
and tunable structures. However, the current methodology
used for polymers sometimes is not efficient enough to provide
the high-precision control over the release timing and rate that
is often required for controlled drug delivery. With the develop-
ment of microfabrication technologies, polymers show superior
properties to silicon for bioMEMS applications with regard to
the low cost and controllability over various physicochemical
properties.
Poly(dimethylsiloxane) (PDMS) is a commercially avail-
able polymer for the production of biomedical devices such
as microfluidic chips, drug delivery devices, and surgical
implants.[61–63] Liquid PDMS prepolymers can be cured by
thermal crosslinking with crosslinkers at temperatures less
than 100 °C or even at room temperature. The exposure to high
energy irradiation or the use of platinum as catalyst can also
be the choice of curing methods for PDMS, making the mate-
rials easy to handle. Additionally, PDMS is chemically inert, gas
permeable, isotropic, and optically transparent down to about
300 nm, allowing UV crosslinking of moldable prepolymers in
photolithographic patterning. The inherent mechanical flexi-
bility of PDMS can be beneficial to construction of micropumps
and microvalves that operate by inducing deformations in the
substrate itself. Nevertheless, PDMS-based devices may have
biofouling problems from nonspecific protein/hydrophobic
analyte adsorption in the physiological environment owing to
the intrinsic hydrophobicity of PDMS.[64] Thus, surface modifi-
cation and treatment may be needed to ensure the performance
of implantable PDMS devices.
Other polymers such as polymethylmethacrylate (PMMA),
polyethyleneglycol, poly(lactic acid) (PLA), polyglycolic acid,
poly(d,l-lactide-co-glycolide) (PLGA), poly(caprolactone) (PCL),
poly(glycerol-sebacate), polyurethanes, and SU-8 are being
investigated as alternative materials in the fabrication of drug
delivery devices.[22,65,66] For example, micro-mucoadhesive
devices (≈100 µm) have been micromachined from PMMA
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to deliver drug to the wall of the intestine through the oral
route.[67] In addition, multipulse drug delivery from a resorb-
able polymeric microchip device made of PLA reservoirs and
PLGA membranes was demonstrated.[68]
For polymers, replication techniques such as soft lithography
and direct plastic micromachining are applicable for microfab-
rication, allowing repeated production of many devices with
a single master to decrease cost. Many traditional manufac-
turing techniques for polymers, such as injection molding and
embossing, can also be applied in the microfabrication field at
a much smaller scale, which provide more design flexibility.
In regard to the immunogenicity-related safety issue, many of
the polymer surfaces, including those that are microstructured,
do not elicit a significant immune response. All of these make
polymers suitable for microfabricated drug delivery devices.
2.1.3. Relationship between Material Properties/Functionality
and Device Design
In the design and fabrication of drug delivery devices, the
matched structures and properties/functionality of device
materials with the carried drugs, play a key role in optimizing
performance for each specific application besides basic consid-
erations of safety, availability, and cost. For example, good drug–
drug carrier compatibility may increase the stability of drugs
in devices and prolong the storage period. Proper mechanical
strength of device helps to maintain the structural integrity of
devices for robust controlled drug delivery. The integrability
and potential interactions of different components for a device
should be also taken into consideration in the device design
step. Among the various properties of materials, degradability
and stimuli-responsive aspects are important in the fabrication
of drug delivery devices.
Degradable materials including metallic materials such as
magnesium alloys[69–71] and polymers[72–74] could be used as
the matrix, coatings, or functional components of a device to
control drug release.[75–77] Preferably, to be the matrix material
(mostly for implantable devices), the material should maintain
optimal mechanical properties until the loaded drug is released
and then degrade, being innocuously absorbed and excreted
by the body. As coatings, the degradation time of materials
should match the needs of specific applications, such as to pre-
vent devices from damage or premature drug release before
reaching the target area. To perform well as functional compo-
nents for drug release, the materials should have tunable and/
or controllable degradation speeds. For example, as a sealing
membrane for drug release outlets, degradation of the mem-
brane might be triggered by specific chemical or biological trig-
gers such as ions, pH, enzymes, etc., or controlled through tai-
loring the material structures.
Stimuli-responsive materials capable of regulating transport/
discharge of drug molecules by shape deformation, movement,
or assembling/disassembling on receiving external signals are
attractive for controlled drug delivery devices.[78–81] They could
be fabricated into different functional components for a device
such as valves,[82–84] gating membranes,[51,85] channels, and
hinges[86,87] or serve as drug depots,[79,88] which can trigger and
stop drug flux in response to environmental stimuli like pH,
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temperature, biological molecules, light, electromagnetic fields.
When choosing responsive materials to fabricate drug delivery
devices, the sensitivity to stimuli, response speed, extent, and
stability of the material are key factors determining the perfor-
mance of products. Integration of stimuli-responsive materials
in the devices with careful and creative design could be a very
promising approach toward smart on-demand drug delivery
devices. More materials and responsive mechanisms are yet to
be discovered to meet the emerging needs in the field of device
development.
2.2. Design Considerations/Principles
Numerous drug delivery devices with different shapes, sizes,
functions, and drug release control mechanisms have been
developed to serve different routes of drug administration and
enhance the control over drug delivery behaviors. To achieve
these objectives, a rational design for the device is a crucial step,
where a number of factors including the way of drug loading/
release and the specific area where the drug will be released
should be considered.
2.2.1. Reservoir Design
Matrix type delivery systems where drugs are dissolved, dis-
persed, or chemically bonded, form a resistant support to disin-
tegration for delay and control of the drug release. However, the
matrix systems may face limitations such as insufficient drug
loading capabilities, burst release, and problems associated
with the biodegradability and metabolism of the matrix after
degradation. In contrast, reservoir-based delivery devices which
contain cavities for loading drug, can offer an isolated space of
a large volume to protect drugs from the outside environment
and allow drugs to be loaded in solid, liquid, or gel state.[89] By
utilizing microtechnologies, these devices are able to be fabri-
cated in a smaller overall size or profile, which can incorporate
features or mechanisms that enable more precise adjustment
of drug delivery rate and provide ways to reach difficult-to-treat
locations.[89]
Through proper designs of the reservoirs, some other
functions can be imparted to the device. For example, highly
localized and unidirectional release of drugs was achieved with
a reservoir-containing microdevice.[90] The devices consisted
of a planar semiclosed reservoir made of drug-impermeable
materials. The top face (the reservoir opening) of the device was
chemically modified to graft protein or other types of ligands
for the bioadhesive purpose. Because of the asymmetric struc-
ture and surface modification, the device could attach and
asymmetrically deliver drugs (especially peptides and proteins)
to the intestinal mucosa in the gastrointestinal (GI) system
after oral administration. The flat reservoir design not only
increased contact area of the device with the intestinal wall to
enhance the adhesion ability, but also minimized shear distur-
bances from the flow of liquids through the intestine. The drug
impermeable walls and base of the device effectively limited the
leakage and exposure of bioactive drugs to enzymatic degrada-
tion in the intestinal lumen.[90]
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Figure 2.  Examples of single-reservoir and multireservoir devices for drug delivery. A) An electrochemically driven microfluidic drug delivery device.[29]
(a) The electric potential is applied between top (gold membrane) and bottom electrodes; (b) Two main electrochemical reactions occur: dissolution
of the gold membrane and electrolysis of water resulting in gas release; (c) The generated microbubbles propel drug solution out; (d) The reaction
continues until fluid transport stops. Reproduced with permission.[29] Copyright 2009, Springer. B) A biodegradable multireservoir device.[68] (a) Dia-
gram of the polymeric device; (b) Pulsatile release of drugs from polymeric device in vitro. Reproduced with permission.[68] Copyright 2003, Nature
Publishing Group.

The drug-containing reservoir can also be totally closed until
signals are given to remove the sealing membranes. Such design
reduces the dependence on the external physiological conditions
and provides a pulsatile fashion of drug delivery. For example, in
an electrochemically driven device, the reservoir is sealed with
a gold membrane (Figure 2A).[29] When an electrical potential
is applied between upper (the gold membrane) and lower elec-
trodes, the capping membrane dissolves and releases drug. The
drug release is able to be accelerated by propelling of microbub-
bles generated from water electrolysis inside the device.
A device can be designed to have a single reservoir or mul-
tiple reservoirs. Single-reservoir devices provide more room for
drug loading which is beneficial to the long-term use, while
multireservoir devices can store drugs separately, allowing for
incorporation of different drugs in one single device for syner-
gistic treatment of diseases such as cancer. Individual control
over drug release from each separate reservoir of the multires-
ervoir device may be achieved by properly choosing the release
mechanism, creating the possibility of achieving many com-
plex release patterns. Accordingly, electrochemically controlled
release was demonstrated successfully in multireservoir devices
for multidose drug delivery.[91] Another example is based on
polymer-degradation controlled mechanism, where each res-
ervoir is sealed by degradable membranes made of PLGA of
different molecular weights (Figure 2B).[68] These membranes
exhibit different degradation speeds, resulting in pulsatile drug
release for different drugs over a period of months. In addition,
the release characteristics are possible to be tailored for specific
applications by simply varying the parameters of the device res-
ervoirs (e.g., numbers, volumes) and membranes (e.g., thick-
ness, molecular mass, materials).
2.2.2. Release Mechanism Selection
The core of a drug delivery device is the method for controlling
drug release behaviors to meet different requirements in real
applications. There exist different control mechanisms for drug
release, which have been proposed and undergoing investiga-
tion for drug delivery devices. Here, three main categories of
controlled release mechanism are discussed.
Diffusion Controlled Release: Diffusion controlled systems
rely on diffusion of drug out of or through a membrane or
matrix that may be nonporous or microporous.[92] The rate
determining step is the transport rate of drugs through the
microstructured media which work as barriers to prevent fast
diffusion of solutes from a region of high concentration (reser-
voir) to a region of low concentration (environment). By using
polymeric semipermeable membranes or crosslinked gels with
differential pores, density, and erosion rates, sustained drug
diffusion was demonstrated in some devices such as ocular
implants for intravitreous drug delivery and drug-eluting stents
for intravascular therapies.[93]
Silicon microchannels with different geometries have been
designed to regulate the passive diffusion of molecules. As
shown in Figure 3A, the simulation of thermal diffusivity in
six different microchannel configurations shows that drug dif-
fusion in each microchannel exhibits different characteristics,
giving rise to different diffusion rates.[94] As the channel width
decreases to approach the hydrodynamic diameter of the solute,
linear non-Fickian behavior of solutes could be achieved. This
could be observed in other microporous media such as zeolites,
which is considered to be a result of traffic control phenomena,
called single-file diffusion and/or pore wall drag effects via

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Figure 3.  Mechanisms of controlled release. A) Simulations of drug diffusion through different microchannel configurations (the pseudocolor images
indicate the local concentration of the drugs). Reproduced with permission.[94] Copyright 2012, Hindawi Publishing Corporation. B) Reciprocating
micropump operation. (a) Schematic configuration of a typical reciprocating pump; (b) Drug release during the pumping mode; (c) Solution refilling
during the supply mode. C) Schematic description of an osmotic drug delivery device. D) Schematic illustration of a magnetic micropump and its
operation.[104,105] Reproduced with permission.[105] Copyright 2011, Royal Society of Chemistry.

molecular interaction. By precisely tailoring the size, length,
density, and surface composition of nanochannels according to
the physicochemical characteristics of the biological molecule
of interest, zero-order long-term drug delivery is achievable for
a wide variety of drug classes.
Outlet Valve Controlled Release: In addition to sustained
release systems, efforts to improve control over the rate and
extent of drug delivery currently center around the design of
triggered-release systems by external signals. In some situ-
ations such as insulin delivery for diabetes, sustained release
may not be the optimal fashion, while pulsatile release that can
be controlled externally by patients or operators would be more
favorable.[92] The direct method for pulsatile release is to open
and/or close the drug release outlet of the device actively. As
mentioned above, the dissolution of sealing membranes by elec-
trochemical/electrothermal reactions allows for the triggered
release of enclosed drugs from each reservoir (Figure 2A).[29,95]
Although the drug release following removal of the membrane
is through diffusion, the rate determining step depends on the
opening of the drug reservoir. This capability of controlling the
outlet opening and/or closing of a device, which named outlet
valve control mechanism, plays a pivotal role in accomplishing

