Th1D.004

ELECTROCHEMICALLY-BASED DOSE MEASUREMENT FOR CLOSED-LOOP DRUG
DELIVERY APPLICATIONS
Christian A. Gutierrez, Roya Sheybani and Ellis Meng
University of Southern California, Department of Biomedical Engineering, Los Angeles, CA, USA
ABSTRACT
We present a method for accurate, real-time trackingof drug dose volume in reservoir-based drug pumpsystemsusingelectrochemical
impedancemeasurements. Detection of physiologically-relevant
drug volumes (500 nL−64 μL) and on-the-fly flow ratevariations (2.78−80 μL/min) from a MEMS drugdelivery system were demonstrated. The sensor consistsof two microelectrodes integrated within the drug
reservoir. This method is attractive for its simplicity,sensitivity (0.2 Ω/nL), and wide drug compatibility. The
capability of electronic, real-time dose measurementpaves the way for fully-integrated closed-loop drugdelivery systems.
Figure 1: (Top): Model of drug delivery system, (bottom):actual integrated device

KEYWORDS
Drug delivery, electrochemical impedance, dosetracking.

INTRODUCTION
Controlled administration of drugs can increase drug
therapy effectiveness, in some cases up to 60% [1].
Although growing evidence supports patient-tailored
regimens to achieve optimum efficacy, most drugdelivery devices are preset to deliver drug at a constantrate [2]. This is in part due to the lack of electronic
dosing control in current devices precluding the ability
to track, adjust and confirm drug dosage.
Nondestructive pharmacokinetic methods have beendeveloped to track and confirm dosage levels; howeverthese techniques are restricted to unique systems such as
direct observation, microdialysis, nuclear imaging andblood measurements but suffer from significant
limitations in their resolution, accuracy, and/or detection
limits. Furthermore, these methods cannot provide realtime feedback and rely on indirect indicators to confirm
dosage. Integration of more traditional fluid monitoring
techniques, such as flow sensor technologies, presents asignificant packaging challenge and can be renderedineffective under the low volume/flow dosage regimens
often required by implantable devices. A direct and realtime method to track and confirm delivered volume
based on electrochemical impedance measurements froma fully-integrated drug delivery micropump (Figure 1) ispresented here.
We previously demonstrated the ability to track subnanoliter liquid volumes, encapsulated within Parylenebased
microstructures,
throughelectrochemical
impedance measurements [3]. This technique offered astraightforward, highly accurate method to realize real-978-1-4577-0156-6/11/$26.00 ©2011 IEEE

time volume tracking. Based on this work, we apply
electrochemical impedance measurements to tracking
larger volumes relevant for drug delivery applications.
Previous attempts to monitor drug dosing utilized
impedance-based measurements of the gas/liquid
fraction within an electrolysis chamber [4]. Active
pumping was demonstrated but utilized rigid materials(silicon/Pyrex®) in a format not well suited to
implantable applications. This approach was also limited
to small drug delivery volumes (<1.5 μL) and would not
be appropriate for sustained long-term use. The ability toaccurately monitor and control delivered volume towithin ±5 nL was, however, achieved. Another approachdemonstrated the ability to monitor the dissolution rateof reservoirs containing 35-45 μg of drug (in solid form)upon exposure to a liquid (1× PBS) environment [5].
The lack of active control over the delivery profile is adrawback to this approach which relies solely on passive
diffusion processes to distribute the drug. For sustainedrelease applications, however, this method provided thefirst demonstration of non-invasive, real-time monitoringof drug dissolution rate.
In this work, we present real-time tracking andaccurate monitoring of a wide range of drug dosage
volumes by electrochemical impedance measurements ina fully-integrated drug delivery system featuring activeelectrolysis-based pumping [6].

DEVICE DESIGN AND OPERATION
Pump Construction
Pump operation is based on electrolytically generated
pneumatic actuation. Hydrogen and oxygen gas are
generated by electrolysis within a pump chamber
initially filled with water. The pressure generated within

2839

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

This phenomenon enables the tracking of volume within
the drug reservoir.
Electrochemical impedance measurements can beperformed with very little power (< 100 μW) andproduce only reversible electrochemical species.
Hydrolysis of the electrolyte does not occur so long as
the magnitude of the applied AC signal is maintained
within the “water-window” of the electrode material; thisvalue is typically greater than 1 V. Details of theelectrochemical interface and associated phenomena
have been studied in our previous work [7] and have also
been thoroughly reviewed in the electrochemistry
literature [8].

