Review
Special Focus: Intelligent Drug-Delivery Systems
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Micro- and nano-fabricated implantabledrug-delivery systems
Implantable drug-delivery systems provide new means for achieving therapeutic drug concentrations over entire
treatment durations in order to optimize drug action. This article focuses on new drug administration modalities
achieved using implantable drug-delivery systems that are enabled by micro- and nano-fabrication technologies,
and microfluidics. Recent advances in drug administration technologies are discussed and remaining challenges arehighlighted.

Recent discoveries of new molecular and cellulartargets coupled with advancements in genomics,
proteomics and other biotechnologies have accelerated the discovery and development of novel
pharmaceutical compounds. This emerging classof substances includes biologics, gene therapies,
siRNAs, small molecules and other nanoparticle-based therapeutics. However, it is typicallynot compatible with standard oral formulationsor the enteral route of administration because
the drugs are not amenable to the absorptive andmetabolic processes of the digestive tract andliver, respectively. Instead, these drugs are well
suited for parenteral administration, for example, intravenous, intramuscular, intra­ocular,
subcutaneous and intrathecal, to attain either
the desired systemic or local effect. While manyof these novel compounds have high specificity
and potency, they possess limited bioactivity,
relatively short half-life and stability, and otherpharmacokinetic properties that require specialized delivery modalities [1,2]. To achieve thehighest bioavailability and efficacy, many drugs
require continuous or repeated administrationto achieve and maintain therapeutic concentration for the desired treatment duration. In
some instances, physiological barriers such as
the blood–brain barrier must be bypassed. The
vascularization and compartmentalization of
the targeted tissue and/or organ may also determine selection of the drug-delivery modalities.
For conditions that have drug targets distributed to several body regions, such as cancer andviral infections, systemic administration withrepeated or continuous dosing is needed toachieve adequate biodistribution. In cases where
focal treatment is needed, such as intrathecal
chronic pain management, delivery directly
to the site of action offers distinct advantages

including localized area of drug exposure, minimized drug quantity required for treatment, andlimited unwanted systemic side effects [3,4].
Implantable drug-delivery devices are often
relied upon to meet these specialized dosing
challenges and provide a means to achieve thedrug delivery required by these novel pharmaceutical agents and their atypical drug regimen.
Implantable drug pumps are routinely utilized inpharmacokinetic and pharmacodynamics studies, which are now an integral process in drug
discovery and preclinical and clinical evaluationof efficacy [5]. These drug-delivery methods offer
a convenient and cost-effective tool to validate
the targets in vivo [6]. They are also used for comparative effectiveness animal studies of different
dosing regimens such as continuous versus bolus
administration. In the clinical setting, several
implantable dosing methods have become thelast line of treatment for patients suffering fromuncontrollable spasticity or severe chronic pain.
Micro- and nano-fabrication technologies
and microfluidics have enabled implantabledrug-delivery systems that achieve the desired
drug-dosing profile in a miniaturized form factor suitable for surgical placement and operationin vivo. Although there are many drug-delivery
technologies that utilize micro- and nanofabrication technologies such as microneedles
and capsules, the focus of this article is specifically on devices and systems that are surgically implanted and best suited for site-specific delivery. Such delivery technologies areeach associated with a range of performanceand limitations. In turn, each drug treatment
should be matched to the appropriate drugdelivery approach based on the method’s particular strengths and weaknesses. The selection
determinants such as drug formulations and10.4155/TDE.12.132 © 2012 Future Science Ltd

Therapeutic Delivery (2012) 3(12), 1457–1467

Ellis Meng* & Tuan Hoang
Department of Biomedical
Engineering, University of Southern
California, 1042 Downey Way,
DRB-140, Los Angeles,
CA 90089–1111, USA*Author for correspondence:
Tel.: +1 213 740 6952
Fax: +1 213 821 3897
E-mail: ellis.meng@usc.edu

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Key Terms
Microfluidics:

Interdisciplinary field focuses on
the manipulation of fluids at
small scales and exists at theintersection of engineering,
physics, chemistry, biology andmedicine. ‘Micro’ typically refers
to length scale or volume.
Microreservoirs andmicropumps are considered
microfluidic devices.

Micropump: Miniaturized

device that produces mechanicalwork in order to move fluids.
Drug pumps are used only tomove liquids (as opposed togases, which are also considered
fluids).