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the triggered release. Moreover, by blocking and unblocking the
micro-orifices of reservoirs with magnetic particles or stimuli-
responsive microgels, reversible control of the outlet valve (on/
off) can be obtained to repeatedly trigger drug release from a
single-reservoir device until the drug is exhausted.[96,97]
Micropump Driven Release: Micropumps are an essential
component in fluid transport systems to precisely meter and
control the motion of liquids.[98] Integration of a micropump
in a delivery device offers a number of options to drive drug
release in a controlled manner and achieve more complex
release patterns.[65,99] Micropumps can basically be categorized
into two types: mechanical and nonmechanical, depending on
the presence of moving parts.[100] The movement mechanisms
for mechanical pumps usually include reciprocating, rotatory,
or peristaltic, in which the reciprocating motion is the most
commonly used in drug delivery systems.[101] The recipro-
cating micropump normally is comprised of a pump chamber
equipped with an actuator and a flexible diaphragm membrane,
and microchannels and microvalves to control fluid flow.[99] The
actuator converts energy into the movement or deformation in
a to-and-fro motion of the membrane to provide force to fluid
flow out and into micropumps. The movement of the mem-
brane generates a positive pressure within the pump chamber,
resulting in opening of the outlet valve for delivery of the drug
to the external environment from the pump chamber. Subse-
quently, the membrane moves back to the original position
creating a negative pressure to close the outlet valve but force
the inlet valve to open to allow the drug supplement by flowing
into the chamber. Figure 3B shows the schematic diagram
of the mechanical pump and its functioning.[99,101] Various
mechanisms have been used to develop different actuators for
mechanical micropumps, including piezoelectric, electrostatic,
thermopneumatic, bimetallic, shape memory alloy, ionic con-
ducting polymer films, and so on.[100] These actuators take
energy from electricity, heat, liquid pressure, or air pressure,
and convert it into some kind of mechanical motion. Thus, they
normally function with the aid of a power supply such as bat-
teries that needs to be integrated with the micropump.
There are mechanical micropumps with no need of an on-
board power supply, such as osmotic pumps and magnetic
pumps. Osmotic-type micropumps usually have two chambers
(Figure 3C).[100,102] One chamber serves as a drug reservoir con-
taining drug solutions and the other chamber which is made
up of a semipermeable membrane contains osmotic driving
agents. These chambers are separated from each other by a
flexible membrane or a piston. In operation, the water mole-
cules diffuse through the semipermeable membrane, resulting
in the volume expansion of the osmotic engine chamber. The
expansion drives a piston forward and expels the drug solu-
tion out through an orifice. Magnetic pumps generate mechan-
ical movement of a piston[103] or deformation of a membrane
(Figure 3D)[104,105] using external magnetic fields which allow
for independent control over the actuation process, and hence
the drug delivery rate and timing.
Unlike mechanical micropumps, nonmechanical ones do
not require moving parts, instead they generate flow through a
number of nonmechanical energies including self-diffusiopho-
resis, electrophoresis, bubble propulsion, and the generation of
density gradients.[106] Although nonmechanical micropumps
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have simple structures, their actuation mechanisms are rarely
used in drug delivery devices because of their relatively lower
driving effect and performance (e.g., flow rate, response
time, and pressure generation) compared to the mechanical
actuation.
Micropumps provide the potential to achieve complex drug
release patterns, but the limitation may be that they are com-
monly only suitable to administer drug solutions or suspen-
sions, which should be considered when designing a drug
delivery device. Some other basic requirements must be
thought about when designing and choosing micropumps for
drug delivery applications, which include drug biocompatibility,
actuation safety, desired and controllable flow rate, small size,
and low power consumption.[107]
2.2.3. Functional Structure and Appearance
For versatility, acceptability, and achievement of functions,
some other factors are involved in designing the device.
The shape and overall device size are major considerations.
The implantable device should be small enough to allow for
intraocular or subcutaneous implantation in a doctor’s office
with a profile that is not obtrusive or apparent. For example,
an intravitreal insert marked as Iluvien is designed as a cylin-
drical shape (Figure 4A), and miniaturized to allow for injection
using a proprietary 25-gauge injector system with a minutes-
long in-office procedure.[108] Another cylindrical magneti-
cally actuated device was also reported for minimally invasive
implantation by a 12-gauge needle for prostate cancer treat-
ment (Figure 4B).[109] The appearance of the device should
be designed and fabricated according to the characteristics of
specific target organs such as devices for installing in or on
eye balls or in internal acoustic meatus. For some devices, the
appearance itself serves as a functional structure for achieving
better performance. A typical example is microneedles, the
appearance of which describes functions. The needle has to be
sharp to pierce through the stratum corneum of the skin and its
length has to be short enough to avoid stimulating the nerves
in the dermis.[110] Moreover, the main part of the microneedle
can also be used as a drug reservoir.[20] Another example is
punctal plugs for drug delivery to the eye by inserting into the
lid punctal (Figure 4C).[111] Various punctal plug designs with
different appearances were proposed by Eagle Vision, as shown
in Figure 4C(c).[111] They have been claimed to provide unique
advantages for applications, including improved patient com-
fort, prolonged retention and easy insertion operation, etc.
For MEMS-based drug delivery devices, several subsystems are
usually required to provide all necessary functions, which include
a power source, wireless communication, and control circuitry
that programs the rate and amount of each dose released from
reservoirs in the device. These subsystems may create a design
hurdle for incorporating a sufficient quantity of drug in the device.
Therefore, an optimal design that can separate different working
components of a device and distribute the components in various
places may be desired and suitable candidate drugs might be
potent and can be formulated in high-concentration forms. Oth-
erwise, a refillable design and structure should be considered to
prolong the use of device for long-term dosing regimens.
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Figure 4.  A) Schematic representation of intravitreal insertion of Iluvien via an injector. B) A minimally invasive drug delivery device: (a) Schematic and
(b) image of the actual device. Reproduced with permission.[109] Copyright 2015, Royal Society of Chemistry. C) (a) Schematic illustration of a punctal
plug delivery device; (b) Schematic illustration of punctum location (inset) and placement of punctual plugs in the punctum of the eye; (c) Schematic
representation of assorted designs of silicone-based punctual plugs and each design has been claimed to provide a unique advantage to the dry eye
syndrome (DES) patients. Reproduced with permission.[111] Copyright 2015, Elsevier.

2.3. Fabrication Technologies
Advances in new micro- and nanotechnologies have been
changing the way of drug delivery and enabled fabrication of
novel devices to deliver drug efficiently and precisely to target
regions. The use of microfabrication techniques allows for the
accurate control over devices’ surface microarchitecture, topog-
raphy, and feature size, which play an important role in the
device fabrication and function accomplishment.[112,113]
2.3.1. MEMS/NEMS Fabrication Technology
Basic microfabrication techniques for the manufacture of
MEMS- or NEMS-based devices are developed from the elec-
tronics industry. These techniques may involve a series of
processing steps: thin-film deposition, lithography, etching,
and substrate bonding, which allow for transferring and con-
structing microscale features on the surface of a desired sub-
strate or into a bulk material. In fabrication of microdrug
delivery devices, the most commonly applied technique is
photo­lithography.[114] It can transfer a computer-generated
pattern from a mask to a substrate (silicon, glass, etc.) via the
localization of light, as shown in Figure 5A(a).[112,115] The sub-
strate is coated with a photosensitive resist material (positive in
the figure), followed by exposure to UV light through a pho-
tomask with the pattern to be transferred. After that, the sub-
strate is immersed in a developer solution, which selectively
removes UV-exposed regions, resulting in a high-fidelity rep-
lica of the mask image on the substrate surface. Subsequent

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Figure 5.  A) Illustration of various micromachining processes. (a) Photolithography-based microfabrication process; (b) “Soft lithography” process
for polymer-based devices. B) Summary of the microfabrication techniques. C) Graphical examples of 3D printed tablets with various designs and
functionality.[118] Reproduced with permission.[118] Copyright 2016, Springer.

micromachining processes could be applied to either selectively
remove or deposit material in the patterned regions. Microma-
chining techniques can be categorized into surface microma-
chining and bulk micromachining.[115] Surface micromachining
is an additive fabrication method by chemical or physical
deposition. Bulk micromachining, in contrast, is a subtractive
method by wet or dry etching. Since the photolithography is
limited by the wavelength of the light used for exposure, high
energy lithographic techniques including X-ray LIGA (lithog-
raphy, electroforming, and molding), e-beam lithography, and
ion-beam lithography have been developed to fabricate finer
structures in the nanometer scale.
A second pattern transfer approach called soft lithography refers
to a group of techniques using elastomeric stamps and molds.[114–116]
Typically, an elastomer (such as PDMS) is patterned by curing
on a conventional micromachined rigid mold (Figure 5A(b)),[112]
which enables rapid prototyping of similar structures. In addi-
tion, the mold can be repeatedly used, which reduces the cost
considerably. Substrate bonding of different materials (silicon–
silicon, silicon–glass, glass–glass, polymer–polymer, and pol-
ymer–silicon/glass) is one of the most important fabrication
techniques in microsystem technology, which may involve
fusion bonding and electrostatic bonding. It can be used for
packaging and encapsulation, or to construct complex 3D struc-
tures as a functional unit in the final microsystem.
There are other techniques developed for microfabrication,
some of which are summarized in Figure 5B.[113,117]
2.3.2. 3D Printing Technology
In recent years, 3D printing, a rapid additive manufacturing
method has started to demonstrate fine enough resolutions
in microfabrication via direct printing of structures. This
approach includes a wide variety of manufacturing techniques
such as stereolithographic, powder-based, selective laser sin-
tering, fused deposition modeling, and semisolid extrusion 3D
printing, which are all based on computer-controlled depositing
of materials (layer-by-layer) to create freeform and complex
structures.

