M3P.119

RAPID AND REPEATED BOLUS DRUG DELIVERY ENABLED BY HIGH EFFICIENCY
ELECTROCHEMICAL BELLOWS ACTUATORS
R. Sheybani, H. Gensler, and E. Meng
Biomedical Microsystems Laboratory, University of Southern California, Los Angeles, CA, USA
Experimentally, generated gas bubbles may occlude
the active electrode surface and prevent contact with theelectrolyte (water) which then leads to a lower pumping
efficiency. Nafion®, a polymer electrolyte coating
possessing high gas solubility, prevents bubble occlusionon the surface of the Pt electrode by allowing rapiddiffusion of gases away from the catalyst surface andresults in a 20% increase in current density [5].
However, the hydrophobic fluorocarbon backbone ofNafion® is electrochemically inactive and may block partof the Pt catalyst surface area, thus reducing the effective
surface area of Nafion® coated Pt electrode by 86%
compared to that of the native, uncoated Pt electrode [5].
The coating layer needs to be thick enough to provide
sufficient effective reaction sites at the interface between
Pt and the Nafion® coating. Optimal performance wasreported for coatings composed of less than 9 wt. %Nafion®. Performance degradation at >9 wt.% Nafion is
attributed to the increasing resistance to gas diffusion into
the electrode or gas desorption from the electrode [6].
Once the current is removed, the gases recombine
through the reverse reactions to form water. However,
due to the large activation overpotential of oxygen
reduction, an electrocatalyst like Pt is required [7]. The
recombination mechanism for Nafion® coated anduncoated electrodes is studied here.
Improved efficiency of electrolysis pumping
electrodes coated with Nafion® (flow rates of up to 141
μL/min at 13 mA) was reported previously [8]. Here, wereport an actuator consisting of an electrolyte-filled
Parylene bellows and these improved electrodes for drugdelivery applications. Specifically, our focus is rapid andrepeatable delivery of drug boluses (one ~100µL dose perminute) to meet requirements for drug addiction studies inmice using a novel self-administration paradigm.

ABSTRACT
For the first time, rapid and repeatable delivery of
precise drug boluses (up to 40 15-second boluses of 19.12± 0.73 μL cocaine within 50 minutes) is achieved with ahigh efficiency MEMS electrolysis actuator. Gas bubble
recombination parameters and drug viscosity wereinvestigated. Nafion®-coated electrodes provided
superior pumping performance (linearity andrepeatability) compared to uncoated electrodes.

KEYWORDS
Bolus drug delivery, drug pump, electrochemical
actuators, Nafion® polymer coating.

INTRODUCTION
Mechanical pumps operating under the principle ofelectrolytically generated pneumatic actuation enable
many interesting biological and medical applications dueto their low power consumption, low heat generation,accurate flow control, large driving force, biocompatible
construction and potential for wireless actuation [1].
Electrolysis dissociates water into hydrogen andoxygen gas [2]. When a potential is applied to anelectrochemical cell consisting of a pair of electrodes incontact with water as the electrolyte, reactions occur atboth electrodes. At the anode, water is dissociated into
oxygen gas, cations and electrons, following:.
E° (25°C) = 1.23V(1)The protons are driven through the electrolyte to thecathode where they combine with the electrons travelingthrough the external circuit to form hydrogen gas:
E° (25°C) = 0.00V

DESIGN(2)

The pumping mechanism for bolus delivery is asfollows: constant current applied to the electrode pairresults in electrolysis and a pressure increase that inflates
the bellows which then expels drug from an adjacentreservoir through a delivery catheter (Fig. 1). The current
magnitude and application time can be adjusted to obtain
the desired bolus volume delivery and administration
time. Once the current is turned off, the produced gases
recombine to form water again, allowing the bellows todeflate to its original position. Pumping cycles between
ON and OFF modes then ceases when all the water iselectrolyzed or should be terminated when the bellows isfully expanded.
The Parylene bellows separates the electrolysis
reaction so that the drug is not electrolyzed or diluted by
the electrolyte (DI water) and the hydrogen and oxygen

The net electrolysis reaction is:.
E° (25°C) = 1.23V(3)and entails a 3:2 stoichiometric ratio of gas to liquid andoccurs via the transfer of four equivalents of electronsthrough an external circuit [3]. Generated gases result inlarge volume expansion which can be harnessed for
actuation and thus pumping [1]. The fluid to be pumped
can be directly electrolyzed, however, it is also possible toseparate the reaction from the fluid to be pumped. This isaccomplished by containing the electrochemical reaction
in a chamber having a flexible wall that is adjacent to thefluid to be pumped.