Microreservoir: Miniaturizedstorage container. The contents
include cells, liquid formulations
and lyophilized drug. The
release of container contents istypically controlled by theproperties or responsiveness ofa membrane structure
integrated into the container.

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stability, routes of administration, and dosing profiles for a given body region will not be
discussed in detail, and is beyond the scope of
this article. These topics for laboratory animals
are reviewed in more detail elsewhere [7,8]. The
focus of this article is to review recent develop­
ments in implantable drug-delivery systems thatare enabled by micro- and nano-fabrication
technologies.
Implantable drug-delivery devices
Implantable drug infusion pumps have been in
use for many years and for both preclinical andclinical applications. Typical implantable systems possess three fundamental components:
drug container, drug release mechanism and an
implantable packaging. Certain systems may
include a catheter for directing the drug, either
systemically or to localized therapeutic targets.
The differentiating factors include the selection ofmaterials that define the drug release mechanism
aswell as the driving force for the drug release.
Two classifications will be reviewed: reservoirbased drug-delivery devices and drug-infusion
micropumps.
Compared with oral or other external drug
infusion modalities such as external drug-infusion
pumps, syringe needles and needle-free injection
devices, implantable drug-delivery systems are
typically associated with three main drawbacks,
which are higher cost, surgical placement andspecialized training to ensure safety and proper
implementation. However, some pharma­ceuticalagents (e.g., drugs with short half life or rapid
metabolic/degradation rates) are not effective or
available for oral or external infusion methods.
In addition, physiological barriers may limit theaccessibility of target treatment sites within the
body by these routes. When chronic administration is necessary to these remote targets such as
in intra­thecal delivery of medications for intractable chronic pain, implantable infusion pumps
are the only practical option. The many benefits of
implantable drug-delivery devices include minimization of side effects, better titration of drug
administration, predictable duration of action,
automation in dosing operation, ambulatory use
and improved compliance to the prescribed drug
regimen. These features enable controlled, continuous release of therapeutics over extended periods(zero order release profile), period release following circadian rhythms or in response to therapeutic measures (nonzero order release profile).
Implantables also achieve and sustain higher drugconcentrations within localized areas, which are
Therapeutic Delivery (2012) 3(12)not easily accessible with peripheral drug administration. In addition to the ‘set-and-forget’ benefits, implantables also avoid the constant discomfort and infection risks associated with chronictranscutaneous catheter drug-delivery techniques.
Conventional technologies for research& preclinical use
For laboratory animals and preclinical research,
conventional technology-based implantables
have become invaluable tools. The Alzet® pump
(ALZA/Durect Corp., Cupertino, CA) has
been the gold standard in implantable, controlled-release drug delivery in animal research(i.e., mice and rats) since their introduction in1977 for a wide range of experimental agents(featured in over 13,500 references) [101]. This
pump operates on the basis of osmotic principles,utilizing the osmotic gradient generated following subcutaneous implantation. The gradientdraws extracellular water across a semipermeable
membrane into an expandable chamber containing an osmotically active agent (e.g., NaCl). Thisin turn applies pressure to a collapsible drug reservoir, and induces drug release at a constant rate
through an orifice, which may be connected to acatheter to allow proper physiological placementof the delivered drug. The iPrecio® microinfusion
pump (Primetech) has integrated electronics forpreprogramming of complex drug regimen prior
to implantation [9]. This microinfusion pumputilizes a battery-powered motor to drive a set ofpins, generating a peristaltic actuation to controllably pump the soluble drug out of a reservoir. These implantable delivery pumps provide
minimal animal handling, stress-free dosing andreduction in needle-injury risks.
Conventional technologies for clinical use

