IMPLANTABLE MEMS DRUG DELIVERY DEVICE FOR CANCER
RADIATION REDUCTIONHeidi Gensler1, Roya Sheybani1, Po-Ying Li1, Ronalee Lo1, Sutao Zhu2, Ken-Tye Yong2, Indrajit
Roy2, Paras N. Prasad2, Rizwan Masood1, Uttam K. Sinha1, Ellis Meng1
1
University of Southern California, USA2
University at Buffalo, The State University of New York, USAparticular model and cannot be altered following
implantation. Delivery duration varies from 1 day to 6weeks, and is therefore not adequate for extended chronicstudies or therapies [www.alzet.com/]. The Med-E-CellInfu-Disk™ is too large for practical implantation in miceand the flow rate is factory set. In addition, the disposabledevice requires a battery and can only be used once forcontinuous drug delivery [www.medecell.com/]. Other
conventional drug delivery methods include tether
infusion and vascular access ports, but these require
frequent handling of laboratory animals and constant care
to prevent infection and other complications. Many
MEMS pumps have been reported but none are refillable
and meet the low power requirements of our application.

ABSTRACT
We present the first implantable MEMS drug delivery
device that includes an electrochemical bellows pump,refillable drug reservoir, and dual regulation valve.
Multiple drug pump configurations were fabricated,assembled, and tested. Delivery of agents for cancer
radiation reduction was demonstrated. In vivo chronicdelivery of radiation sensitizing agents in the form ofsmall interfering (siRNA)-gold nanorod complexes(nanoplexes) directly to tumors induced in mice wasachieved. Radiation therapy in conjunction with active
drug pumping by electrolysis actuation resulted insignificant reduction of colon cancer tumor (HT29) size(~50%) over diffusion-based delivery and intravenous
injections. To our knowledge, this is the first MEMS drugdelivery pump suitable for safe, efficacious, and local
delivery of short half-life siRNA in vivo.

DESIGN
Our drug delivery approach utilizes low powerelectrolysis actuation to deliver drug from an adjacentreservoir through an integrated cannula directly to the siteof therapy (Figure 1). The operation principle and refill
method are summarized in Figure 2. A bellows actuator
format [3] was adopted to separate the drug from theelectrolyzed fluid and prevent associated drug
degradation, an undesirable effect reported in our previous
work [4]. The electrochemically-actuated bellows imposesa pneumatic driving force on drug contained in theadjacent reservoir, forcing it out through the delivery
cannula. Both wire and wireless actuator operation werepreviously demonstrated [5]. Integration of a check valve
in the drug delivery cannula with bandpass flow
regulation ensures on-demand and safe dosing [6].

INTRODUCTION
Chronic delivery of therapeutics with spatiotemporal
resolution ensures both adequate bioavailability andtherapeutic efficacy but remains a medical challenge.
Cancer treatment often involves radiation therapy which
results in severe systemic side effects; reduction of thedose of ionizing radiation required for therapeutic efficacy
is sought to limit damage to normal tissues. However,tumor cells may exhibit resistance to radiation-induced
damage. The protein sphingosine kinase-1 (SPK-1) is
implicated in the radioresistance of tumor cells [1]. Bysilencing the gene expressing SPK-1, it is possible tosensitize cells to radiotherapy and thus decrease ionizing
radiation dosage. Gene silencing technology using siRNAhas emerged as a promising therapeutic modality for anumber of diseases including cancer, but the lack of asuitable delivery method has limited its use to date [2].
We have developed a MEMS drug delivery pump thatallows direct delivery of siRNA-gold nanoplexes (HNB001) targeting the gene expressing SPK-1 to tumors(Figure 1). Electrostatic interactions between the goldnanorods and siRNA result in formation of nanoplex
structures that facilitate cellular uptake of the siRNA.
These combined events block the formation of SPK-1
leading to radiation-induced apoptosis in tumors for lower
doses of ionizing radiation.

Figure 1: Left to right: Conceptual depictions ofplacement of implanted drug pump to deliver nanoplexes
to tumors, the drug delivery system and components, andthe nanoplex that delivers siRNA.

Several commercial drug delivery devices exist but are
not suitable for our application, which requires periodic
infusion of a drug bolus under low power operation insmall animals (mice). The osmotically-driven Alzet®
pumps are suitable for use in mice but provide onlycontinuous infusion; the flow rate is specific to theElectrolysis was chosen as the actuation method for its
low power consumption (~µW to mW), low heatgeneration, large driving force, and flow rate control
through adjustments of the applied current. The
electrolysis actuator consists of a pair of interdigitatedelectrodes, electrolyte (in this case, deionized (DI) water),

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and a flexible pressure transmitting membrane. A flexible
bellows was chosen over corrugated membranes and flatmembranes; higher deflections were achieved withbellows while imposing lower material stress underpressure loading [3, 5].