978-1-4577-0156-6/11/$26.00 ©2011 IEEE

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Transducers’11, Beijing, China, June 5-9, 2011

gases produced. This configuration also prevents gases
from entering the body through the catheter which could
potentially have harmful consequences.

configuration (maximum flow rate 100.6 ± 1.11 μL/min
for 1.5 convolution bellows at 10 mA). High flow rates
acceptable for rapid bolus dosing were achieved for all
configurations (Fig. 2).

Figure 2: Current controlled flow delivery with different
bellows configurations performed in a custom test fixture.

Flow rates obtained are listed in Table 1. As expected,
the three bellows configurations had similar flow rates.
Bellows were operated below the elastic limit and did notundergo plastic deformation. However, the one
convolution bellows was irreversibly damaged during thetesting at 10 mA. 2 convolution bellows were chosen forfurther testing due to their higher deliverable volume [9].
Table 1: Flow rate values for 1, 1.5, and 2 convolutions
Parylene Bellows.
Flow Rate [µL/min]Current
1
1.5
2[mA]
Convolution
Convolution
Convolution
17.33 ± 0.17
9.88 ± 0.31
7.04 ± 0.29
217 ± 0.29
19.54 ± 0.54
17.33 ± 0.44544.33 ± 2.42
49.05 ± 3.05
48.17 ± 0.33875.5 ± 1.80
72.44 ± 5.35
73.66 ± 0.44
10N/A
100.61 ± 1.11 87.33 ± 0.83

Figure 1: Electrochemical actuator with drug separating
bellows: (a) operation concept; (b) fabricated Pt electrode on
glass substrate and assembled actuator consisting of bellows,electrolyte, and electrodes.

FABRICATIONInterdigitated Pt electrodes (100 mm wide elements
separated by 100 mm gaps, 8 mm diameter footprint, 300
Å/2000 Å Ti/Pt) were fabricated on soda lime substrates
by liftoff [1]. The electrodes were then potentiostaticallycleaned at ±0.5 V (Gamry Reference 600 Potentiostat,Warminster, PA) in 1X phosphate buffered saline. To
produce a 1μm thick coating, Nafion® (Dupont DE521
Solution, Ion Power, INC, New Castle, DE) was applied
to the electrodes by dip coating twice [8].
Parylene bellows (1, 1.5, and 2 convolutions; 9 mmdiameter) were fabricated as described in [9] and thenfilled with DI water and combined with the Nafion®
coated interdigitated Pt electrodes using double-sided
pressure sensitive adhesive film (3M™ Double Coated
Tape 415, 3M, St. Paul, MN). The seal was further
reinforced with marine epoxy (Loctite, Westlake, OH).

Recombination Studies
Bolus delivery requires power cycling, thus
recombination is an important factor. Recombination ofgas bubbles to water commences once current is removed.
Recombination rate was measured in uncoated andNafion®-coated electrodes (Fig. 3). Electrodes wereclamped in the test fixture, filled with water, and operated
without bellows. Different gas volumes were generated
by varying the current application time (10 mA constantcurrent). When turned on, the electrode-only actuatorpumped water through a calibrated 100 µL pipette andforward displacement of the liquid front was observed.
Recombination volume was calculated based on theobserved backwards displacement of the liquid front after
the pump was turned off.
For uncoated Pt electrodes, recombination isdependent on factors such as available reaction sites andEXPERIMENTS AND RESULTS
Actuator Characterization
Flow rates were measured by clamping the actuator ina test fixture filled with water and weighing pumped
water accumulated over 2 minutes for each bellows

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the slow diffusion of oxygen atoms through water [10]. InNafion® coated electrodes, recombination proceeds fasterin comparison to uncoated ones. This is attributed to therapid diffusion of gas through the Nafion [5] which likely
sets up a gas concentration gradient in water which drives
the diffusion of gases to the Nafion surface. The more
efficient generation of gas may also contribute to thegreater recombination rate. At a sufficiently high gas
volume, the Nafion® becomes saturated andrecombination is reaction limited (as opposed to diffusion
limited). These regimes are apparent in Fig. 4 in which theactuator (Nafion® coated electrode integrated with 2
convolution bellows) was clamped in a test fixture filledwith water and repeatedly turned ON and OFF in 15
second and 1 minute intervals, respectively (10 mA
constant current). Recombination rate was observed toincrease (downward slope in OFF cycle) to a maximum.
Repeatable and accurate delivery of 40 boluses (19.12 ±0.73 μL) over 50 minutes was demonstrated.

relationship between recombination flow rate andremaining drug volume which confirms the diffusionlimited mechanism for this study.

(a)

(b)

Figure 3: Comparison between recombined volume foruncoated and coated electrodes (current controlled flow ratedelivery at 10 mA).