Several US FDA-approved implantable drugdelivery systems are currently in use for a selectnumber of indications. Most clinical applications
address chronic drug therapy for palliative care.
Insulin, steroids, chemotherapeutics, antibiotics, analgesics, contraceptives, heparin, vaccinesand hormones are examples of drugs that may
benefit from the use of implantable pumps [10].
Duros® (ALZA/Durect Corp.) is a nonbiodegradable osmotic pump for clinical use. It has
been paired with Viadur® (leuprolide acetate,
Bayer, FDA approved in March 2000) for thepalliative treatment of prostate cancer for a 1 year
duration, offering an alternative to frequent leuprolide injections; however, this product was discontinued. Duros® was explored for the delivery
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Micro- & nano-fabricated implantable drug-delivery systemsof sufentanil, an analgesic, using the Chronogesic® Pain Therapy System for chronic pain management [11] and for exenatide (type 2 diabetes)
and w-interferon (Hepatitis C) [102]. ALZAmer®
depot system (ALZA/Durect Corp.) is an injectable biodegradable polymer containing lyophilized proteins and small-molecule compounds.
Similar biodegradable systems for sustaineddelivery include SABER™ Delivery System(Durect Corp. Cupertino, CA), Atrigel® (QLT,
Inc., Vancouver, Canada), Durasert™ (pSivida)
and Gliadel® wafer system (MGI Pharmaceutical,
Eisai, Woodcliff Lake, NJ, USA).
Actively driven drug-infusion systems are also
in clinical use for long-term chronic administration, relatively large drug-volume dosing, andaqueous drug formulation. Approved for severe
spasticity (2003) and chronic pain (2004), Synchromed® II (Medtronic, , Minneapolis, MN,
USA) utilizes a hybrid pumping mechanism, pressurized gas expansion combined with a batteryoperated peristaltic action. The Codman­® 3000
(Codman and Shurtleff/Johnson and Johnson,
New Brunswick, NJ, USA) utilizes a pressurizedgas expansion mechanism. Prometra® (Flowonix,
Medical, Mt. Olive, NJ, USA; FDA approved in2012) and Medstream™ (Codman and Shurtleff/Johnson and Johnson; FDA approved in2011) utilize a similar pressurized gas expansion
actuation but regulates drug flow with batterypowered valves. Limited telemetric capabilities
have been incorporated into most pumps forin-clinic programming by the care provider. A
number of pumps with integrated sensors, forexample, AMF Medallion (Alfred Mann Foundation, Valencia, CA, USA), which are currently
under development or clinical testing will not be
reviewed. Implantable pumps with conventional
dosing mechanisms offer a suite of desirable features. These implantable infusion systems offer
ease of use by the clinician and ambulatory use
for the patient to improve comfort, mobility andquality of life. By contrast, conventional catheters
driven by external pumps may require significant
assistance for operation by healthcare specialists
and in the clinical environment, limiting practical ambulatory use in home environments.
Remaining challenges include dosing accuracy,
MRI-compatibility, pump size and infection risks
associated with the surgical procedure.
Micro- & nano-technology enabled

implantable drug-delivery systems
Micro- and nano-technology has enhanced thedesign features of implantable systems. The
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size of individual components as well as wholesystems has been miniaturized to a minimallyinvasive implantable form factor. Surface modification techniques and biocompatible material
selection have been utilized to provide a stable,chemically inert interface between the implant
and the body. These technologies have enabled
tunable drug-release mechanisms to achieve
great control of drug-release profiles including
programmable, cyclic, pulsatile or continuous.
Reservoir-based drug-delivery devices
Microfabricated reservoirs (microreservoirs)
are simple drug containers that allow temporarystorage of drug payloads prior to their releasein the body. The drug may be released either
slowly over time through nanoporous membranes, orifices located in the reservoir wallor at precise times when an impermeable sealis removed, to allow drug release by diffusion
or expulsion through other transport processes.
Reservoir-based delivery devices are advantageous for their simple format and often simple
implementation. However, in current embodiments, drug payloads cannot be replenishedlimiting the therapeutic lifetime of such drugreleasing implants. Illustrations describing the
drug-release mechanism for passive diffusionbased and actively driven reservoir devices areshown in Figure 1.
Passive diffusion-based reservoir devices

The earliest micro- and nano-fabricated reservoir delivery systems relied on simple diffusionmediated transport of drugs stored or produced
within. The precise control of feature dimension
was exploited in in silico-based immunoisolating capsules, consisting of a nanoporous membrane integrated into a reservoir. Pancreatic islet
cells contained within these reservoirs achieved
glucose-responsive insulin delivery through themembrane, while immunologic cells and antibodies were excluded by virtue of size from interacting with the transplanted cells [12–14]. As analternative to joining multiple micro­fabricatedsubstrates to form reservoirs, recently, a method
to form self-folding polymer polyhedral containers to house particles and cells for drug delivery was described [15]. Containers were initiallyfabricated as a flat structured sheet that folded
into the final polyhedral shape following heatapplication.
Drug reservoirs microfabricated by etching
into silicon substrates can alternatively be cappedwith temporary thin metallic membranes. The
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A Passive reservoirs
Reservoir