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3D printing may enable direct fabrication of personalized
drug delivery devices with tailored functionality, due to its
precise spatial control over the device geometry including size,
shape, and internal structure (Figure 5C).[118] The printed device
may enhance the stability of multiple drugs with a tablet, ensure
precise dosing for each drug, and regulate release kinetics of
each component by incorporating well designed structures that
can modulate dissolution and diffusion profiles.[119] 3D printing
technology brings us a step closer to customized medicine and
makes the automated and high-speed manufacture of various
complex structures possible for microfabricated drug delivery
systems in future.[120,121]
3. Microfabricated Devices for Different
Administration Routes and Disease Models
Biomedical researchers have attempted to explore different
devices capable of drug administration through essentially
every portion of the body in order to achieve the convenient
but efficient treatment. According to specific physiological
structures, features, and functions of different tissues, organs,
and systems in body, various devices have been engineered and
fabricated to adapt to and meet requirements of different drug
administration routes in applications.[122–124] The representative
samples in this section are summarized in Table 1.
3.1. Ocular Delivery
Intraocular diseases such as glaucoma, retinitis pigmentosa,
age-related macular degeneration (AMD), and diabetic retin-
opathy, are the leading causes of serious vision loss around the
world.[125–128] However, effective drug delivery to ocular tissues
remains a major challenge to pharmacologists and scientists
due to the unique anatomy and physiology of the eye. Struc-
tural layers of ocular tissue (cornea, sclera, conjunctiva, etc.),
tears and blood–ocular barriers (blood aqueous and blood–ret-
inal barriers) represent the protective barriers restricting the
entry of drugs to the target sites such as the ciliary body, retina,
and choroid.[129–131]
Conventional ocular drug delivery therapies including topical
eye drops, oral medications, and intraocular injections, are lim-
ited in efficacy. For example, eye drops that account for 90%
of currently available ophthalmic formulations suffer very low
intraocular bioavailability of around 5% owing to rapid dilution
by tears and require frequent administration.[132] Ointments,
gels, and liposomes have been used in eye drops to prolong
drug contact time with the cornea and enhance drug delivery,
but only limited increases in intraocular bioavailability (about
10%) can be reached, since most of the drug is cleared by the
local systemic absorption. Drug delivery via oral routes needs
large systemic doses to ensure adequate intraocular thera-
peutic levels after passing through the blood–retinal barrier.
This is often associated with significant side effects. Intravit-
real injections provide a direct approach to delivering drugs to
ocular tissues, especially those in the posterior segment. How-
ever, repeated injections and potential complications including
cataract formation, vitreous hemorrhage, endophthalmitis,
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and elevation of intraocular pressure, result in poor patient
compliance.[130] Because of the limitations associated with
the current methods of ocular drug delivery, attention has
turned to developing novel therapeutic strategies and new sys-
tems such as microfabricated devices for high drug delivery
efficiency.[129,133–136]
3.1.1. Contact Lenses
Contact lenses usually composed of poly(2-hydroxyethyl meth-
acrylate) (pHEMA)[137,138] or silicone hydrogels[139] are com-
monly used today for vision correction and present an attractive
platform for ocular drug delivery because they are noninva-
sive, replaceable, and well accepted by patients. Although the
drug-containing contact lenses are still in preclinical stages,
in vitro testing has shown better drug bioavailability than the
topical eye drops due to reduced tear mixing between the lens
and the cornea, which prolongs the retention time of drugs.
The challenges for the contact lens-based drug delivery devices
are to increase drug loading amounts and to achieve sustained
drug delivery over a long time period. Approaches including
adjusting the component ratios of lens and incorporating drug
encapsulated nanoparticles or liposomes in the lens matrix have
shown varying degrees of promise in lengthening sustained
release of drug (days to weeks). A recent study reveals that by
loading vitamin E or vitamin A could remarkably increase the
loading of hydrophilic glaucoma drugs (timolol and brimoni-
dine), but their release duration time was not significantly
altered.[137] In another example, sustained zero-order release of
drugs was achieved by modifying contact lens designs.[140,141] In
this special design, a drug-containing annular film made with
degradable poly(lactic-co-glycolic) acid is created as a drug depot.
Then, the film depot is coated in the nondegradable pHEMA
hydrogel to form the lens. These lenses showed sustained drug
delivery with zero-order kinetics for up to four weeks and the
drug release rate can be tuned by changing the proportion of
drugs in the PLGA film.[140,141] Limitations of the usage of con-
tact lenses as drug delivery devices include the necessary long
wear time that may raise safety concerns (e.g., corneal abrasion
and infection), and possible drug leaching out of the lens due
to the hydrated storing environment for lenses.
3.1.2. Iontophoretic Devices
Iontophoresis is another noninvasive technique for ocular
drug delivery, in which a mild direct electric current is applied
to enhance penetration of charged drugs across the sclera/
cornea and into the choroid, retina, and vitreous.[142,143] The
iontophoretic device generally is composed of a direct cur-
rent power source and two electrodes. To deliver the drug, an
electrode carrying the substances with the same charge as the
electrode is applied at the target area, and the ground elec-
trode is placed elsewhere on the body to complete the circuit.
The drugs then are driven into the tissue by electrorepul-
sion at either the anode (for positive drug) or the cathode
(for negatively charged drug).[144] The majority of the current
ocular iontophoretic devices use a relatively large eye cup or
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Table 1.  A summary of different drug administration routes described in the text.

Administration Device categories Characteristics Ref.

routes
Ocular delivery Contact lenses pHEMA-hydrogel contact lenses with increased load of hydrophilic glaucoma drug [137]
Sustained zero-order release with a degradable drug-loaded annular film [140,141]
Iontophoretic devices Delivering charged drugs into the vitreous cavity through the sclera without tissue damage [145]
Punctal plugs Tiny biocompatible lacrimal plugs with different shapes and appearances for drug release through a [111]
diffusion-controlled release mechanism
Intraocular inserts and I-vation: a titanium helical implant anchored within the sclera, containing drugs in the coating [152]
implants
Vitrasert (Retisert): a device sutured to the sclera with the drug reservoir inserted into the vitreous cavity [150,152]
Renexus (NT-501): a tube-shaped device with RRE cells to secrete CNTF to treat retinitis pigmentosa and dry [150,152]
AMD
Iluvien: a rod-shaped device for sustained delivery of fluocinolone acetonide from both ends of the device to [148,152]
treat diabetic macular edema
Capsule drug device: a refillable device with a ring shape inserted in the lens capsule to deliver Avastin [153]
Microneedles: stainless-steel microneedles inserted halfway into the cornea or scleral for 20 s to 2 min to [157,158]
dissolve drug-containing coatings
MEMS devices PDMS-based devices with a refillable drug reservoir, flexible cannula, check valve, and suture tabs to release [165–169]
drug by manual actuation or electrolysis pumps
Magnetically actuated PDMS devices composed of a drug-loaded microreservoir sealed by a thin elastic [173]
magnetic PDMS membrane with a laser-drilled microaperture for drug release
Oral delivery Bioadhesive intestinal Mucoadhesive disks with layered structure for sticking to the intestinal wall to prolonging drug release [176–178]
patch-like devices duration
Microfabricated PMMA devices containing single or multiple microdrug reservoirs [179–186]
Wireless endoscopic Swallowable capsule endoscopes usually consisting of a drug reservoir, a piston, and an energy [198–201]
capsules producer-transmission system for triggered drug release in the GI tract
Capsule endoscopes with a set of legs capable of active and controllable locomotion [202–205]
Capsule devices with magnetic parts to release drugs controlled by the external magnetic field [207–210]
Self-folding Stimuli-responsive self-folding microdevices with patterned rigid segments connecting with [86,87]
microcontainers flexible polymeric hinges
Transdermal Microneedles Four general types of microneedles: solid microneedles for skin pretreatment, drug-coated microneedles, [225–234]
delivery dissolvable microneedles, and hollow microneedles
Other designs of microneedles: biphasic microneedles with enhanced adhesion strength in the skin, [235–240]
bendable microneedles to avoid breakage and detachment, rapidly separating microneedles to optimize
dissolvable microneedles, hollow silicon microneedles with a flexible reservoir for manually controlled drug
delivery, a smart wearable microneedle system for diabetes monitoring and therapy
Optical lens-microneedle array for percutaneous light delivery for dermatologic applications and [241]
photodynamic skin cancer therapy
Other transdermal Stretchable patch-type devices with multiple reservoirs to release drug by bending and stretching the device [242]
devices to deform the reservoir
MEMS-based devices for electric fields triggered release with actuate shrinking of an electrosensitive [243]
hydrogel
Implantable Sustained delivery Microgeometry-based devices comprising of three functional layers and an array of micro-orifices to control [244]
devices devices drug diffusion
Silicon nanochannel membranes controlled drug release which is independent of the concentration [31,32,245]
gradient
Pulsatile delivery Drug layers separated by degradable blank polymer layers to achieve sequential and pulsatile drug release [246,247]
devices
Electrochemically activated and electrothermally activated microchips for pulsatile drug release [30,251]
Composite membranes embedded with thermosensitive nanogels and magnetic nanoparticles to control [96,254]
drug release by an oscillating magnetic field
Device with thermally responsive hydrogel for ultrasound triggered drug release [255]

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Table 1. Continued.

Administration Device categories Characteristics Ref.

routes
Magnetic fields controlled movement of Fe3O4 particles to block/open device pores for reversible switching [97]
of drug flux
MEMS devices with pump-like release mechanisms using magnetic films, magnetic blocks, magnetic [103,109,257]
sponges, or magnetic actuated plungers
Devices applied to Intracerebral delivery: microprobes with microfluidic channels for controlled drug infusion [264]
specific sites
Intracochlear delivery: a microfluidic reciprocating delivery device with a single microcannula to release drug [270]
to the cochlea
Intraoral delivery: a mechatronic device as part of a dental prosthesis for drug release through the buccal [271,272]
mucosa
Vaginal/intra- Vaginal rings Sandwich type rings consisting of a drug-containing central core surrounded by a drug-free outer layer of [279]
uterine delivery polymer
Vaginal rings with compartments for loading drugs in different forms such as silicone rods, compressed [280]
tablets, and lyophilized gels
A device with a flux controlled pump driven by swelling of drug-containing polymers [281]
Intrauterine devices Mirena system: a plastic device with a T-shaped polyethylene frame and drugs in the vertical part [285]
T-shaped devices with copper nanoparticles dispersed in plastic matrix
Other delivery Intranasal olfactory A system containing an aerosol generator (inhaler), a charging chamber, a focusing chamber, and external [286]
routes delivery systems electrodes to guide drugs to the targeted olfactory receptor
Surgery sutures A suture surrounded by a drug-containing PLGA sheet for sustained drug release without sacrificing the [287]
mechanical strength of the suture
Devices for rectal drug A hollow-type suppository made of oleaginous base with different gel agents to prolong the plasma [289]
delivery concentration of drug

a probe-type electrode, which has to be pressed on the eye
manually. The drug release from these devices is through
a large area on the eyeball, raising a risk of damage to the
sensitive cornea or sclera. Recently, a simple device based on
PDMS in a cup shape with a planar poly(3,4-ethylenedioxy-
thiophene) electrode was created by the microfabrication tech-
nology (Figure 6A).[145] Due to its small size, the device can
be placed under the eyelid and deliver drugs into the vitreous
cavity through a small area of the sclera, reducing the possi-
bility of tissue damage. The in vivo drug delivery test showed
high iontophoretic efficiency of 396 ng mL−1 Mn2+, which
was achieved compared to the delivery result (2.69 ng mL−1)
without iontophoresis.[146]
3.1.3. Punctal Plugs
Punctal plugs (PPs), also called lacrimal plugs, are very tiny
biocompatible devices in the treatment of dry eye syndrome
since 1975.[111] They are used to block tear drainage through
the canaliculi by inserting into the lid puncta, which have been
proved in the improvement of tear film stability and tear osmo-
larity and have good acceptance by both patients and physi-
cians.[147] In addition to the physical occlusion of puncta, the
administration of drugs such as cyclosporine A (an immune
suppressant) has shown promising results for the dry eyes.
Thus, the use of PPs for the simultaneous delivery of oph-
thalmic medications to the tear fluid and the nasolacrimal duct
offers a novel approach for treatment of other anterior condi-
tions.[111] The potential advantages of using PPs over topical
drug delivery include reduction in loss of drug due to lacrimal
drainage of drug, enhanced efficacy, and enhanced patient
compliance.
PPs can be classified into two kinds: semipermanent and
temporary, depending on the material used for their prepa-
ration. Semipermanent PPs are made from silicone, HEMA,
PCL, or Teflon and intended for six-month use. Removal of
such plugs is accomplished by either flushing or being man-
ually removed by a physician. Temporary PPs that are made
from animal collagen last for 4–10 d and dissolve. To give drug
delivery ability to PPs, a common method is to load drugs
within the core of the PPs coated with a layer of material that is
impermeable to the drug and tear fluid on all sides except the
head portion. The release of the drug from PPs is through a
diffusion-controlled release from the head cross-section facing
to the tears (Figure 4C(a)).[111] The forms of the drug can be
solutions, suspensions, microemulsions, nanoparticles, or
liposomes. For some plugs, the drug is loaded by soaking the
plug in drug solution before insertion. However, the quantity
of loaded drug is limited due to the small surface area. In a
report from Gupta and Chauhan,[147] a three-month zero-order
release of cyclosporine A at a rate of 3 µg d−1 was achieved
with a cylindrical plug consisting of HEMA core covered by an
impermeable silicone shell. A mathematical model was also
built up to estimate of the drug release behaviors from the
PPs.[147]

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Figure 6.  Different types of devices for ocular drug delivery. A) Schematic view of the ocular iontophoretic device that can be placed on a small area of the
eyeball, allowing ions penetration into the vitreous cavity by an electric field through the corneal epidermis. Reproduced with permission.[145] Copyright
2016, Elsevier. B) Selected drug delivery devices and their locations in the eye. Reproduced with permission.[153,158] Copyright 2010 and 2016, Elsevier.
C) MEMS ocular drug delivery pumps. (a) Illustration of an implanted passive MEMS pump.[165–167] Reproduced with permission.[167] Copyright 2009,
Springer; (b) Cross-section of an ocular drug delivery with the electrolysis pump.[168,169] Reproduced with permission.[169] Copyright 2010, Informa Health-
care; D) Conceptual illustration of a magnetically controlled MEMS device and its working principle. Reproduced with permission.[173] Copyright 2013, IEEE.

