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A MEMS MICROPUMP SYSTEM WITH ONE-WAY VALVEFOR CHRONIC DRUG DELIVERY
H.M. Gensler1, R. Sheybani1, and E. Meng1
1
University of Southern California, USA
ABSTRACT
Implantable micropump systems capable of user-controlled and site-specific chronic drug delivery in small animals are acritical unmet need in drug discovery and development. Our electrochemical bellows actuator provides current-controlled
flow rate and is integrated to form a fully implantable system with a refillable reservoir and one-way valve that prevents
mixing of biological fluids with the drug. Periodic dosing performance was demonstrated with minimal reverse leakage
through the valve and flow rate error of no more than 3-10%. Similar performance was obtained using a wireless micropump
driven using a Class E inductively coupled powering system for remote on/off control.

KEYWORDS:

Implantable Micropump, Drug Delivery, MEMS, ValveINTRODUCTION
Rodent disease models have an important role in the investigation and validation of novel drugs prior to clinical studies.
Drug administration technology suitable for freely behaving animals is, however, limited for chronic studies (lasting morethan a day). Alzet® osmotic pumps [1] operate at a factory set continuous flow rate, are not refillable, and have a lifetime ofdays to weeks before needing to be removed or replaced. The iPrecio® peristaltic pump [2] can be programmed before, but
not after, implantation, is limited by battery life, and is too large for mice.
Previously we demonstrated a bellows electrochemical actuator packaged ina prototype silicone rubber reservoir [3]. The actuation principle is based onelectrolysis, which is reversible and has no side reactions. Electrical current
applied to electrodes converts water (electrolyte) into hydrogen and oxygengases. A water-filled bellows covers the electrodes and isolates the electrolysis
reaction from the drug. The phase change results in a pressure increase that
displaces the bellows in a piston-like manner, which then forces drug out of thereservoir and to the delivery site (Figure 1). When current is turned off the gases
recombine into water, allowing for repeated administration.
Here we present a redesigned rigid packaging scheme that results in a morerobust implant and more reliable drug delivery. An integrated one-way valve
prevents mixing of biological fluids and drug in the reservoir duringrecombination and between dosing periods. The reservoir includes a built-in refill
port to extend duration of use. We also demonstrate integration of the valved
Figure 1: Conceptual drawing of thedevice with an inductive wireless powering system for battery-less operation forelectrolysis-based micropump system.
extended chronic studies in freely behaving small animals.

METHODS
Platinum electrodes were patterned on glass as described in [4] and Nafion®-coated to improve actuator performance [5].
Then, a Parylene C bellows [3,4] was mounted over the electrodes to isolate electrolysis from the drug reservoir.
Polypropylene resin was injection molded with custom aluminum molds to form the top and base of the rigid reservoir, whichhoused the bellows actuator and the drug (Figure 2). The reservoir
refill port was filled with medical grade silicone rubber. Wires
adhered to the electrodes with epoxy connect directly to an
external current source for wired micropumps, or to a circuit
mounted on the reservoir for wireless powering. An integrated
cannula constructed of polyetheretherketone (PEEK) (wiredmicropumps) or silicone (wireless micropump) directs the drug tothe desired target site of delivery. A commercial one-way valve(Figure 2; 2.0 mm duckbill; Minivalve, Cleveland, OH) made of
medical grade silicone was packaged in heat shrink tubing and
Figure 2: Micropump (left) and one-way valve
attached with epoxy to the PEEK cannula for benchtop testing.
(right).

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Figure 3: Transmitter and micropumpwith integrated receiver coil and circuit.

The Class E inductive wireless powering system consists of a 12-volt
power supply, transmitter coil and circuit, and receiver coil and circuit(Figure 3). The transmitter transfers power to the receiver components
mounted on the micropump reservoir. For future in vivo studies, a Parylene C
coating will insulate the electronics and reduce permeability through thereservoir wall. A further coating of medical grade silicone rubber will soften
the packaging edges for reduced tissue irritation.
The valves were tested with a custom pressure setup in a wet
environment (deionized water at inlet and outlet) to determine the cracking
pressure. Three wired micropump systems were assembled with the valve
and tested on the benchtop to demonstrate performance with a periodic
dosing regimen. Constant current of 0.5 mA was applied (Keithley
SourceMeter) to achieve a 30 μL dose each day for three days. Flow rates
were measured using a calibrated micropipette attached to the cannula outlet.
Then a valved micropump was integrated with the wireless powering system.

RESULTS AND DISCUSSION
The measured valve cracking pressure was less than 0.69 kPa (5.17 mmHg). Valved and wired micropump systems
demonstrated consistent flow rates of ~4 μL/min across all doses. With each subsequent dose, a time delay corresponded topressure build up compensating for reduction in reservoir volume [6]. A representative graph is shown in Figure 4. Accurate
dosing was indicated across all devices with flow rate standard error between 3-10%. Reverse leakage of the valve was ~1-2μL, or 3-9% of the dose volume, validating the one-way capability of the valve in this periodic dosing application. Thevalved wireless micropump system was then evaluated. Power transfer occurred when the receiver coil was within 20 cm of
the transmitter coil. The valve opened immediately to allow forward flow and flow rates on the order of μL/min wereobserved. When current was removed to turn the system off, < 0.33 μL reverse leakage through the valve was observed overa 24-hour period.

Figure 4: (Left) Accumulated
volume over time for 3 periodic
doses in a wired, valved micropump
system. (Right) ON/OFF control ina wirelessly powered, valved
micropump system.

CONCLUSION
We developed an implantable micropump system with the potential for chronic drug delivery in small animals. An
integrated valve ensures accurate dosing without mixing and potential dilution from biological fluids. The refillable reservoir
and wireless powering system make possible extended chronic studies in untethered animals. Future work includes
reconfiguring the reservoir to reduce overall implant size and dead volume in the drug reservoir, and in vivo validation ofanti-cancer drug delivery to tumors in freely behaving, untethered mice.

REFERENCES[1] "ALZET® Osmotic Pumps - Implantable pumps for research.” http://www.alzet.com/.
[2] “iPRECIO®, Innovative Drug Infusion Technology for Laboratory Animals.” http://www.iprecio.com/.
[3] H. Gensler, et al., “An implantable MEMS micropump system for drug delivery in small animals,” Biomed Microdev,
vol. 14, no. 3, pp. 483–496, Jan. 2012.
[4] P.-Y. Li, et al., “A Parylene Bellows Electrochemical Actuator,” J Microelectromech. Syst., vol. 19, no. 1, pp. 215–228,2010.
[5] R. Sheybani, and E. Meng, “High-Efficiency MEMS Electrochemical Actuators and Electrochemical ImpedanceSpectroscopy Characterization,” J Microelectromech. Syst., vol. 21, no. 5, pp. 1197–1208, Oct. 2012.
[6] R. Sheybani, et al., “A MEMS electrochemical bellows actuator for fluid metering applications,” Biomed Microdev, vol.
15, no. 1, pp. 37–48, Jul. 2012.