Drug

Hydrogel

Cells

Nanoporous

Biodegradeable

Metal

Hydrogel

B Active reservoirs
P1

Actively driven reservoir devices

P2

Electroyltic
bubbles

Thermalbubbles

P2 > P1

Magnetic

Figure 1. Reservoir-based drug-delivery approaches. (A) Four embodimentsof passive-diffusion-based reservoir drug-delivery devices. The release rate and/or
onset of delivery of drug stored or produced in the reservoir is regulated by amembrane that may be modified to be nanoporous, biodegradable,
electrochemically or electrically removable (metal thin film), or shrunken byapplication of thermal energy (hydrogel block valve). (B) Four embodiments ofactively driven reservoir drug-delivery devices. The mechanism by which drug isactively displaced from the reservoir is depicted including electrolyticallygenerated bubbles, thermally generated bubbles, preloaded pressure difference,or magnetic modulation of membrane displacement and delivery orificedimensions.

lyophilized drug contained in the reservoirs was
selectively exposed for diffusive release by electrochemical dissolution [16,17] or electrothermal
degradation of the membrane cap [18]. Later, thedrug-reservoir array chip was integrated withwireless electronics to allow pulsatile releaseof leuprolide in canines for several months[19]. After more than a decade of development,
MicroCHIPS™ (MA, USA) recently reported
first-in-human results using an investigational
device consisting of two chips with ten reservoirs
each for the delivery of the human parathyroid
hormone fragment in the treatment of osteoporosis [20]. This line of work demonstrated thepossibility of pulsatile release of discrete drug
amounts at distinct time points.
Temporal control of drug release was alsoachieved from reservoirs gated with thermo­
responsive hydrogel valves. Valves were activatedwirelessly by inductive coupling between metallic coil pairs. Heat dissipation following wirelessactivation from the planar microfabricated coils
integrated with the reservoirs resulted in reversible shrinking of the hydrogel valves to allow
drug release [21].
In addition to electronically controlled release,biodegradable membrane seals have also been
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explored, in which physicochemical properties
control membrane dissolution rate and the onsetof drug delivery [22–24]. The use of resorbablepolymer membranes such as poly(l-lactic acid)or poly(lactide-co-glycolide) eliminates the needfor electronics. Delivery of pulses of dextran,
heparin, human growth hormone, glucose andglycerol was demonstrated using arrays of reservoirs capped with membranes having differing
molecular masses to control release time [23,24].

Therapeutic Delivery (2012) 3(12)Diffusion-based drug-releasing reservoirs arelimited by small dose volumes, the slow release
rate and dependence on favorable physiological conditions. Therefore, active mechanisms
to expel drugs following removal of the membrane seal were proposed. To improve upon theconcept of exposing the drug loaded into siliconwells following electrochemical dissolution of ametal capping film, electrodes were integrated
into the interior of the well to enable the drug
solution to be expelled by electrolysis. Deliveryof vasopressin intended for emergency treatmentof hemorrhagic shock was achieved, but only
37% of the drug solution was recovered fromreservoirs (15 µl) and chemical degradation of
the drug during electrolysis of the solution wasobserved [25]. Another group proposed an alternate concept, using thermal energy to generate
bubbles to both mechanically rupture the sealing
membrane and rapidly expel drug from the reservoir (20 µl). The thermal energy was provided
by resistive heating of a metallic resistor at thebottom of the reservoir and the mechanism could
recover 85% active drug with minimal thermal
degradation [26].
Rapid release of reservoir contents can also be
achieved by prepressurizing the reservoir. Temporary valves formed from polymer membranes
with metallic resistor structures were robust
enough to securely contain reservoir contents.
A short current pulse applied to the metallic
resistor was used to thermally degrade the polymer membrane and allow release of reservoir
contents [27,28].
An alternative to removal of membrane capping of the drug reservoir is to control the releaseof drug by modulating the size of a tiny aperture through which the drug is released. Sucha device was described for intraocular deliveryof low solubility docetaxel, intended for drug
management of diabetic retinopathy. The drug
was contained in a polymer reservoir sealed on
one side with an elastic, magnetically responsive
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Micro- & nano-fabricated implantable drug-delivery systems
membrane containing the release aperture. Wireless activation with an external magnetic field
deformed the membrane, resulting in release of
discrete drug volumes (171 ± 16.7 ng) [29].
Drug-infusion micropumps
Micropumps can be classified as either passiveor active, as distinguished by the mechanism
employed to displace and deliver the drug.
Active pumps require electrical power for operation whereas passive pumps utilize alternative
sources of energy (e.g., chemical or mechanical) to supply the pressure differential to drive
drug pumping. Infusion pumps, although more
complicated than simple reservoirs may, in somecases, be refilled to allow chronic dosing. Recent
work on drug-infusion micropumps, with anemphasis on implantable pumps is reviewed.
Passive micropumps