Although the advantages of PPs as ocular drug delivery newer and effective PPs with different shapes and appear-
devices have been demonstrated, some complications such ances have been fabricated to overcome some of the current
as epiphora, corneal abrasion, plus extrusion and suppu- drawbacks (Figure 4C(c)).[111] Some of them are under clin-
rative canaliculitis have also been observed. To date, many ical trials and some are already commercially available for

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www.advancedsciencenews.com
different purposes of application (tear retention or sustained
drug release).
3.1.4. Intraocular Inserts/Implants
In addition to the noninvasive means, some invasive routes
of drug administration have also been under investigation,
including implantable and injectable devices, designed to keep
effective therapeutic levels in eyes and reduce the frequency
of conventional intraocular injections. Using the sclera as an
anchor site, various devices have been designed for intravit-
real release of different drugs to the posterior segment of the
eye.[148,149]
I-vation is a titanium helical implant (0.5 mm long and
0.21 mm wide) containing triamcinolone acetonide in the
coating of nondegradable polymers (Figure 6B).[150,151] It can be
implanted and anchored within the sclera through a 25-gauge
needle stick. The helical structure of the device increases the
surface area available for drug coating and enables sutureless
operation of anchoring.[152] The implant was designed to elute
drug sustainedly for two years and showed its effectiveness
in treating diabetic macular edema (DME) in phase 1 clinical
trials.
Vitrasert is a marketed reservoir-type device to deliver
ganciclovir for the treatment of cytomegalovirus retinitis
(Figure 6B).[148,150,152] The drug pellet was encapsulated in a
non-biodegradable polymer shell consisting of sandwiched
layers of polyvinyl alcohol (PVA) and ethylene vinyl acetate
(EVA). The PVA layer is permeable for drug diffusion and the
EVA layer is drug impermeable. The composite structure of two
polymers allows the release of ganciclovir at a rate of 24 µg d−1
for five to eight months. Retisert is another surgically implant-
able device similar to Vitrasert, which is designed for the sus-
tained delivery of fluocinolone acetonide for the treatment of
chronic noninfectious posterior uveitis (Figure 6B).[148,150,152]
It is 5 mm long, 2 mm wide, and 1.5 mm thick, and consists
of a tiny tablet packed inside a silicone elastomer cup which
is attached to a PVA suture tab. The silicone cup has an ori-
fice for drug release and a PVA membrane between the tablet
and the orifice to avoid premature drug leakage. The drug is
released out slowly when the vitreous environment hydrates
and dissolves the drug. The release rate is 0.3–0.4 µg d−1 for
≈30 months. Both Vitrasert and Retisert need to be sutured
to the sclera through a pars plana incision procedure with the
drug reservoir inserted into the vitreous cavity. Renexus (also
known as NT-501) is a tube-shaped device containing geneti-
cally modified human retinal pigment epitheliums which can
secrete recombinant human ciliary neurotrophic factor (CNTF)
(Figure 6B).[150,152] The retinal pigment epithelium (RPE) cells
are seeded in a polyethylene terephthalate scaffold surrounded
by an outer shell made from a semipermeable polyether sulfone
membrane. The device is implanted into the vitreous by a small
sclera incision and fixed with a suture through a titanium loop
at one end of the device. The semipermeable membrane allows
outward diffusion of CNTF and protects the RPE cells from
host cellular immunologic attack. Clinical studies show that
the device can release CNTF over 18 months for the treatment
of retinitis pigmentosa and dry AMD. The above-mentioned
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non-biodegradable devices are anchored on the sclera and a
removal may be needed to implant other devices if required.
Iluvien is a rod-shaped device for sustained delivery of
fluocinolone acetonide to treat diabetic macular edema
(Figure 6B).[108,148,152] The drug is encapsulated in a PVA matrix
inside a polyimide tube and then released from the membrane
caps on both ends of the device. Unlike the implant Retisert,
Iluvien is a miniaturized injectable insert (3.5 mm in length
and 0.37 mm in diameter) which is small enough to be injected
into the vitreous through a 25-gauge needle without any
sutures. The drug release can last for up to 36 months with a
rate of about 0.6 µg d−1. However, due to the non-biodegrada-
bility of Iluvien, the device would remain in the vitreous humor
after the drug payload is exhausted. The surgical removal of
this insert has not been reported so far. Different biodegrad-
able devices have been designed and tested in order to over-
come the issues associated with non-biodegradable implants.
Ozurdex is the first biodegradable intravitreal insert approved
by the US Food and Drug Administration.[66] It is a cylindrical
PLGA platform (6.5 mm in length and 0.45 mm in diameter)
containing 0.7 mg dexamethasone for treatment of macular
edema and noninfectious uveitis (Figure 6B).[151,152] After injec-
tion of Ozurdex into the vitreous via a 22-gauge needle, the
drug release is fast over the first two months and then becomes
slow in the following four months following the degradation of
PLGA. Although the drug release can be regulated by adjusting
the ratio of lactide and glycolide in PLGA matrix, a zero-order
release is still quite challenging. However, because the degra-
dation products of Ozurdex are water and carbon dioxide, no
surgical removal is required.
In addition to the intravitreal insert, an interesting drug
delivery device was designed and manufactured to insert in
the lens capsule during cataract surgery for the treatment of
wet AMD (Figure 6B).[153] The device consists of a ring-shaped
PMMA drug reservoir, a semipermeable membrane on one
side of the reservoir for controlled delivery, and silicone valves
for drug refilling. The drug bevacizumab is dispersed within a
PVA matrix and then placed in the reservoir. A near-zero order
release kinetic with a rate of 60–80 µg d−1 was achieved but only
lasted for a few days. A long-term release profile is required to
estimate the device feasibility for sustained drug release.[153]
Mild invasive methods using miniaturized devices such
as microneedles have been proposed to better overcome the
ocular barriers and enhance localization of the drug close to
the target tissues (e.g., retina).[154–156] For example, individual
drug-coated microneedles with a length of 500–750 µm and a
width of 200 × 50 µm were developed for anterior and poste-
rior drug delivery through intracorneal and intrascleral routes
(Figure 6B).[157–159] The microneedles were fabricated by laser-
cutting the needle structures from stainless-steel sheets and
then dip-coated in a drug/polymer solution. The drug-con-
taining microneedles were inserted halfway into the cornea or
sclera and then removed after 20 s to 2 min. The drug coating
could rapidly dissolve off the needles, generating a much higher
concentration in tissues compared to a topical administration of
a free drug solution. And, the small abrasion formed at the site
of microneedle insertion disappeared after 3 h. However, the
very low surface area of microneedles limits their drug carrying
capacity. To address this limitation, microneedles with complex
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through-thickness fenestrations (i.e., windows) were designed
and fabricated using the titanium deep reactive ion etching tech-
nique. The fenestrated Ti MNs offered larger drug reservoirs and
consequently increased drug carrying capacity up to fivefold rela-
tive to the solid counterpart.[157,158] In order to facilitate infusion
of drug solutions such as nanoparticle and microparticle (20 nm
to 10 µm) suspensions into the eyes, hollow glass and metal
microneedles were developed and tested in ex vivo experiments
on rabbit, pig, and human eyes.[160–163] For drug delivery, the
hollow microneedles were initially inserted into the sclera and
then partially retracted to enable drug solution infusion into the
tissue. An infused volume of 10–35 µL per microneedle could
be achieved, which was affected by the microneedle length,
applied pressure, and particle size in the fluid. The infused solu-
tion using microneedles forms a drug depot within the sclera
and gradually diffuses drug to neighboring tissues, such as
choroid, retina, or ciliary body.[160,161] In general, the drug mole­
cules were primarily cleared from the suprachoroidal space in
1 d, while the drugs encapsulated in particles could prolong the
clearance period to one to two months. Microneedles have dem-
onstrated a minimally invasive means for localized ocular drug
delivery. However, it was found that solution infusion by hollow
microneedles caused more pain than intravitreal injection (to
be discussed subsequently), because of distension by the drug
solution. This may further limit the acceptable dose each time
and require repeated injections. Moreover, further research on
optimization of microneedle designs, drug formulations, and
operation procedures is needed to enable controlled and long-
term drug delivery.
3.1.5. MEMS-Based Devices
As noted above, a long-term sustained drug release is able to be
achieved with the currently available implants/inserts. Beyond this,
benefitting from MEMS technologies, more sophisticated small-
scale devices may now be fabricated for ocular drug delivery.[164]
Meng and co-workers developed and tested a MEMS
device which was an assembled three-layer structure made
from PDMS containing a refillable drug reservoir, flexi­ ble
cannula, check valve (a one way valve), and suture tabs
(Figure 6C(a)).[165–167] The device can be implanted underneath
the conjunctiva with the cannula outlet inserted through an
incision into either the anterior or posterior segment for dif-
ferent treatment requirements. The first generation of this
device was designed for manually actuated drug release by
pressing the reservoir with a finger. When the pressure was
high enough, the valve was opened to discharge drug solu-
tion. The drug refilling was accomplished by puncturing the
reservoir layer using a 30-gauge needle attached to a syringe.
Obviously, manual actuation could not ensure precise control
over the amount of drug delivered. Later, an improvement
was made by incorporating an electrolysis pump and batteries
into the device (Figure 6C(b)).[168,169] The pump can generate
hydrogen and oxygen gas through electrolysis of water, which
increases the internal pressure in the reservoir and thus
pushing drug out from the cannula. When the pump is turned
off, these gases recombine to form water. The electrically con-
trolled manner with low power requirements (microamperes
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to milliamperes) allows a more precise drug release and makes
this device clinically practical for the treatment of chronic
ocular diseases. Recently, a triboelectric nanogenerator (TENG)
device that can harvest ambient mechanical energy and transfer
it into electricity was introduced to offer the power for the elec-
trolysis pump, giving a self-powered ability and battery-less
possibility to the current system. The concept of TENG-based
self-powered device was demonstrated with the ex vivo trans-
sclera drug delivery in porcine eyes by generating the biokinetic
energies of human hands.[170]
The prototype of the refillable MEMS-based device (the
MicroPump system) has been realized by Replenish Inc. (Pasa-
dena, CA) to deliver a programmable microdose of medicine
(such as ranibizumab) into the vitreous cavity for DME.[171,172]
The surgical feasibility and safety of the device have been dem-
onstrated in an animal model for up to one year and then in
human patients with retinal disease for 90 d. As the Micro-
Pump device is supposed to be used for five years or longer
before replacement, long-term clinical studies are necessary
to evaluate the stability, sustained function, and in-office drug
refilling of the device.
Another MEMS-based ocular implant is a magnetically con-
trolled MEMS device capable of on-demand release of an anti-
proliferative drug, docetaxel to the posterior segment of the
eye (Figure 6D).[173] The device is composed of a drug-loaded
microreservoir (6 mm in diameter and 580 µm in depth) sealed
by a 40 µm thick elastic magnetic PDMS membrane with a
laser-drilled aperture (100 × 100 µm2) in its center as an outlet
of drug release. By applying a magnetic field from the bottom
of the device, the PDMS membrane incorporated with iron
oxide nanoparticles deforms and pushes the drug solution out
from the reservoir. The amount of released drug is tunable by
changing the strength and duration of the applied magnetic
field. Ex vivo release studies performed on human cadaveric
eyes demonstrated a promising application of this device for the
treatment of ocular posterior segment diseases such as diabetic
retinopathy by controlled drug delivery through an external
magnetic actuation. Likewise, the safety and reliability in the
long-term use of the device need to be further investigated.
3.2. Oral Delivery
Oral drug delivery is a convenient and highly patient-compliant
route of drug administration among various conventional
delivery routes such as invasive injection manners (intravenous
and intramuscular). However, a unique set of physiological bar-
riers in the GI tract limit the overall efficacy of drugs delivered
through the oral route. The acidic environment of the stomach
combined with an array of intestinal enzymes may cause drug
degradation, especially for the active therapeutics such as pro-
tein and peptides. The adherent mucus layer and tight junc-
tions of intestinal epithelium limit permeation of drugs with
high molecular weights. Additionally, the shear forces and
flow conditions due to peristalsis of the GI tract may further
decrease drug retention and result in low bioavailability. To
overcome these obstacles, different delivery devices with special
design and precise engineering have been fabricated through
microfabrication for safe and effective oral drug delivery.[174,175]
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
3.2.1. Bioadhesive Intestinal Patch-like Devices
Inspired by the success of transdermal patches, some similar
mucoadhesive patch-like systems have been created for local
drug delivery in the GI lumen. These patch systems usually
consist of several layers that have different functions including
adhesion, drug encapsulation, and protection from the sur-
roundings. For example, a three-layer patch device was devel-
oped by Mitragotri and co-workers for oral protein delivery,
which was prepared by sandwiching a layer of drug between a
layer of a mucoadhesive polymer and a polymer layer with poor
permeability (Figure 7A).[176–178] The mucoadhesive layer made
of carbopol and pectin allows the device to stick to the intestinal
wall. The backing layer was made of ethyl cellulose (EC), which
is relatively impermeable compared to the mucoadhesive layer,
allowing the drug to be released primarily from the mucoadhe-
sive side into the epithelia layer and preventing drug diffusion
into the outer lumen. The backing layer, at the same time, may
protect drug from enzymatic degradation. The patches with a
square or circle shape (2–4 mm2 large and 40 µm thick) could
be encapsulated in a capsule and delivered into the intestine
(Figure 7A(b)).[177] The design of planar and layered structure
of the device offers several advantages over standard tablets or
mucoadhesive microspheres. Specifically, compared to micro-
spheres with limited contact area, the patches provide larger
surface area due to the planar design, thereby enhancing their
adhesion ability on the intestinal wall and prolonging the dura-
tion of drug release at the target site. The flat design with
minimized side area also decreases the shear disturbances
from the flow of liquids through the intestine. Unlike multi-
directional release from a spherical system, the layered struc-
ture of the patch with the low permeable backing film allows
unidirectional release of drug toward the intestinal epithelium
and reduces loss of drug into the intestinal lumen. In vitro
experiments with rat intestine showed that trans-lumenal flux
of model drugs from the patches was about 100-fold higher
than that from a solution form. The potential drug leakage
from the side edges of the patch delivery system is one unre-
solved issue for the layered device. A simple solution would be
to coat individual patches with materials of low permeability,
which was later achieved by Mitragotri and co-workers.[178] In
the new system, the drug was dispersed in a mucoadhesive
matrix made of carbopol, pectin, and sodium carboxymethylcel-
lulose by pressing the mixture into a 400 µm thick disk. The
disk was then coated on all sides but one with EC to form a
layer of about 50 µm. The protective coat minimized drug loss
and resulted in significant bioavailability enhancement in por-
cine models.
Similar to the patch device introduced above, another type
of bioadhesive intestinal device has been designed and investi-
gated by Desai and co-workers, which contains single[179–184] or
multiple microdrug reservoirs[67,185,186] to incorporate a number
of drugs or biomolecules of interest (Figure 7B). The drug res-
ervoir is constructed mainly with PMMA through a series of
standard microfabrication process including photolithography,
deposition, and reactive ion etching. The size of the devices is
designed on a microscale level and the shape can be tailored
according different requirements, ensuring that the device is
small enough to have adequate contact with the intestinal wall
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but large enough to avoid endocytosis. The bioadhesion ability
of the device is achieved by conjugating bioadhesive tomato
lectin to the surface of reservoir side after chemical modifica-
tion. The drug is loaded in the device by forming hydrogel/drug
matrix in the reservoir via photolithography. By choosing a spe-
cific type of hydrogel material, the drug release behaviors from
the device can be predetermined and tuned. When loading the
different drugs with different hydrogels in the separated reser-
voirs of a device, independent controlled release of each drug
can be realized. The device was further improved by being
sealed with a nanostraw membrane with which enhanced adhe-
sion of the device to the epithelial tissue and limited influx
of outside molecules into the device reservoir were observed
(Figure 7B(d)).[187] All of the features of the planar microdevice
delivery system, including bioadhesion ability, unidirectional
controlled release, and decreased drug leakage, enable a local
sustained drug release with enhanced therapeutic bioavail-
ability in the GI tract by oral route.
3.2.2. Wireless Endoscopic Capsules
Swallowable wireless endoscopic capsules are types of small
device for diagnostic inspection of the GI tract and in some
cases, a drug chamber is incorporated in the device to per-
form a targeted therapeutic treatment.[188–190] Various commer-
cial prototypes of capsule endoscope such as IntelliCap,[191,192]
InteliSite,[193] Pulsincap,[194] and Enterion capsule,[195] have been
designed and fabricated to achieve triggered drug release via
different mechanisms. These devices generally consist of a cyl-
inder polymer capsule with an embedded assembly of a drug
reservoir, a piston, and an energy producer-transmission system.
Drug release from the devices is triggered by the piston move-
ment driven using self-produced energy or energy transformed
from the external stimuli. For example, the InteliSite capsule
(10 mm in diameter and 35 mm in length) contains a drug res-
ervoir of 0.8 mL in volume adjoining a compressed spring that
is held with two shape memory alloy wire clips.[193] Once acti-
vated by the remote antenna for 2 min, the wire clips deform
to let the spring propel the inner drug reservoir out and away
from the capsule body, releasing contained drugs. Similarly, in
other capsule endoscopes, a thermosensitive spring made of a
shape memory alloy,[196] or a compressed stretchable compo-
nent[197] is used to drive the piston and push the drug out of the
reservoir. In addition to the spring-like mechanics that acts on
the piston, the gas pressure is also used to cause piston move-
ment. One example was reported by Gröning et al., in which the
gas was produced by the electrolysis of hydrochloric acid and/
or sulfuric acid in the capsule (Figure 7C(a)).[198,199] The energy
triggering the electrolysis was received from an oscillating cir-
cuit located inside the capsule through the resonance with an
external high frequency transmitter (24–27 MHz). Accordingly,
the drug release could get controlled. Another example was
from Pi et al.’s reports.[200,201] They developed a solid propellant
microthruster that can be ignited by an external radio frequency
signal to convert the solid propellant into gas, offering the pro-
pulsion energy for the piston (Figure 7C(b)).[201] The produced
gas could provide sufficient pressure to empty the drug reser-
voir and decrease possible drug reflux.
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Figure 7.  Various devices for oral drug delivery. A) Layered intestinal patches.[176–178] (a) Schematic representation of the patch design; (b) Images of
capsules containing patches with the backing membrane is stained with sulforhodamine B, and a schematic representation of the drug delivery using
intestinal patches. Reproduced with permission.[177] Copyright 2004, Elsevier. B) Asymmetric microfabricated devices. (a) Schematic representation
of spherical particles and microdevice interface with intestinal epithelial cell surface. Reproduced with permission.[186] Copyright 2014, Wiley-VCH;
(b) Patches with a single reservoir[184] and (c) multiple reservoirs.[185] Reproduced with permission.[184,185] Copyright 2009 and 2012, Wiley-VCH; (d) An
asymmetric microdevice with nanostraw structure. Reproduced with permission.[187] Copyright 2016, American Chemical Society. C) Endoscopic cap-
sules for drug delivery in the gastrointestinal (GI) tract. (a) Schematic diagram of a remote-controlled capsule with a gas producing cell and a high
frequency receiver to control drug release. Reproduced with permission.[199] Copyright 2009, Elsevier; (b) Schematic diagram of a solid propellant micro-
thruster. Reproduced with permission.[201] Copyright 2010, Elsevier; Endoscopic capsules of (c) twelve legged design[205] and (d) two legged rounded
shaped design with a needle. Reproduced with permission.[204,206] Copyright 2009 and 2013, IEEE; (e) Capsule made of two magnets. Reproduced with
permission.[208] Copyright 2012, Elsevier; (f) Capsule with two internal on-board permanent magnets. Reproduced with permission.[209] Copyright 2012,
IEEE. D) Microcontainers: (a) Self-folding microcontainers. Reproduced with permission.[86] Copyright 2008, Royal Society of Chemistry; (b) Stimuli-
responsive theragrippers. Reproduced with permission.[87] Copyright 2014, Wiley-VCH.