EXPERIMENTAL METHODS
Figure 2: Device cross-section demonstrating impedance
measurement and electrolysis-based actuation.

the pump chamber actuates a thin diaphragm that thendisplaces liquid contained within the attached drugchamber. This results in outflow through an integrated
cannula and delivery of the drug (Figure 2).
Interdigitated electrolysis pump electrodes (Ti/Pt300Å/2000Å, 100 μm width/spacing) were fabricated ona soda lime substrate by liftoff and thenpotentiostatically cleaned at ±0.5 V in 1× phosphatebuffered saline. Nafion® was applied to the electrodes by
dip coating two times (1μm thick coating) to improvegas generation efficiency. The remaining parts wereproduced by replica casting of polydimethylsiloxane(PDMS) from conventionally machined acrylic mastermolds.
To assemble the pump, first, electrolysis electrodes
were adhered on the pump chamber base. Then the pump
diaphragm (400 µm thick) and drug reservoir wereattached using PDMS prepolymer and cured in place.
Impedance measurement electrodes were then integrated
into the drug reservoir. Two dedicated impedance
measurement microelectrodes (standard solid 30 AWGwire) were inserted and attached to the reservoir using
PDMS prepolymer and cured in place. Finally, the pumpchamber and reservoir were filled with deionized (DI)water (serving as electrolyte and model drug,
respectively) using a syringe.
Electrochemical Impedance Measurements
Electrochemical impedance is measured throughapplication of a small alternating current across theelectrodes. The electrode-electrolyte interface ismodeled by the Randles circuit which consists of thesolution (electrolyte) resistance in series with the parallel
combination of the double layer capacitance andpolarization resistance. By applying a sufficiently highfrequency (> 1 kHz), the impedance response isdominated by the solution resistance. Consequently, theimpedance response can be approximated as a simple
classical resistance that is inversely proportional to thetotal cross-sectional area of fluid between the electrodes
and is directly analogous to a variable “fluidic” resistor.

The drug reservoir was filled with DI water which
represents an aqueous drug solution. Direct delivery ofdrug to a targeted location can provide therapeutic
effects with smaller doses or more dilute formulations
when compared to systemic routes. Here, DI waterprovides an analog for an aqueous drug dilution.
Electrolysis-based actuation of the pump diaphragm
was accomplished by applying varying levels of
stimulation current between the interdigitated pumpchamber electrodes. Current levels ranging between 1-10
mA were applied to generated pneumatic pressure within
the pump chamber, thereby displacing the diaphragm
upwards into the drug chamber. The displaced liquid in
the drug reservoir was then ejected via the attachedcannula. For large delivery volumes (> 10 μL), theejected fluid was collected and measured by weightusing a precision balance. For low delivery volumes (<10 μL), the delivery cannula was attached to a calibratedmicropipette in which delivery volume was tracked
optically by recording the displacement distance of theliquid front within the micropipette.
Impedance measurements were acquired in real-time
via a LabVIEW-interfaced precision LCR meter (1 Vpp,5 kHz) connected to the impedance measurement
electrodes. At this voltage level, only completely
reversible chemical processes took place at theelectrodes and no chemical modification of the drug
occurred. Impedance measurements were acquired
throughout each experiment without any additionalsignal conditioning or filtering.

RESULTS AND DISSCUSION
Two-electrode
impedance
spectroscopy
wasperformed between 0.1–100 kHz to determine thefrequency range over which solution resistancedominates the impedance response (Figure 3). A 5 kHz
measurement frequency was selected. This value issufficient to bypass the double layer electrodecapacitance while avoiding parasitic effects encounteredat higher frequencies.

2840

1mm

Figure 3: Two-electrode electrochemical impedance
spectroscopy of electrode/reservoir system indicating resistive
region where solution resistance dominates and capacitiveeffects are minimized.

Figure 4: Detection of pump ON/OFF states at 1min/30sec
intervals respectively. Total delivery volume was 64μL at apump current of 5mA.

ON/OFF State Detection
The ability to detect pump ON/OFF states was firstevaluated. A 5mA pump current was applied during theON condition and no current was applied in the OFF
condition. Consecutive ON/OFF states were applied in
1min/30sec intervals, respectively, while impedance wascontinuously monitored (Figure 4). Pump ON states
were readily detected by an immediate and sustained
increase in the impedance magnitude. Immediately after
turning the pump off, a sustained decrease in theimpedance magnitude was observed. This sustained
decrease is a combined result of the restorative elastic
forces of the pump diaphragm and the recombination ofgases that occurs in the OFF state. The result is a pullback effect that restores the drug chamber to its resting
volume and consequently reduces the measuredimpedance. A total dose of 64 μL (8% of reservoir) wasproduced by the combined 3 minutes of pump activation.
A corresponding increase of 6% was observed in theimpedance magnitude over baseline.

Figure 5: Detection of 500 nL bolus delivery as measured bycalibrated micropipette. Pump is activated with 1.5mA current
in step-wise fashion. Measured detection sensitivity of0.2Ω/nL was achieved using impedance-based technique.