Passive micropumps broadly include mechanisms utilizing osmosis or prepressurized reservoirs. As these do not require a separate electrical
power source, the overall size of the pump can be
minimized. Both osmotic and spring-powered
passive micropump concepts are illustrated in
Figure 2 .
Osmotic micropumps

The osmotic mechanism, as described previously,
allows continuous delivery of agents independent| Reviewof their specific molecular conformation, physical properties and chemical properties. These
pumps do not require electrical power. However,its simplicity also imposes limits on the control
of dosing profile and timing; once the osmotic
gradient is initiated, the osmotic pumps operate continuously with constant rate release andcannot be turned off. The osmotically active
agent cannot easily be restored to its originalstate and therefore, osmotic pumps are typicallysingle use.
A microfabricated osmotic pump wasreported containing a 2 ml drug charge capableof slow release (< 2 µl/h) release. While similar
in operation to an Alzet pump, this micropump
was produced using microfabrication methods
resulting in a stacked and planar arrangement of
the osmotic chamber, drug reservoir and delivery port [30,31]. Subsequent work carried out by
one of the authors resulted in an larger cylindrical osmotic piston pump for release of bone morphogenetic proteins to facilitate bone growth inmaxillofacial distraction osteogenesis [32].
A biodegradable osmotic implant for localized delivery of bFGF with application in tissue regeneration was reported (40 ng/day) [33].
Among osmotic micropumps, this particulardevice is unique for its synthetic biodegradable
polymer construction. However, difficulties incontrolling the material properties, especially its
controllable degradation, still remain.

A Osmotic
Drug

Diaphram
Osmotic driving agent
Water flow

Semipermeable membrane
B Spring powered

Mechanical compression

Drug

Valved conduit

Figure 2. Passive micropumping approaches. (A) The operation of an osmotically powered
pump. A semipermeable membrane regulates water uptake by the osmotic driving agent, which
results in a pressure increase that deflects a flexible diaphragm. The diaphragm in turn displaces the
drug stored in the adjacent reservoir. (B) A spring-powered pump concept. External mechanicalcompression of a compliant drug reservoir provides the pressure differential required to displace
drug from the reservoir. Drug delivery is regulated by a valve in line with the pump outlet.

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Key Terms
Microelectromechanicalsystems: Systems consist ofcomponents having nano- tomilli-meter scale features andare produced using specialized
micro- and nano-fabrication
methods, typically performed inbatch processes that originate
from the integrated circuit
industry. These tiny devices
benefit from interesting physicalphenomena that dominate at
small size scales.

Diaphragm: Thin mechanicalelement anchored at its
periphery and constructed of asemi-flexible material that canbe used to displace fluid in
microreservoirs andmicropumps.

Spring-powered micropumps

Few have investigated mechanical springloaded mechanisms to drive drug displacement,
but such pumps offer distinct advantages overosmotic and other actively driven pumps. The
Spring Zone® insulin pump uses a spring-based
mechanism, Intellispring™, which allowed
elimination of the motor found in other pumps
to achieve the smallest size and low weight [103].
An alternative to conventional implantable intrathecal drug-delivery pumps is the spring pressurized dual-reservoir-pump system, which isenabled using microfabricated parts [34–36]. Thissystem was introduced to allow multidrug capability for polyanalgesia, which offers significant
benefits over monotherapy in the managementof chronic pain [37,38]. The use of springs simplifies the system design. Polymer drug reservoirs
were pressurized using external springs and thedrug was accurately metered using smart, electronically activated microvalves and delivered
through a single catheter [35]. The delivery rateof pain medications could be monitored usingpressure sensors integrated on the same pieceof silicon as the microvalves; such integration
affords great advantages in overall system miniaturization. Measurement of drug flow allowed
compensation against changes in spinal fluidpressure.
Active micropumps