Adv. Funct. Mater. 2017, 27, 1703606 1703606  (17 of 31) © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
Most existing capsule endoscopes move by the natural
peristalsis of the GI tract, known as passive locomotion. This
system has a lack of good controllability over their position,
orientation, and moving speed. This limits their application
for advanced diagnostic and therapeutic purposes at the target
area in different sections of the GI tract. To overcome this
problem, several systems capable of active and controllable
locomotion have been proposed. One of these systems uses a
legged mechanism with small brushless DC motors powered
by an on-board battery.[202–204] A set of legs in the capsule can
be deployed to resist peristaltic force in the GI tract such as the
intestine. The experiment in a porcine colon demonstrated that
the capsule with four legs could travel a distance of 15 cm in
a period of 5 min, and the speed was able to be adjusted from
10 to 40 mm min−1.[203] The four-leg device was later improved
to achieve high propulsion by increasing the number of legs to
12 (Figure 7C(c)).[205] In another device, besides an anchoring
system, a needle positioning mechanism[204,206] was incorpo-
rated in the capsule for targeted dosing of 1 mL of medication
to the GI tract (Figure 7C(d)). When the device is anchored
after its two round-shaped legs are fully deployed, the needle
positioning mechanism allows the needle to penetrate into the
GI tract wall to inject medication from any one of 16 predefined
outlet ports.[204]
The above capsule endoscopes to some extent achieve the
controlled drug release in the GI tract. However, because all
the components including on-board batteries and electronic/
mechanical systems need to be integrated in a small cap-
sule, there usually is limited volume left for drug loading. To
enhance the capability of drug loading and maintain the locali-
zation functionality, a capsule device using purely magnetic
effects was proposed.[207,208] The capsule was comprised of two
metallic parts (Figure 7C(e)).[208] In magnetized state, the two
metallic parts were attached to each other and kept the capsule
closed when travelling through the GI tract. The position of the
capsule could be monitored. Once the capsule reached the area
of interest, it was opened and released drugs by applying an
external magnetic field to demagnetize the metallic parts. As
the device just consists of two magnetic capsule shells, it offers
more volume as the drug reservoir compared to the device
with the same size. One drawback of this system is that drug
release is a one-time release event at one location. A design
that can give multiple doses in a controlled way may provide
more possibilities in practical applications, such as allowing
drug delivery to more areas in the GI tract by a single cap-
sule. A prototype of a magnetically actuated soft capsule was
designed and investigated for this purpose.[209,210] The device
contains two permanent magnets in two ends of the capsule,
and the drug-containing chamber is situated between the
two magnetic heads (Figure 7C(f)).[209] When the chamber is
compressed by the movable magnetic head under an external
magnetic field, the drug is released through the slits of the
chamber. When the external magnetic field moves away, the
chamber can return to its previous shape and stop the drug
release by closing the slits. This process can be repeated until
the chamber is fully emptied. If the external magnetic field is
strong enough, the whole drug can also be released out due
to the collapsing of the chamber. Despite the feasibility of this
system, further improvement is still needed such as increasing
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the volume of the drug chamber, decreasing drug leakage,
miniaturization of the device, and enhancing the repeatability
of drug release.
3.2.3. Self-Folding Microcontainers
Microdevices with stimuli-responsive self-folding abilities are
able to be used for encapsulation and delivery of drugs. Gra-
cias Laboratory has developed various polyhedral shaped,
self-folding microcontainers using a hybrid fabrication method-
ology of photolithography and self-assembly.[211–214] The micro-
containers consist of patterned rigid segments (metallic or
polymeric) connecting with flexible polymeric hinges that are
sensitive to temperature. Increasing the temperature of envi-
ronment enables spontaneous transformation of 2D templates
into 3D structures, which allows parallel loading of drugs or bio-
logical objects. The untethered nature of these microcontainers
allows free or remotely guided travel of the devices in the GI
tract. The encapsulated drugs can be released from the pores in
the porous walls of the microcontainer (Figure 7D(a)).[86] Photo-
lithographic patterning enables precise control over the proper-
ties of the microcontainers including the wall thickness, sizes,
shapes, and porosity, all of which are important for controlled
drug delivery applications. A microcontainer referred to as a
theragripper (Figure 7D(b)) was fabricated for drug delivery in
the stomach of a pig after griping into tissue with its stiff tips
and the drug release could last for up to 7 d, which offers an
exciting strategy to treat the various diseases of the intestine.[87]
3.3. Transdermal Delivery
Skin is the largest accessible organ of the human body and
offers a compliant interface for painless drug delivery by
methods such as transdermal patches. Drug delivery across
skin has a variety of advantages including avoidance of first-
pass metabolism and drug degradation of the GI tract com-
pared with the oral route, as well as less pain and reduced side
effects due to transiently high plasma drug concentration com-
pared with hypodermic injections.[215] In addition, transdermal
systems can provide sustained drug release for long periods of
time and can be self-administered, highly improving patient
compliance. The greatest challenge for transdermal delivery
might be that only small hydrophobic drugs (molecular weight
<500 Da) can effectively be delivered by this route because the
resistance to drug transport resulted from the outermost layer
of skin, known as the stratum corneum lipid bilayers.[216] Much
effort has been made in order to overcome this barrier by devel-
oping new technologies involving microfabricated transdermal
devices.[217–219]
3.3.1. Microneedles
Microneedles, usually an array of microscopic needles on a base
substrate, have been developed as a minimally invasive means
to deliver drugs into the skin. They are designed to be long
enough to penetrate through the skin’s stratum corneum and
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
create holes for drugs permeation, but short enough to avoid
stimulating the nerves in the dermis, therefore achieving pain-
less and less bleeding drug delivery.[220,221] Earlier microneedles
were made of silicon due to easy adaptability to microelectronic
fabrication process of silicon etching.[222] However, issues
associated with fragility of silicon microneedles arose. Subse-
quently, metal materials such as titanium, nickel, and stain-
less steel were explored to decrease fracture of the tip of the
microneedle in operation. Fabrication techniques for such
materials include 3D laser ablation, laser cutting, wet etching,
and metal electroplating, which are relatively expensive. Poly-
meric microneedles that can be fabricated using photolithog-
raphy and micromolding methods provide an alternative with
low cost for large scale manufacturing.[222]
In general, microneedles may be categorized into four
different types including solid microneedles for skin
pretreatment, drug-coated microneedles, dissolvable
microneedles, and hollow microneedles (Figure 8A(a)).[223,224]
Different designs of these microneedles enable drug
delivery through different mechanisms. Solid microneedles
(Figure 8A(b))[28,225,226] are used for pretreatment to enhance
skin permeability of drugs by making microscopic holes in the
skin. After piercing the skin and removing the micro­needles,
a drug formulation such as a transdermal patch or drug-con-
taining gels may be applied to the skin, allowing diffusion
of drug into the tissue through the holes. When an electric
field is applied, fast penetration of drugs can be realized by
iontophoresis. Drug-coated microneedles (Figure 8A(c)) are
solid microneedles containing a layer of drug coating, typi-
cally a water-soluble formulation.[227–229] When inserting
the microneedles in the skin, the drug coating starts to dis-
solve and release drugs into the skin. After dissolution of the
coating in a short time, the microneedles are removed. Dis-
solvable microneedles (Figure 8A(d)) are a further improve-
ment, in which the needle body is made of water-soluble or
biodegradable polymers with the drug of interest incorporated
inside.[230,231] In this way, the microneedles could be left in
the skin after insertion and the encapsulated drug can slowly
be released along with the dissolution or degradation of the
microneedles. As the whole microneedle body is used as a drug
reservoir, it greatly increases the drug amount in each dose.
The last type, hollow microneedles (Figure 8A(e)),[37,232–234]
can enable active drug fluid flow through the needle bore and
into the skin, which may achieve a fast drug delivery that can
be easily modulated over time.
Some other designs were also proposed to improve the
existing microneedle systems. For example, a biphasic
microneedle (Figure 8B(a)) was fabricated to enhance the
adhesion strength between the microneedle patch and the
skin.[235] The microneedle is composed of a poly(styrene)-block-
poly(acrylic acid) swellable tip and nonswellable polystyrene
core. After insertion of the microneedles in the skin, the needle
tip swells to mechanically interlock with tissue and create
high adhesive strength, decreasing the premature detachment
of the device from the target site. Another design is aimed to
overcome the risk of microneedle breakage induced by buck-
ling forces from the deformation or lateral movement of the
skin. To achieve this purpose, a bendable microneedle device
(Figure 8B(b)) was made by fixing a rigid sharp microneedle
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with a stretchable base that contains four soft beam pillars
made of PDMS.[236] These pillars may serve as anchors to fix
microneedles and allow bending of the microneedles when the
lateral force applied onto the microneedle exceeds the threshold,
avoiding the breakage and detachment of the microneedle. This
device may be applied on the joint such as elbow and knuckle
for transdermal drug delivery in osteoporosis treatment. Rapi­dly
separating microneedles (Figure 8B(c)) were fabricated to opti-
mize dissolvable microneedles, which usually need several min-
utes for full dissolution in the skin tissue and are difficult to be
completely inserted into the skin.[237,238] The rapidly separating
microneedles are drug-incorporated PLA microneedles mounted
on the top of solid microneedles.[238] Such stacked design not
only enabled full insertion of the drug-containing microneedles
into the skin due to the increased length, but also allowed rapid
separation of the top part from the bottom part to achieve the
high drug delivery efficiency with a quick operation process
compared to the counterpart. By bonding an array of hollow
silicon microneedles with a flexible PMDS reservoir, manually
controlled drug delivery was achieved by pressing the reservoir
with a finger (Figure 8B(d)).[239] The pressure of a finger could
push drug solution or microparticle suspension in the reservoir
into the skin through the hollow microneedles, giving a real
time control on drug injection. Recently, Lee et al. reported a
smart wearable microneedle system for diabetes monitoring
and therapy (Figure 8B(e)).[240] This system is an assembly of
a heater, temperature, humidity, pH, and glucose sensors and
drug-containing microneedles made of a phase-change mate-
rial. The sensors can monitor the sweat glucose concentration
and trigger the embedded heaters to dissolve microneedles once
the glucose concentration is high. As a result, the drug can be
released from the bioresorbable microneedles in response to the
glucose sensing. Successful reduction in blood glucose level was
demonstrated by thermally actuated delivery of Metformin with
this smart system in diabetic mice.
So far, microneedles for transdermal drug delivery have been
investigated in vitro, in animal and in human. It has shown that
microneedle piercing can increase skin permeability by orders
of magnitude for a broad range of drugs including small mole­
cular weight compounds, DNA, proteins, inactivated viruses,
and nanoparticles. In addition to drug delivery, microneedles
have been designed and fabricated for percutaneous light
delivery in the dermatologic applications of antimicrobial blue-
light therapy and photodynamic skin cancer therapy. The proto-
type device, termed optical microneedle array (Figure 8C), con-
sisted of a press-molded PLA microneedle array bonded with
a matched microlens array.[241] The microlens array was used
to focus incident light into each microneedle at appropriate
converging angles to achieve an optimal intensity in the tissue.
The experiment with bovine tissues demonstrated that the
lens-assisted microneedles enabled a ninefold enhancement
of light delivery at the target depth compared to direct surface
illumination.
3.3.2. Other Transdermal Devices
There exist some stretchable patch-type release systems able to
be used in transdermal drug delivery. An example was reported
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Figure 8.  Methods of drug delivery to the skin using microneedles (MNs). A) MNs of four basic designs for transdermal drug delivery. (a) Schematic diagram
of drug release mechanisms of different MNs; (b) Solid MNs. Reproduced with permission.[28,226] Copyright 1998, Wiley and Copyright 2004, Plenum Publishing
Corporation; (c) Coated MNs.[227–229] Reproduced with permission.[228,229] Copyright 2009 and 2010, Elsevier; (d) Dissolving MNs Reproduced with permis-
sion.[230,231] Copyright 2010, Nature Publishing Group and Copyright 2010, Springer; (e) Hollow MNs. Reproduced with permission.[37,234] Copyright 2006 and
2010, Springer. B) MNs with other special designs. (a) Swellable biphasic MNs with the mechanical interlocking mechanism. Reproduced with permission.[235]
Copyright 2013, Nature Publishing Group; (b) Bendable MNs. Reproduced with permission.[236] Copyright 2016, Wiley-VCH; (c) Rapidly separating MNs.
Reproduced with permission.[238] Copyright 2016, Elsevier; (d) A MN-based miniature syringe. Reproduced with permission.[239] Copyright 2009, Springer;
(e) Thermoresponsive MNs with a electrochemical device for diabetes monitoring and therapy. Reproduced with permission.[240] Copyright 2016, Nature Pub-
lishing Group. C) Optical lens-microneedle array for percutaneous light delivery. Reproduced with permission.[241] Copyright 2016, Optical Society of America.