Integrated Valve
Dual regulation passive check valves that permit forward
flow only over a predetermined pressure range wereintegrated into the cannula [6]. The valve consists of fourstacked disks (valve seat, pressure responsive valve plate,spacer plate, and pressure limiter) packaged in fluorinatedethylene propylene (FEP) heat-shrink cannula without theuse of any adhesives.
Passive Pump Assembly
Passive pumps were assembled (Figure 4). These units did
not contain the electrochemical bellows actuator or valve
and consisted of the silicone rubber/PEEK base, cannula,and silicone reservoir cavity. Without the actuator, these
implanted pumps provided drug by diffusion from thereservoir through the cannula.

Figure 2: Illustration of drug delivery device operation.

FABRICATION AND ASSEMBLY
Electrolysis Actuator Fabrication and AssemblyElectrolysis electrodes were fabricated on thin film
Parylene C membranes (5 !m thick) supported on asilicon substrate then released. Pt (2000 Å) and Pt/Ti(2000 Å/500 Å) electrodes were patterned using astandard liftoff process described in [3, 5]. Following
removal from the supporting Si substrate, electrodes weremounted on a flexible polyetheretherketone (PEEK)
substrate (Figure 3). Parylene bellows were fabricatedusing a polyethylene glycol (PEG) molding processdescribed previously [3, 5]. Briefly, a silicone rubber
master mold was used to cast PEG bellows forms.
Parylene C (10 µm) was deposited over the PEG form,and then the PEG was dissolved in hot DI water (85 ºC).
The Parylene bellows was filled with DI water andadhered to the electrode substrate with double-sided
pressure sensitive adhesive film (Figure 3). The seal was
further reinforced with epoxy.

Figure 4: Photographs of active and passive drug delivery
systems: (bottom) active device and (top row) passivedevices.
Active Pump Assembly
All parts required to assemble the cancer drug delivery
pump are shown in Figure 5. The assembled bellows
actuator was mounted onto a silicone rubber (MDX44210, Dow Corning) and PEEK base with an integratedcannula (silicone rubber, 0.305 mm ID x 0.610 mm OD,VWR International) and then fully encapsulated by anoverlying silicone rubber reservoir cavity. A small
protruding bump on the reservoir served as a refill port
and allows port location by palpation through the skin.
Furthermore, the refill port was offset from the bellows
below to prevent puncture of the actuator bellows by therefill needle. All silicone rubber parts were fabricated bycasting from laser-machined acrylic molds.
The pump used for the cancer studies did not include avalve. A smaller intraocular drug pump for glaucoma
therapy integrated a valve at the tip of the cannula toprevent accidental dosing and backflow of fluids (Figure6). The valve module was inserted into a short silicone
rubber cannula attached to the pump housing to complete
the assembly of the valved pump.

Figure 3: Parylene bellows actuator assembly process:(left) top view of electrode base assembly, (right) crosssection of actuator components (top) and the assembly
process (bottom).

24phenomenon is not fully understood and is the subject offurther investigation.

Figure 5: Drug delivery device components for assembly
including assembled cancer drug delivery device for small
animals (far right) and (left) a close-up of the electrolysis
electrodes prior to release from silicon substrate.
Figure 7: Electrochemical impedance spectroscopy results
for the Pt-Ti electrode before and after current application.
Fluid Dynamic TestingStand-alone electrodes and fully packaged pumps weretested at the benchtop prior to implementation in animals.
Temporal control of drug delivery was successfully
demonstrated. Stand-alone electrodes (without bellows)
were fixed in a custom laser-machined (Mini/Helix 8000,Epilog, Golden, CO) acrylic test fixture filled withdeionized water. The application of constant current (2400
Sourcemeter, Keithley, Instruments Inc., Cleveland, OH)
induced electrolysis, which dispensed fluid through thefixture output and into a calibrated micropipette (AccuFill 90, Becton, Dickinson and Company, NJ). Flow rates
for the applied currents were observed with a computercontrolled CCD camera (PL-A662, PixeLINK, Ottawa,Canada) attached to a microscope. Figure 8 displays theflow rates generated when current is applied to the Pt/Tielectrodes. A similar method was use to obtain flow rates
and delivered volume from the assembled pumps (insetFigure 8).