A major advantage of microelectromechanicalsystems technologies is the ability to miniaturize
electronically controlled pumping mechanisms
into tiny form factors suitable for implementation in implantable or external transdermal patch
pumps. Various methods have been explored forpumping at the microscale including nonmechanical mechanisms, such as electrohydrodynamic, electroosmotic, ultrasounic and thermocapillary mechanisms [39], as well as mechanicalmechanisms such as electrostatic [40–44], piezoelectric [45–55], electrochemical [56–64], thermal[65–69], shape memory alloy [70,71], bimetallic
and electromagnetic mechanisms. These andother drug-delivery mechanisms are exploredin more depth in several engineering-focused
reviews [72–75].
Herein, the focus will be on the more commonly employed mechanical pumps in which a
flexible membrane is actuated using one of theaforementioned mechanical driving mechanisms(electrostatic, piezoelectric, electrochemical orthermal) to displace liquid drug from a reservoir. These driving mechanisms are distinctly
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Therapeutic Delivery (2012) 3(12)different from those used in meso- and milliscale devices and are favored for specific advantages gained as a result of miniaturization [76].
These electronically controlled micropumps
allow great control over the onset, profile andtermination of drug administration. However,moving components, such as valves and pumping diaphragms are required, which complicates
their manufacture. The reduction in power consumption achieved with miniaturization introduces the possibility of wireless-powered and-operated pumps, while eliminating the need for
implantable batteries. The two common micropump formats, reciprocating and peristaltic, aregenerically depicted in Figure 3.
Electrostatic micropumps

A significant mechanical force results from thecoulombic attraction between closely spaced (atthe micron scale) but oppositely charged metallic plates. If one or more of the plates is movable,
then this electrostatic attraction phenomenon canbe controlled by modulating the charge on one
or more of the plates, as to sequentially squeeze
out and resupply fluid between the plates sourced
from a reservoir. Therefore, packets of fluid aredelivered in a pulsatile manner. Both reciprocating diaphragm [40,41] and peristaltic (multiplereciprocating diaphragms) [42] type electrostatic
micropump configurations have been explored. In
peristaltic pumps, the reciprocating diaphragms
are linearly arranged, controlled individually andtriggered in a prescribed sequence to coordinate
the action of the diaphragms, so as to achieve net
pumping in one direction. As opposed to reciprocating pumps that require mechanical valves
to regulate fluid flow direction, each diaphragm
acts as an electronically controlled valve that can
shut off the fluid flow path to prevent reverse backflow into the reservoir. Electrostatic mechanisms
enjoy fast mechanical response and low power
consumption but act over short distances, which
limits the fluid volume that can be displaced witheach stroke. Moreover, high voltages are requiredfor operation.
Although electrostatic pumping has been
widely explored for microfluidic applications,the aforementioned limitations impede their use
in drug-delivery applications. To improve thelinearity of reciprocating diaphragm electrostatic
micropumps, a circular disk was attached to thediaphragm to better define the drug volume
displaced [41]. A promising peristaltic electrostatic pump was designed and simulated, but not
implemented [42].
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Micro- & nano-fabricated implantable drug-delivery systems| Review

A Reciprocating pump
Inlet

OutletOne-way valve

Drug
Diaphram
Actuator

Discharge

SupplyB Peristatic pump
Drug

Actuators

Overall flow
flow direction
direction
OverallFigure 3. Active pumping approaches. (A) The fundamental configuration of a reciprocating
diaphragm pump showing the major components. Pumping is achieved when the reciprocating
actuator (pumping mechanism) alternates between the supply and discharge states. During thesestages, the drug chamber above the diaphragm is filled and emptied, respectively, as regulated by
two opposing one-way valves. (B) Peristaltic pump consisting of three pumping chambers. Eachchamber is separately controlled and activated in a prescribed sequence, such as the one illustrated,
to squeeze drug in one direction.

Piezoelectric micropumps

Piezoelectric materials exhibit the propertyof mechanical deformation that can be controlled by an applied electric field. By attachinga piezoelectric thin film or sheet to a flexible
diaphragm and applying the appropriate electronic control signal, the diaphragm can bereciprocated to pump fluid in a pulsatile manner as in the previously described electrostatic
micropumps. Piezoelectric pumps can also
be configured for peristaltic action. Overall,piezoelectric mechanisms provide high force
and fast mechanical response, but require highvoltages.
Debiotech, a Swiss company, has pioneered
piezoelectric micropumps for medical use including the nonimplantable JewelPump™, insulin
Nanopump™ for diabetes treatment and the
MIP implantable micropump. The JewelPump
is designed to be worn on the skin as a patch andcomes with a 4.5 ml reservoir [104]. The piezoelectric pump contains a pair of mechanical oneway (check) valves to control flow direction andalso a double limiter feature that provides accurate and repeatable control of fluid packets delivered by the pump with each reciprocation cycle[45,47]. An active microport system concept was
proposed by an academic group using a piezoelectric pump for patient-specific, continuous
release of antiangiogenic drugs targeting metronomic and chronotherapies against cancer [54,55].
Piezoelectrically-actuated micropumps were also
described in recent work to address the challenge
future science groupof delivering suspensions containing aggregatesor particles [50,51].
Electrochemical micropumps