Adv. Funct. Mater. 2017, 27, 1703606 1703606  (20 of 31) © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
by Kim et al., in which mechanical strain from human body
motions was used as means of stimulation for drug release.[242]
The patch-type device is based on a stretchable layer with mul-
tiple reservoirs which can deform and undergo a decrease in
volume by bending and stretching the device to release drug
from the micro-orifices. The use of elastic microchannels with
different channel lengths attached to the opening of the res-
ervoir enables reduction of the diffusional leakage and better
control over the drug release. Moreover, the reservoirs of the
device can be refilled with a microsyringe to achieve long-term
drug release. Liu et al. presented a MEMS-based drug delivery
device consisting of a metallic contact array with a meander
structure.[243] This device is able to create a uniform electric
field to actuate shrinking of the electrosensitive polymethacrylic
acid hydrogel, leading to drug release from the hydrogel matrix.
By controlling the applied voltage and its duration, the amount
of released drug may be controlled.
3.4. Implantable Devices
Implantable drug delivery devices are designed to be placed in
desired bodily compartments (for example, close to the target
region beneath the skin) and offer a prolonged drug effect by
a sustained, preprogramed, or externally controlled way. This
approach to drug delivery is very appealing for many kinds of
drugs, particularly those which cannot be given via conven-
tional routes and for patients with chronic diseases who need
long-term and repeated dosing.
3.4.1. Sustained Delivery Devices
Sustained long-term drug therapy is difficult to achieve by con-
ventional means such as daily oral dosing. Implantable devices,
however, offer a possible solution to this challenge. For most
local drug delivery systems made of biodegradable polymers,
drug release relies on the degradation of the scaffold and usu-
ally exhibits burst release due to the high initial concentration.
Such degradation controlled release is often limited by the
property of the scaffold polymer. However, through different
designs, devices made of the same material could provide an
alternative measure of controlling drug release. An example is
a microgeometry-based drug delivery device reported by Ryu et
al.[244] In their design, the device comprises of three functional
layers: a drug reservoir layer, a diffusion layer, and a diffusion
control layer. The diffusion control layer contains an array of
micro-orifices through which the drug can diffuse out. Drug
release from the patch-type device could be modulated by the
variation of the microgeometries in the release control layer
such as the size, number, and spatial distribution of the micro-
orifices or the reservoirs. As it is made from biodegradable
PLGA, the device can release drugs in predetermined rates and
degrade away afterward finally after being implanted close to
the target area.
Similarly, subtly designed silicon nanochannel membranes
have been fabricated to control diffusion kinetics of different
drugs. In general, diffusion of solutes in unconstrained cases
from a region of higher concentration to a region of lower
Adv. Funct. Mater. 2017, 27, 1703606 1703606  (21 of 31)
www.afm-journal.de
concentration follows Fick’s diffusion laws. The diffusion flux
is proportional to the concentration gradient. However, when
the solute passes through pores or channels with the size com-
parable to the molecular hydrodynamic radius of the solute,
unexpected effects may occur and result in significant devia-
tions from the kinetics predicted by Fick’s laws. For example,
in the case of single file diffusion, the molecular flux is inde-
pendent of the concentration gradient, because the solute
molecules cannot pass each other in pores that approximate
the dimensions of the molecule itself. Utilizing this phenom-
enon, silicon nanochannel membranes (NMs) (Figure 9A(a))
have been created with top-down microfabrication methods to
control drug diffusion, which consist of arrays of parallel rec-
tangular channels with the smallest aspect ranging from 2 to
50 nm.[31,32,245] The NMs have been demonstrated to deliver
a wide range of therapeutic agents in a constant, controllable
way. As shown in Figure 9A(b), a discoidal implantable cap-
sule (260 µL drug reservoir, diameter = 15 mm, thickness =
4.5 mm) and a cylindrical one (1 mL drug reservoir, diameter =
11 mm, length = 26 mm), were fabricated for the constant and
sustained delivery of therapeutically relevant doses of different
drugs in three animal models (mice, rats, and dogs) for up to
70 d.[245] By tailoring the geometrical parameters and surface
properties of the nanochannel according to the size and mole­
cular properties of each therapeutic agent, a constant release
with appropriate release rates including zero-order release
could be obtained. And, the drug could be loaded in both liquid
and solid form. Such NM implants represent a viable nanotech-
nological approach for the controlled administration of various
drugs to improve the therapeutic efficacy of treatment.
3.4.2. Pulsatile Delivery Devices
In numerous cases, sustained release is not an optimal method
for drug administration. Instead, pulsatile release where drugs
are delivered at variable time intervals, may work better in cer-
tain cases such as the treatment of diabetes via pulsatile insulin
delivery, and alleviating pains according the patients’ needs
in the therapy of chronic illness. A simple method of making
devices with sequential and pulsatile delivery abilities is to
sequentially load drugs in a reservoir with a separating polymer
layer between two drug layers (Figure 9B(a)).[246,247] With the
degradation/erosion of the blank polymer layer, the drug may
be released sequentially in a pulsatile manner. The drug release
timing can be programed by choosing polymers with different
degradation speeds or varying the thickness of the polymer
layer. This device has limitations that the drug release is basi-
cally through a passive manner at predetermined release timing
which cannot allow an active control over the release behaviors
after administration.
An alternative method for achieving pulsatile release is
to develop active devices which can be triggered by external
stimuli to release drug. One prototype of this kind of devices
(Figure 9B(b)) was designed and fabricated by Langer and co-
workers.[30,91,248] It is an electrochemically activated microchip
comprised of an array of reservoirs in a silicon substrate. The
outlet for drug release of each reservoir is sealed by a thin
gold membrane that serves as an anode in an electrochemical
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com www.afm-journal.de