Figure 6: Photographs of fabricated drug delivery
systems: (left) device used for cancer studies and (right)
device to be used for intraocular drug delivery. The dark
metal ring in the intraocular device is used to locate therefill port through the conjunctiva (part of the eye wall).

EXPERIMENTS AND RESULTS
Electrolysis Electrodes
Previously reported Pt electrodes deposited on glass
substrates [3, 5] were robust up to currents greater than 5mA (data not shown). Pt electrodes on Parylene, however,exhibit delamination even for modest applied currents.
Improvement in Pt adhesion to Parylene was obtained
following annealing (150 ºC and 205 ºC) and a moreaggressive descum prior to metal deposition. Electrodes
having a Ti adhesion layer were also fabricated and asubset were annealed (200 ºC). Overall, the greatest
improvement in electrode adhesion under applied current
was attained by inclusion of the Ti adhesion layer but
without subsequent annealing of the metal/Parylene
composite film.
Electrodes
werealso
characterizedusing
electrochemical impedance spectroscopy (EIS) (Gamry
Reference 600 Potentiostat and EIS300 Software, Gamry
Instruments) performed in 1X phosphate buffered saline
before and after application of current (0.2, 0.6, and 1.0mA were applied successively to the same Pt/Ti
electrodes). As expected, the impedance decreased withincreasing frequency (Figure 7). After the first applicationof (low) current, the impedance decreased at lowerfrequencies and exhibited little change for increasing
current. This behavior was consistent across the tests inelectrodes and indicates a change in the effective surface
area that is likely a result of electrolysis. This

Figure 8: Electrolysis-induced flow rate (µL/min) in Pt/Ti
electrodes (mean ± SE). Inset shows delivered volume
versus time for an assembled pump (0.5 mA).
In Vivo Drug Delivery
HT29 cells were implanted subcutaneously in both sidesof the flank in nude mice to induce tumors (Figure 1).
Implanted pumps (without a flow regulation valve) (Table251) were operated under constant current (0.78 mA) using acustom battery-powered pack (Figure 9). Reservoirs wereplaced subcutaneously up the middle of the back of thenude mice and the cannula tip was directed to the left
tumor. The right side tumor was untreated.

Additional animal studies are planned including more
cancer radiation reduction experiments and intraoculardelivery for the treatment of glaucoma to prevent
blindness using a valved pump.

Figure 9: Photograph of in vivo testing setup andillustration showing battery pack connection to pumps.
Figure 10: Photographs comparing size of the tumors after
delivery of the controls and nanoplexes from a pump. The
treated tumor is on the left.

Table 1. Cancer drug delivery device specifications.
Components
Dimensions
Drug Reservoir
Diameter = 18 mm
Height = 3.5 mm
Volume = 560 µL
CannulaLength = cut on site
ID = 0.305 mm
OD = 0.610 mm
Pump Electrodes
Width = 20 µm
Gap = 100 µm

ACKNOWLEDGEMENTS
This work was funded in part by the NIH/NEI underaward number R21EY018490 and a Wallace H. CoulterFoundation Early Career Translational Research Award.
The authors would like to thank Dr. Donghai Zhu, Mr. Jun
Seob Shin, and the members of the USC BiomedicalMicrosystems Laboratory for their assistance with thisproject.

Passive pumps (without the bellows actuator) werealso implanted and continuously delivered phosphatebuffered saline, gold nanorods, free siRNA, or nanoplexes
via diffusion. Free siRNA and nanoplexes were alsodelivered by pumping daily for two weeks (~50 !L bolus
infusion). Pumps were refilled two times per week. A
subset of treated tumors was exposed to radiation (100rad). Tumors were periodically monitored and thenremoved at the conclusion of the study. Active delivery of
the nanoplexes in combination with radiation therapy
showed significant tumor regression (~50%) overdiffusion and injection based delivery (Figure 10), withthe greatest effect observed adjacent to the delivery site.

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At the conclusion of the in vivo studies, devices wereexplanted and re-tested. Evaluation under the CCD
camera verified that two of the three devices still
functioned (data not shown). The third device exhibited aperforation in the bellows and some delamination of theelectrodes; the exact cause and time of failure areunknown but may be attributed to the explant procedure.

CONCLUSION
We successfully demonstrated integrated drug delivery
systems consisting of an electrochemical bellows actuator,
a transcutaneous cannula, and a dual regulation valve.
Future work includes in vivo studies with improved,delamination-resistant electrodes and wireless actuation.
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