Tracking of Sub-Microliter Delivery Boluses
Discrimination of sub-microliter delivery volumes
was possible and demonstrates the sensitivity of thismethod. Delivery of 500 nL boluses (0.625% ofreservoir) was measured by impedance and confirmed
using a calibrated micropipette (50 μL). Boluses weregenerated by applying 1.5 mA current pulses (3.4seconds). Corresponding impedance variations ofapproximately 150 Ω were observed per delivery bolus
and provided a very clear, robust impedance-based
measurement (Figure 5). A sensitivity of 0.2 Ω/nL wasobtained in this mode of delivery. The ability to trackeven smaller volumes with this technique was alreadydemonstrated by our group and others, however,limitations imposed by the experimental setup andcompliance within the pump/reservoir system present
challenges to achieving similar detection resolution.
Further improvement in detection limit is expected forpumps having rigid drug reservoir walls.
Real-time Tracking of Flow Rate Variations
Lastly, discrimination of on-the-fly changes indelivery rate (and hence flow rate) was demonstrated.
Calibrated flow rate measurements were first obtainedfor pump currents of 10 mA, 5 mA and 1 mA (80µL/min, 44 µL/min, and 2.78 µL/min, respectively).
These three pump current levels were then applied
consecutively for 30 second durations and withtransitions occurring in real-time while impedance wasmonitored. A clear variation in the slope of themonotonically increasing impedance magnitude wasobserved and directly corresponded to changes in theapplied pump current levels.
The time-derivative of the measured impedance
signal was plotted and yielded distinct levels for eachapplied current and clearly indicated tracking of their2841

ACKNOWLEDGEMENTS
This work was funded in part by Wallace H. CoulterFoundation Early Career Translational Research Awardand the Bill and Melinda Gates Foundation (CG). An
OAI Model 30 UV light source was used in thefabrication of the electrodes featured in this work. Theauthors also would like to thank Dr. Donghai Zhu andthe members of the USC Biomedical Microsystems
Laboratory for their assistance.

REFERENCES:

Figure 6: Measurement of on-the-fly flow rate variations atdifferent
pumpcurrent
levels.
10mA=80μL/min,
5mA=44μL/min and 1mA=2.78μL/min.

transitions, (3.4 Ω/s per μL/min change in flow rate,
Figure 6). This procedure allowed for the discriminationand measurement of the rate of delivered volume andthus delivery flow rate. A maximum flow ratemeasurement of 80 μL/min was demonstrated here but awider range is possible by applying greater current levels
to the electrolysis pump. Current levels up to 13 mA
have been typically utilized to generate high throughput
flow rates in excess of 100 μl/min. Current device
construction and design may impose limitations to the
maximum achievable flow rates but their effect was notstudied here.
Closed-loop operation based on electrochemical
impedance feedback can be easily realized in a complete
system. Both delivered volume and flow rate can bemeasured and utilized as control parameters forcalibrated, real-time adjustments to pump inputs, namely
the magnitude of applied pump current. Impedancebased feedback enables for the first time real-time
control and confirmation of physiologically-relevantdelivery volumes in a fully integrated, active drug pumpsystem.

CONCLUSION
Measurement of physiologically relevant volumes aswell as on-the-fly flow rate changes using
electrochemical impedance in a MEMS electrochemicalpump was demonstrated as a promising technique forclosed-loop drug delivery. This method is attractive forits simplicity, sensitivity, wide-compatibility and serves
as an important step towards fully-integrated closed-loop
drug delivery systems.

[1] B. Bruguerolle and G. Labrecque, "Rhythmic patternin pain and their chronotherapy," Adv. Drug Deliv.
Rev., vol. 59, pp. 883-895, 2007.
[2] L. Peppas-Brannon, "Recent advances on the use of
biodegradable microparticles and nanoparticles incontrolled drug delivery," Int J. Pharm., vol. 116, pp.
1-9, 1995.
[3] C. A. Gutierrez and E. Meng, "Improved SelfSealing Liquid Encapsulation in Parylene Structures
by Integrated Stackable Annular-Plate Stiction
Valve," in IEEE MEMS. Hong Kong, China, 2010,
pp. 524-527.
[4] S. Bohm, B. Timmer, W. Olthuis, and P. Bergveld,"A closed-loop controlled electrochemicallyactuated micro-dosing system," J. Micromech.
Microeng, vol. 10, pp. 498-504, 2000.
[5] A. M. Johnson, D. R. Sadoway, M. J. Cima, and R.
Langer, "Design and Testing of an Impedance-Based
Sensor for Monitoring Drug Delivery," J.
Electrochem. Soc., vol. 152, pp. H6-H11, 2005.
[6] P.-Y. Li, R. Sheybani, C. A. Gutierrez, J. T. W. Kuo,and E. Meng, "A Parylene Bellows Electrochemical
Actuator," J. Microelectromech. Syst., vol. 19, pp.
215-228, 2010.
[7] C. A. Gutierrez and E. Meng, "Parylene-based
Electrochemical-MEMS
Transducers,"
J.
Microelectromech. Sys., vol. 19, pp. 1352-1361,
2010.
[8] D. Erickson and D. Li, "Integrated microfluidic
devices," Analytica Chimica Acta, vol. 507, pp. 1126, 2004.
CONTACT
C.A. Gutierrez, tel: 213-821-3949; cagutier@usc.edu

2842