Figure 9.  A) Silicon nanochannel membranes. (a) Schematic diagram and the scanning electron microscope (SEM) image of membrane microstructure
and the diffusion path of molecules across the membrane. Reproduced with permission.[32] Copyright 2011, Springer; (b) Photograph and schematic
rendering of the discoidal (left) and cylindrical (right) implantable capsules with nanochannel membranes.[31,32,245] Reproduced with permission.[245]
Copyright 2013, Elsevier. B) Different devices for pulsatile drug release: (a) Multilayered devices for sequential drug release. Reproduced with permis-
sion.[247] Copyright 2015, Wiley-VCH; (b) Multiwell silicon-based drug-release device for electrochemically actuated drug delivery. Reproduced with
permission.[30] Copyright 1999, Nature Publishing Group; (c) The microchip-based drug delivery device (MicroCHIPS). Reproduced with permission.[250]
Copyright 2006, Nature Publishing Group. C) Actuated devices for pulsatile drug delivery: (a) Magnetically triggered nanocomposite membranes with
thermoresponsive nanogels and superparamagnetic nanoparticles. Reproduced with permission.[254] Copyright 2011, American Chemical Society;
(b) Magnetically triggered device for reversible controlled drug delivery. Reproduced with permission.[97] Copyright 2009, Wiley-VCH; (c) Ultrasound-
based approach for triggering implanted devices: cross-section diagram (top) and top-down photograph (bottom). Reproduced with permission.[255]
Copyright 2016, Nature Publishing Group.

triggering reaction. When an electric potential is applied to the
gold membrane in a solution containing physiological levels of
saline, the anode membrane dissolves away and releases the
encapsulated drugs which could be loaded in solid, liquid, or gel
form. The release mechanism of this device allows the precisely
timed release of drugs from an implant. This prototype was fur-
ther improved by using the electrothermal method to open res-
ervoirs instead of electrochemical dissolution approach.[95,249,250]
The metal membrane (gold or a platinum and titanium lami-
nate) can be removed by resistive heating from an applied
current within microseconds, which is much faster than the
electrochemical method. The implantable microchip-based
drug delivery device developed by MicroCHIPS (Figure 9B(c))
has been demonstrated to have an excellent in vitro to in vivo
release rate correlation.[251,252] It has also been tested in human
by being implanted subcutaneously in the abdomen to deliver
pulsatile parathyroid hormone for osteoporosis treatment.[253]
Some other devices were designed for the pulsatile delivery
of therapeutic agents without the integration of a microbat-
tery, multiplexing circuitry, and memory into the device. One

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Figure 10.  A) Magnetically triggerable microspouter with a magnetic sponge for on-demand drug delivery. Reproduced with permission.[257] Copyright
2017, Wiley-VCH. B) Intracerebral drug delivery system (the NeuroMedicator) with microprobes. Reproduced with permission.[264] Copyright 2012,
Springer. C) Microfluidic reciprocating intracochlear drug delivery system with a flow pump and a miniature electromechanical actuator. Reproduced
with permission.[270] Copyright 2014, Royal Society of Chemistry. D) Exploded view of an intraoral drug delivery device and its prototype (“IntelliDrug”)
embedded in a partial lower jaw denture.[271,272] Reproduced with permission.[272] Copyright 2009, Springer.

type of such device was based on composite membranes made
of an ethylcellulose film with embedded thermosensitive
poly(n-isopropyl acrylamide) nanogels and magnetic nanopar-
ticles reported by Hoare et al. (Figure 9C(a)).[96,254] When the
membrane was heated by the embedded magnetic nanoparti-
cles in the presence of an oscillating magnetic field, the nano-
gels shrank, increasing the permeability of the membrane for
drug release from the reservoir. A thermally responsive hydrogel
(N-isopropylacrylamide-co-acrylamide (NiPAAm-co-AAm)) was
also used for stimuli-controlled drug release. The hydrogel
was loaded with drugs and placed in a capsule. When heating
the capsule above body temperature with a focused ultrasound
transducer, the hydrogel contracted and released drugs through
the opening of the capsule (Figure 9C(c)).[255] In another device,
Fe3O4 particles are used to block/open the pores of a membrane
covering on the reservoir by controlling their movement inside
the drug reservoir, achieving a reversible switching of drug flux
and finally pulsatile release (Figure 9C(b)).[97]
Drug release from the above devices is through a diffu-
sion manner after the device outlet is opened remotely, while
pump-like release mechanisms allow a quicker release by
pumping drug solutions out in a short time. By incorporating
magnetic materials with soft PDMS membranes, Chiao and co-
workers have developed various microdevices for on-demand
release of drugs with remotely controlled magnetic fields. In the
button-like device (Figure 3D),[104,105] PDMS was incorporated
with magnetic microparticles, forming a magnetic membrane
to seal the drug-containing reservoir. When the membrane
deflected under external magnetic fields, the drug was released
through a microaperture at the center of the membrane. In
the cylindrical device (Figure 4B),[109] a piece of rectangular
magnetic block was bonded at the center of PDMS mem-
brane facing the reservoir, which created larger deformations
of the membrane under the same magnetic field compared
to the device with the magnetic membrane. In their recent
reports, magnetic PDMS sponges made of porous PDMS scaf-
folds with embedded magnetic microparticles were fabricated
and used for remotely triggered drug release.[256,257] A power-
less drug delivery device termed a microspouter was prepared
to provide active and precise control of localized drug delivery