The liquid–gas phase change resulting from electrolysis of water offers intriguing possibilities for
implantable pump applications. A small current
or voltage applied through a pair of electrodes towater drives the generation of oxygen and hydrogen gas bubbles, which produce an increase inpressure that can be used to drive a flexible diaphragm. The reaction is reversible and the gases
recombine into water when power is removed
to allow a reciprocating action. In contrast withother mechanisms, electrochemical micropumps
utilize a slightly different configuration thatoffers smooth continuous delivery. The flexible
diaphragms displace the drug directly from thereservoir. The low power consumption coupledwith large achievable mechanical displacement
are unique advantages of this method.
Electrochemical micropumps were describedfirst for ocular drug-delivery applications [56–59]
followed by gene delivery to treat cancer [60,61]
and experimental drug-delivery paradigms insmall animals [62–64]. These electrolysis pumps
share a similar format: a flexible bellows diaphragm is adjacent to a drug reservoir with anattached delivery catheter. The bellows diaphragm houses a pair of electrodes and water(serving as the electrolyte in the electrochemicalcell). The catheter may also be connected to aflow regulating valve that prevents backflow of
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fluids into the reservoir. The magnitude of theelectrical power source, usually current, is linearly correlated to the resulting flow rate and so awide range of rates are accessible. In ocular drugdelivery applications, small concentrated doses ofdrug (approximately in the nanoliter to microliter range) are instilled by the pump directly into
the intraocular space to avoid blood retina andcorneal barriers that limit penetration of oral or
topical drugs while avoiding trauma sustained
under repeat intraocular injections [77,78]. Pumps
were refillable to allow practical use in the treatment of chronic, incurable eye disease without
requiring repeat surgical procedures.
The ability of electrochemical micropumps
to deliver larger drug doses was demonstrated
in two applications. To sensitize cancerous cells
to radiation, small interfering RNA targeting
SPHK1 was electrostatically conjugated with gold
nanorods and locally delivered to tumors (daily
dose of 50 µl over 30 min) in the hind flanks
of nude mice [60,61]. Greater tumor regression
was demonstrated over delivery of conjugates byneedle injection and diffusion. An ongoing challenge in small-animal drug delivery is the ability
to perform administration while still enablingnormal animal behavior and interaction withthe environment. The use of implantable pumps
overcomes the challenges faced by external pumps
with catheter tethers, but only offers low infusion rates. High flow rate intravenous delivery(~100 µl/min) or small boluses (in the microliter
range) with wireless-operated electrolysis-based
pumps was investigated for use in a tetherless selfadministration paragdigm in freely behaving rats
and mice for the study of drug addiction [62–64].
Thermal micropumps

