CLOSED-LOOP ON-DEMAND DRUG DELIVERY MICROPUMP FOR
CHRONIC PAIN MANAGEMENT APPLICATIONS
R.Sheybani, S. Elyahoodayan, and E. Meng
University of Southern California, USA
ABSTRACT
We present a low power (0.66-51.31mW) electrochemical micropump capable of accurate delivery of a diverse
assortment of liquid drug formulations within a wide dynamic range of flow rates (0.33 - 141.9μL/min) suitable for chronic
pain management applications. This system rapidly responds to changes in regimen (<1sec) for on-demand control and has anelectrochemically based dose tracking system that is capable of real-time tracking and confirmation of delivery. Tracking ofbolus delivery down to 83nL (0.004% of reservoir) was achieved. On demand delivery and dose tracking of Lidocaine HClhydrate (20mg/mL dissolved in PBS) was demonstrated.

KEYWORDS:

Drug Delivery Micropump, Closed-loop Dose Tracking, Electrochemical

INTRODUCTION
Drug delivery is essential for disease management of an estimated 50 million Americans that live with chronic pain
caused by disease, disorder or accident [1]. Pain intensity is rarely constant over a 24 hour period and patients require
individually-tailored therapies to account for different patterns and inter-individual differences [2]. Treatment efficacy could
be greatly increased with precise drug delivery devices that can deliver medications on-demand and include sensors thatwould enable the delivered dose to be tracked or confirmed [2].
Here, we present the design, fabrication and characterization of a programmable, low power electrochemical micropump
capable of delivering liquid drug formulations within a wide dynamic range of dose volumes and flow rates. The system
rapidly responds to changes in regimen (<1sec) for on-demand control with a fully integrated electrochemically based realtime dose tracking system.

MATERIALS & METHODSElectrochemical pumping was achieved by supplying a constant current to a pair ofNafion® coated interdigitated Pt electrodes, which converts water into hydrogen andoxygen gases. This inflates a compliant Parylene bellows, displacing adjacent drug in areservoir through a directed catheter to the delivery site [3]. The delivered dose is trackedand confirmed through measuring electrochemical impedance (EI) by applying a smallsinusoidal excitation voltage across a set of bulk wire Pt electrodes placed in the drugreservoir. At sufficiently high frequencies (100kHz for PBS), the impedance response isdominated by the solution resistance, which can be modeled as a simple variable
resistance dependent on the cross sectional area of the fluid. When the fluid is contained ina rigid reservoir, this dependency can be used to correlate the measured impedance value
Figure 1: Operation concept.
with the volume of fluid remaining in the chamber [4] (Fig 1).
Delivery performance of device prototypes with 2mL reservoirs was characterized by benchtop delivery of sterile PBS(Amresco, Solon, OH). The fluid was injected into the drug chamber through the PDMS refill port using a 30 gauge needle.
Electrical current supplied was varied using a current source (Keithley 2400, Keithley Instruments, Cleveland, OH).
Impedance measurements were acquired using a precision impedance analyzer connected to the EI electrodes and recorded
via a LabVIEW interface in real-time. An alternating excitation voltage (100mVpp and 100kHz) was applied. At this voltage
level, only completely reversible chemical processes took place at the electrodes and no chemical modification of the drug
was observed [5].
A range of currents (0.1-13mA) were applied to characterize the micropump operation. The delivered volume and flowrate were calculated by measuring fluid displacement in a 100μL calibrated micropipette. When no current was supplied, nodrug was delivered [3].
In order to calibrate the performance of the EI electrodes, 3mA current was applied to the electrolysis electrodes and thevolume dispensed from the pump, as well as the change in impedance was recorded for each run (n=10). The results wereused to obtain averaged trends and the impedance values were normalized to the baseline value for each measurement. The
calibration curve was calculated using the linear fit of the data. A LabVIEW graphical user interface previously designed for
DI water as the model drug [4] was modified to reflect the calibration curve obtained (results not shown). Real-time dosetracking and on-demand operation of the micropump were demonstrated by successively applying 5, 1, 8, and 2mA andrecording the impedance response (30sec for each current).
Lidocaine HCl hydrate (Enzo Life Sciences, Farmingdale, NY) was dissolved in PBS (20mg/mL) and loaded into thereservoir. 1mA current was applied for 1min, immediately followed by 10mA for 10sec, 1mA for 1min, and lastly 5mA for
30sec (n=5). Real-time dose tracking of the Lidocaine solution was confirmed by applying 3mA for 90 seconds.

RESULTS & DISCUSSION
A range of flow rates with linear dependence on current were achieved(0.33 - 141.9μL/min for 0.1-13mA applied current or 0.66-51.31mW,
respectively; data not shown) [3].
Delivery of 83nL boluses (0.004% of reservoir) was measured byimpedance and confirmed using a calibrated micropipette (25μL). Boluses weregenerated by applying 3.25mA current pulses (1 second). The actuator
responded to “on the fly” changes in current with <1sec response time. Flowrates (35.2µL/min, 5.12µL/min, 72µL/min, and 13.34µL/min) were measured
for pump currents of 5mA, 1mA, 8mA and 2mA respectively and werecomparable to those previously measured for each current individually (Fig 2).
On demand delivery of the Lidocaine solution was achieved (Fig 3). No
Figure 2: Real-time dose tracking ofsignificant difference was observed between the flow values for Lidocaine vs.
sterile PBS (no compensation for viscosity; t-test (p<0.05)). Lastly, real-time dose actuator response to “on the fly”
tracking of the Lidocaine solution delivery was confirmed by applying 3mA for 90 changes.
seconds (Fig 4).

Figure 3: Flow performance for Lidocaine solution:
accumulated volume and flow rate (n=5, Mean ± SE).

Figure 4: Real-time dose tracking of Lidocainedelivery.

CONCLUSION
We demonstrated a programmable, low power electrochemical micropump capable of accurate delivery of a diverse
assortment of liquid drug formulations on-demand with high accuracy suitable for chronic pain management applications.
The system is integrated with an electrochemically based dose tracking system capable of real-time tracking, confirmation ofdelivery, and closed-loop control. Delivery and dose tracking of Lidocaine was studied as a model drug. Future work
includes integration of a wireless inductive powering and data transfer for practical dosing in chronic animal studies.

ACKNOWLEDGMENT
This work was supported by Wallace H. Coulter Foundation Early Career Translational Research Award, NationalScience Foundation (NSF) IIP-1157852, and Henry M. Jackson Foundation Agreement #2267 through theQualcomm/TATRC Wireless Health Innovation Challenge. The authors thank Ms. H. Gensler for providing the Parylene
bellows, and the members of the USC Biomedical Microsystems Laboratory for their assistance.

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