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www.advancedsciencenews.com
on demand (Figure 10A).[257] The microspouter consisted of a
magnetic sponge to provide the force for drug release based on
magnetic field-induced reversible deformation, a reservoir for
the sponge installation and drug loading, and a soft membrane
for sealing the device. Following application of a magnetic field
to the microspouter, the shrinking of the sponge could trigger a
spouting of drug through a membrane’s microaperture and the
spouted dosage was highly repeatable and adjustable by varying
the number of magnetic actuations or the magnetic strength.
Controlled release was demonstrated in experiments in vitro
and ex vivo. Other research describing magnetic pump for on-
demand drug administration was reported by Lee et al.[103] In
their design, a magnetic actuator equipped with a plunger and
a barrel was employed to pump insulin solution out the device
through the to-and-fro movement of the actuator under an
external magnetic field. The implantable device was designed
to be refilled, which may prolong the service life of the device.
3.4.3. Devices Applied to Specific Sites
Intracerebral Delivery: Poor permeability of high mass and polar
molecules across brain barriers is a major limiting factor for
the pharmacological treatment of many brain disorders. Some
microprobes mostly combined with microelectrodes have been
created to deliver bioactive compounds directly into the brain
or central nervous system and simultaneously record and
manipulate neuronal activity.[258–263] Microfluidic channels are
fabricated within these probes, which can serve as drug depots
and pathways for drug discharge (Figure 10B).[264] Drug release
from such devices can be through ways of passive diffusion and
controlled infusion.
Intracochlear Delivery: Direct delivery of drugs into the inner
ear is required for many therapies.[265] However, the small
space and limited fluid volume within the cochlea present
a challenge for conventional drug delivery systems.[266,267] A
microfluidic reciprocating drug delivery device has been fabri-
cated and tested to overcome this challenge, with which soluble
drugs can be delivered to the cochlea via a single microcan-
nula (Figure 10C).[268–270] The microcannula is connected to a
closed microfluidic reciprocating circuit which allows infusing
and withdrawing a constant volume of drug in a cyclic fashion.
This drug delivery strategy not only ensures in zero net volume
transfer to protect the delicate structures in ear from damaging
changes in perilymph volume and pressure, but also achieves
effective drug delivery through the diffusion and mixing of the
high concentrated drug with perilymph. The effective drug pen-
etration of this device has been demonstrated with in vitro and
in vivo studies in guinea pigs.[270]
Intraoral Delivery: Dental delivery systems today are used for
the local treatment of diseases affecting the oral cavity itself
(e.g., periodontitis or fungal infections), or for systemic drug
delivery through the buccal mucosa. A mechatronic device (the
IntelliDrug device) (Figure 10D) has been designed to be part
of a dental prosthesis for intraoral drug delivery.[271,272] It is an
assembly of a drug reservoir, an electronic control system, sen-
sors, power supply, microvalves, and an osmotic pump. The
water from the saliva enters the system through an osmotic
membrane, generating a pressure in the drug reservoir which
Adv. Funct. Mater. 2017, 27, 1703606 1703606  (24 of 31)
www.afm-journal.de
will switch the microvalve to allow drug release to the buccal
side. This device is convenient to be used, worn, removed,
refilled, or reinserted in the oral cavity without the need for
surgery. It can also be fixed to a mouth guard, which has been
used to deliver naltrexone for the treatment of chronic diseases
and addiction.[273]
3.5. Vaginal/Intrauterine Delivery
Site specific delivery to the female reproductive tract (vaginal
or intrauterine drug delivery) has been studied not only for
contraceptive purposes but also for treatment of diseases and
disorders.[274,275] In addition to localized drug delivery for
antifungal or contraceptive purpose, the vaginal route is suit-
able for systemic administration of drugs due to its dense
vasculature and avoidance of first-pass metabolism and enzy-
matic degradation of drugs associated with the oral route.[276]
Vaginal rings are flexible, circular ring-shaped devices made
of silicone elastomer or thermoplastic polymers for controlled
drug delivery after insertion in the vagina.[277,278] Compared to
common intravaginal drug formulations such as tablets, gels,
creams, and suppositories, vaginal rings allow sustained and
long-term delivery of pharmaceutical substances, which can be
controlled by the user and does not interfere with any sexual
experiences. In simple vaginal rings, drug is homogeneously
dispersed within the circular ring polymeric matrix that gener-
ally is 55 mm in diameter and 4–9 mm in cross-sectional diam-
eter. Such rings sometimes have an initial burst release due to
the fast dissolution and release of drugs at the ring’s surface.
To obtain stable drug release from vaginal rings, devices of new
designs such as sandwich and reservoir type rings have been
developed. The sandwich type rings consist of a drug-loaded
polymer layer positioned between a nonmedicated inner central
core and a nonmedicated outer shell (Figure 11A).[279] The res-
ervoir design is a drug-containing central core surrounded by a
drug-free outer layer of polymer. The drug-containing reservoir
in a single ring could either be an integrated core or several
discontinuous segments for different drugs (Figure 11A(b)),
thereby allowing delivery of multiple drugs from one device.[279]
For example, in the report by Chen et al., hydroxychloroquine,
an anti-inflammatory and anti human immunodeficiency virus
(HIV) drug, was loaded in one or three reservoir segments in a
vaginal ring to achieve near-zero-order release kinetics for the
prevention of HIV transmission and other sexually transmitted
infections.[279] Drug release rates from the sandwich or reser-
voir type rings may be modified by changing the core diameter
or thickness of the nonmedicated coating.
Vaginal rings have proven quite successful in delivery of
small lipophilic drugs such as steroids and spermicidal agents
which are not thermolabile because the manufacturing pro-
cess of vaginal rings usually involves temperatures ranging
80–120 °C. However, it is challenging for conventional vaginal
rings to deliver macromolecular actives and hydrophilic drugs
due to poor solubility and diffusivity of these drugs in the matrix
polymers of vaginal rings. An insert vaginal ring was designed
and fabricated to address this issue, which contained some
compartments in the ring body for placing various drug-loaded
inserts. As shown in Figure 11B, the drug-loaded inserts can
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com www.afm-journal.de

Figure 11.  Vaginal/intrauterine delivery devices. A) Schematic illustrating large- and small-matrix intravaginal rings with drug (orange) dispersed
within the polyether urethane matrix.[279] B) Silicone insert vaginal ring with three equidistant holes for loading drugs (left to right: silicone insert,
directly compressed tablet insert, and lyophilized insert). Reproduced with permission.[280] Copyright 2011, Elsevier. C) Intravaginal flux controlled
pump for drug release through polymer hydration and swelling. Reproduced with permission.[281] Copyright 2014, Springer. D) A schematic image of
T-shaped intrauterine device (Mirena system) for birth control. E) A copper-containing intrauterine device. Reproduced with permission.[285] Copyright
2011, Springer.

be silicone rods, compressed tablets with polymeric excipients,
and lyophilized gels.[280] The study demonstrated that both the
release rate and duration of the model protein bovine serum
albumin (BSA) could be tailored by choosing the insert type and
number. In particular, the lyophilized gel inserts are a proper
matrix for biological agents loading because of the mild manu-
facturing conditions. In another design, a flux controlled pump
(FCP) was suggested (Figure 11C).[281] The FCP is composed
of a cylinder chamber made of a rigid thermoplastic and two
orifices, in which a drug-containing polymer pellet is placed.
The orifices on the chamber allow influx of water/vaginal fluid
to hydrate the pellet and efflux of drugs with the swollen poly-
mers. By altering the property of the swelling poly­mer and ori-
fice diameter, drug release behaviors can be controlled. An oval
shaped vaginal retainer was used with this FCP to achieve a 30 d
sustained release of insulin in female rabbits.
Intrauterine devices are another type of topical drug delivery
systems for women. The geometry of these devices basically

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is designed as an inverted triangle shape to match the uterine

cavity. A commercial product is the Mirena system (Figure 11D),
a small, flexible, plastic device with a T-shaped polyethylene
frame, for sustained releasing of a progestin hormone (lev-
onorgestrel) into the uterus.[282] The vertical part of the device
is a reservoir consisting of a mixture of the drug and PDMS
surrounded by a silicone membrane for controlling drug
release. This device is able to slowly release levonorgestrel for
contraception or treatment of heavy menstrual bleeding for
up to five years. Copper-bearing intrauterine devices are also
widely used for the contraceptive purpose, which can release
cupric ions in uterine secretions to lead the spermatozoa to
lose activities.[283,284] The existing copper-bearing devices are
made by enwinding copper wires on the device body, which
usually causes side effects such as pain and bleeding due to
the fragmentation or rough surface of copper after long-term
use. Incorporating copper nanoparticles in plastic matrix of the
device may achieve controlled release of cupric ions and elimi-
nate the above-mentioned adverse factors (Figure 11E).[285]
Moreover, a custom-made fabrication of such drug-containing
matrix-type devices could be realized with 3D printing
technology.

3.6. Other Delivery Routes and Devices

To bypass the blood–brain–barrier and directly deliver medica-

tion to the brain and spinal cord, a new protocol was proposed
to efficiently deliver drugs by guiding electrophoretic drug par-
ticles to the olfactory region where the central nervous system
is in direct contact with the outer environment. The intranasal
olfactory delivery system is shown in Figure 12A.[286] It contains
an aerosol generator (inhaler) to form small pharmaceutical
particles, a charging chamber to make the particles acquire
a given number of charges, a focusing chamber to allow the
charged particles to form a finely focused beam, and finally
external electrodes to offer the electrophoretic force guiding the
particles to the targeted olfactory receptor. The feasibility of this
method was numerically evaluated in 2D and 3D nose models.
Figure 12.  A) An electrophoretic olfactory drug delivery system consisting
The study results indicated that olfactory drug delivery could be of components with four functions: aerosol generation (inhaler), particle
significantly enhanced after appropriate electrophoretic guid- charging, particle focusing, and particle navigation control. Reproduced
ance of the motion of drug particles. with permission.[286] Copyright 2014, Public Library of Science. B) Schematic
Surgery suture can be used as a drug delivery device to treat procedure for preparation of the drug delivery sutures and the SEM images
postoperative pain originating from the wound and avoid the of the suture. Reproduced with permission.[287] Copyright 2013, Elsevier.
side effects from taking drugs via the oral route or injection.
However, drug incorporation for the suture by solution dip-
ping, drug grafting, or encasing drugs directly in the suture especially for children and the elderly.[288] A hollow-type sup-
thread itself, somehow decreases the mechanical strength of pository was developed by Watanabe and co-workers to solve
the suture needed for wound closure. To address this problem, some drawbacks of conventional solid suppositories, such as
Lee et al. fabricated a drug delivery suture by physically assem- poor dose-volume control and undesired interaction of the
bling a PLGA sheet which contains pain-relief drugs onto a drug with base materials during preparation.[289] The shell of
clinically used surgical suture (Figure 12B).[287] This resulting the hollow-type suppository was made of oleaginous base alone
suture was able to achieve sustained drug release for effective or with gel agents of sodium alginate (Alg-Na), sodium poly-
pain relief without sacrificing the mechanical strength of the acrylate (PANa), or polyacrylate–PANa copolymer (PA–PANa).
suture. The drug release period could be varied for up to 6 d by The suppository could contain the drug (aminophylline) only
modifying the drug-loaded polymer sheet. or the drug with Alg-Na or PANa in the cavity (hollow space).
The rectal route is considered a good alternative to the oral The hollow-type suppository provided a prolonged plasma
route for certain groups of patients with difficulties of dys- concentration of drug in rabbits and could be used for rectal
phagia such as vomiting, nausea, or unconscious condition, administration of various drugs.

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www.advancedsciencenews.com
4. Conclusions and Prospects
Drug release properties from many conventional delivery sys-
tems are currently unsatisfactory or at least, suboptimal, due
to poor drug biodistribution, unfavorable pharmacokinetics,
systemic toxicity, and low therapeutic efficacy. This may arise
from poor design, limited selectivity of materials for drug
scaffolds, weak control mechanism of drug release, or rela-
tively antiquated matrix/device fabrication methods. The fast
development of microfabrication technology such as MEMS
technology has speeded up the rise and evolution of innovative
drug delivery systems which have great potential to overcome
these existing hurdles.[18,290]
Microfabrication technologies allow for greater miniaturiza-
tion of active delivery components such as valves and pumps
and construction of finer structures in a single device, which
may not only reduce the volume and power required for a
portable or implantable device but also introduce new control
mechanisms for accurate dosing, complex release patterns,
and improved drug availability. A variety of microfabricated
devices have been designed and fabricated over the years and
demonstrated to be powerful tools for controlled delivery of
drugs locally or systemically. For example, microfabricated
microneedles have changed traditional drug delivery by trans-
dermal routes, offering painless delivery of macromolecules
such as proteins, to cells, targeted regions, and systemically.
In addition, oral drug delivery microdevices fabricated using
novel MEMS and NEMS technology have exhibited poten-
tial advantages such as patient compliance, rapid availability,
and low cost over the conventional pills.[18] The implantable
microdevices with MEMS elements have shown promise in
sustained and on-demand drug release within the therapeutic
window through an external control manner. There devices pro-
vide alternative routes of drug delivery that can benefit a large
number of patients.
One of the long-term goals for drug delivery devices is to
integrate the controlled drug release functionality with sensor
technology, which can monitor continuously to physiological
changes and deliver precise amounts of therapeutic com-
pounds when needed, forming a closed loop of diagnosis and
therapy.[100,290] This may permit the personalized or custom-
ized medicine to optimize treatment of patients. Additionally,
to produce viable devices for clinical applications, certain issues
such as the biocompatibility, long-term stability of performance,
and replacement procedures, are especially important for new
devices, especially the implantable ones where tissue adhesion
or polymeric degradation products may cause inflammation.
Therefore, careful material selection and more in vivo assess-
ments are certainly needed when developing a new delivery
device in future.
However, microfabrication technologies with incomparable
advantages over other fabrication technologies are assured to
significantly influence the future of drug delivery. This may
have a considerable impact on next generation of life-saving/life-
enhancing medical therapies and the way people live their lives.
Conflict of Interest
The authors declare no conflict of interest.
Adv. Funct. Mater. 2017, 27, 1703606 1703606  (27 of 31)
www.afm-journal.de
Keywords
controlled release, design, drug delivery devices, MEMS, microfabrication
Received: June 30, 2017
Revised: August 2, 2017
Published online: October 9, 2017
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