Thermal principles such as thermally induced
material expansion or phase change (e.g., fromliquid to gas) can be used to drive the flexible
pump diaphragm [65,66,68,69]. Expansion thatcan be harnessed for pumping, for example,
may result when a heater is used to apply heatto and expand working fluid that acts on a flexible diaphragm. A thermopneumatic pumpusing a two-phase liquid–vapor perfluoro­carbon
propellant was reported, which included demonstration of pulsatile flow [68]. However, inreciprocating-type thermal pumps, the longthermal time constant, especially during cooling, limits the mechanical response time. Highpower consumption is also of concern especiallyfor in vivo applications in which the pump ishoused entirely within the body.
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Therapeutic Delivery (2012) 3(12)Thermal micropumps were investigated for
intracerebral delivery to freely moving rodents,
also with the motivation of enabling natural
behavior which are not possible with current
tethered infusion systems. These skull-mounted
micropumps featured micromachined siliconprobes (8 mm long) with etched orifices (25 µm
diameter) to allow intracerebral delivery of an
NMDA-receptor antagonist to the prefrontal
cortex of rats for studies on visual attention andimpulsivity. Drug was delivered as quantizedpackets (0.3 µl) from individual reservoirs using
the thermally-induced expansion of microspheres(expansion up to 60-times [79]) and modulationof impulsivity was demonstrated [69].
Future perspective
As implantable drug systems are miniaturizedusing micro- and nano-fabricated technologies,
challenges such as the limitation in drug payload
within the small footprint and the availabilityof appropriate drug formulations that are stablefor extended storage at body temperature will
become more prominent. Future efforts requirejoint collaborations with chemists, pharmaco­
logists and pharmaceutical manufacturers at
the earliest design phase of device development.
Another challenge for actively driven implantables will be the power supply with appropriate
weight and size parameters. Future emphasis will
be on high density implantable batteries, wirelesspowering and technologies that scavenge powerfrom natural sources such as body temperature, body motion or tissue micromotion. New
material selection and packaging approaches
will be developed that integrate form and function into compact implants with advance dosing control beyond passive diffusion. Potentialrefinements may include flexible or dissolvablemicroelectronic sensors, actuators and integrated
implants. As more dynamic biological processes
and biorhythms are identified, advance temporalcontrol of repeated dosing, for example, metronomic dosing, will become increasing in demandby patients and care providers for chronotherapy
and drug therapy synchronized to biologicalcycles, for example, insulin production.
With future advancements in affordable andpersonalized genomic and proteomic profiling, innovative drug-delivery systems will beneeded to realize the full potential of personalized medicine and drug therapy. These futuresystems must be capable of more complex drug
regimens and improved time-resolved chrono­
therapies to provide better clinical outcomes with
future science group

Micro- & nano-fabricated implantable drug-delivery systems
minimized unintended side effects. Micro- andnano-fabricated technologies will continue todrive innovation towards greater functionality,
packaged in a miniature form factor. Integrated
electronics and sensors for diagnostics will provide feedback-controlled drug delivery – drug
release that is modulated or triggered in responseto an acute marker detection or biological event.
This will require major advances in in vivo sensor technology as well as greater knowledge of
which markers are appropriate to track. Two-way
telemetry will enable drug-delivery systems tolog dosing events coupled with other relevant
physiological events and real-time connectivity
with electronic medical health systems to facilitate access for instantaneous review and ana­lysis
by the patient, care giver and clinician. Emergence of wireless/telehealth will allow the migration of drug administration by implantable,
portable and wearable systems from the clinicalsetting to the home-care setting. Wearable and| Review

implantable hybrid dosing systems will be industrial designed for both aesthetics and mobility.
Next generation drug-delivery systems will
provide improved capability to capture, shareand act upon actionable medical information
to mediate improved clinical outcomes in a
potential therapeutically effective care.
Financial & competing interests disclosure
The authors acknowledge the NIH (R21EY018490,
R21DA026970 and R01NS050171), Qualcomm/TATRC
Wireless Health Innovation Challenge and Wallace H
Coulter Foundation for financial support. The authors havea financial interest in Fluid Synchrony LLC (Alhambra,
CA, USA). The authors have no other relevant affiliations
or financial involvement with any organization or entitywith a financial interest in or financial conflict with thesubject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production ofthis manuscript.

Executive summary
Implantable drug-delivery devices
Peripheral drug administration methodologies and associated technologies offer limited control of dosing profiles.

Implantable systems offer long-term access with repeated dosing of remote therapeutic targets.

Implantable systems with conventional technologies suffer from many challenges, which limit their application.

The implementation of micro- and nano-technologies for implantable drug-delivery systems offer new possibilities in achieving control ofin vivo drug release.
Reservoir-based devicesThe simplest miniaturized implantable drug-delivery systems feature a reservoir with a membrane that controls the onset or rate of drug
administration.

Reservoir-based drug-delivery systems may require additional energy to overcome the diffusion limited transport of drug in theimmediate vicinity of the implant.
Drug-infusion micropumps
Drug infusion micropumps utilize a wide variety of mechanisms to propel drugs to in vivo targets.

Each mechanism must be carefully selected based on the dosing profile desired and other system-level constraints.



Chronic-controlled drug administration is possible with drug infusion pumps having refill capability.
new directions. Nat. Rev. Clin. Oncol. 7(8),455–465 (2010).

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Websites
101 Alzet® Osmotic pumps.

www.alzet.com
102 Intarcia therapeutic, Inc.

www.intarcia.com
103 Spring: simple and clever diabetes solutions.

www.springnow.com/insulin-pumps.html
104 Debiotech, Switzerland.

www.debiotech.com

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