Figure 5: Rapidfire bolus delivery with actuator (2 convolution
bellows, at 10 mA): (a) 15 sec ON/10 sec OFF with 5 minutegaps (inset shows repeatability of delivery) and (b)recombination rate linear with generated gas volume.

Nafion® Coating
Bolus delivery and recombination were studied inuncoated and Nafion®-coated actuators with attached
Parylene bellows (Fig. 6). In [8], Nafion® coating wasshown to result in higher linear flow rates forelectrode-only actuators. This was confirmed with theintegrated bellows. In the electrode–only case, thepolymer coating facilitates recombination and avoids
high pressure buildup that would eventually result in
irreversible mechanical failure (both tearing and plasticdeformation) of the bellows (data not shown).

Figure 4: Actuator ON/OFF test with coated electrodes and 2
convolution bellows (at 10 mA).

Drug Concentration and Viscosity
A 300 μL silicone rubber reservoir was integrated
with the actuator to form a drug pump and study theeffects of drug concentration (and effectively viscosity)
on flow rate. Cocaine was dissolved in 0.9M saline toobtain five different concentrations (0.0, 12.4, 14.0,15.33, 25.73 mg/mL). Solutions were loaded into theRapidfire Bolus Delivery
Rapidfire delivery of 3 boluses at 10 mA (15 secondsON, 10 seconds OFF) separated by 5 minute OFF cycles
was demonstrated (Fig. 5a) with repeatable dosing(25±0.6 μL; Fig. 5a inset). Fig. 5b demonstrates the linear492

authors would like to thank Dr. D. Holschneider, Dr. J.M.
Maarek, and the members of the USC Biomedical
Microsystems Laboratory for their assistance with thisproject.

drug reservoir via syringe and pumped. As expected, flowrate decreased with increasing cocaine concentration (Fig.
7).

REFERENCES[1] P.Y. Li, R. Sheybani, C. Gutierrez, J.T.W. Kuo, andE. Meng, “A Parylene Bellows ElectrochemicalActuator”, J. Microelectromech. Syst., 19, pp.
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[4] D. E. Lee, S. A. Soper, and W. Wang, “Fabricationand mathematical analysis of an electrochemical
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[5] J. Maruyama, M. Inaba, K. Katakura, Z. Ogumi, andZ. Takehara, “Influence of Nafion® film on thekinetics of anodic hydrogen oxidation”, J.
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[6] T. Ioroi, K. Yasuda, Z. Siroma, N. Fujiwara, and Y.
Miyazaki, “Thin film electrocatalyst layer forunitized regenerative polymer electrolyte fuel cells”,
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[7] E. Yeager, “Electrocatlysts for O2 reduction”,
Electrochemica Acta, 29, pp.1527-1537, 1984.
[8] R. Sheybani, and E. Meng, “High efficiency WirelessElectrochemical Actuators: Design, Fabrication andCharacterization by Electrochemical ImpedanceSpectroscopy”, MEMS Conference, Jan 23-27, 2011.
[9] H.Gensler, R. Sheybani, and E. Meng, “RapidNon-Lithography Based Fabrication Process andCharacterization of Parylene C Bellows forApplications in MEMS Electrochemical Actuators”,
The 16th International Conference on Solid-State
Sensors, Actuators and Microsystems, June 5-9, 2011,
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[10]L.K. Verheij, “Kinetic modeling of thehydrogen-oxygen reaction on Pt (111) at low
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Figure 6: Pumping using uncoated vs. coated actuator:
polymer coating enables higher flow rate and predictable
recombination (at 10 mA, 2 convolution bellows).

Figure 7: Current controlled flow delivery of Cocaine (in 0.9Msaline) loaded in a pump at different concentrations (at 8 mA,1.5 convolution bellows).

CONCLUSION
We demonstrated high efficiency MEMS electrolysisactuators capable of rapid and repeatable delivery of
precise drug boluses. Gas bubble recombination
parameters and drug viscosity were investigated.
Nafion®-coated electrodes provided superior pumpingperformance (linearity and repeatability) for pumping andrecombination compared to uncoated electrodes. Future
work will entail integration of wireless power transfer [8]to enable tetherless self-administration of cocaine boluses
for drug addiction studies in freely-behaving mice.

ACKNOWLEDGEMENTS
This work was funded in part by a Wallace H. CoulterFoundation Early Career Translational Research Awardand NIH/NIDA under award number R21DA026970. AnOAI Model 30 UV light source was used in thefabrication of the electrodes featured in this work. TheCONTACT* R. Sheybani, tel: 1-213-821-3949; rsheyban@USC.edu

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