**Development of Integrated Protection for Miniaturized Implantable
Controlled Drug Delivery System**

Han-Kuan A. Tsai^1^, Kuo-Sheng Ma^2^, Chong Wang^3^, Han Xu^3^, Chunlei
Wang^3^, Jim Zoval^3^, Lawrence Kulinsky^3^, Marc Madou^1,3^[^1]

^1^Department of Material Science and Engineering, ^2^Department of
Electrical Engineering,

^3^Department of Mechanical and Aerospace Engineering,

University of California, Irvine, CA 92697, USA

**Abstract**

> A bi-layer structure comprising a thin gold layer and a polypyrrole
> (PPy) film is developed as a valve. To create such structures, the
> thin metal layer is used as a working electrode, and the polypyrrole
> film is electrochemically deposited on the metal electrode. A layer of
> Cr deposited under a stationary part of the bi-layer flap adheres
> strongly to the gold layer and anchors the hinge of the flap, while
> the layer of polyimide deposited under a movable part of the flap
> adheres weakly to the gold layer of the flap. This bi-layer flap
> structure functions as an actuator valve for the opening and closing
> of an aperture. An actuation mechanism of the valve is based on a
> volume change in the PPy layer as cations move in and out of the
> polymer film during reduction and oxidation reactions. A bias of 1.2 V
> is used to actuate the flap. A method is proposed to increase the drug
> release system's functionality by placing the drug release flap within
> a protective enclosure that also serves as a drug reservoir. This
> integrated protection ensures reliable operation of the drug release
> flap unencumbered by surrounding tissues when used *in-vivo*. A
> prototype system using a PDMS drug reservoir has been successfully
> tested in PBS buffer solution. The proposed integrated protection
> system holds promise for implantable biomedical devices.

Keywords: bi-layer; actuator; polypyrrole; protection; drug delivery

**1. Introduction**

Drug delivery technology *(1*-5) is becoming an increasingly important
component of the overall drug development cycle. Medications are
continuously improved to combat a wider range of disease with higher
efficiency. Many new treatments require drug delivery systems to be more
sophisticated so that the potentially harmful side effects of the drugs
can be minimized. Traditional drug delivery techniques include oral drug
administration and injections. In these systematic drug delivery
technologies, a patient is administered with a high medication dose
which is quickly diluted and loses its efficiency. When drug
concentration drops below the therapeutic level, administration of a new
dose is required to sustain the drug effect. Extensive work has been
performed to improve controlled release techniques for various drug
delivery methods, such as biodegradable microspheres *(5*-7),
microneedles *(8,* 9), and implantable microchips *(2,* 10). While these
systems establish controlled temporal drug profile, they can not react
to the changing physiological environment. Another advanced alternative
for drug delivery is an implantable responsive drug delivery system
*(11,* 12). The responsive drug delivery systems contain biosensors,
drug reservoirs, control circuitry, and an independent power supply.
When biosensor's reading indicates that a physiological parameter of
interest is outside the normal range, the control circuit will activate
drug release valves and drug administration can take place
automatically. With the responsive drug delivery system, drug levels in
patients can stay within the window of optimal efficiency for an
extended period of time, resulting in improved compliancy, minimized
drug side effects, and elimination of the risk of infection with
non-sterile needles *(13,* 14).

A reliable valve to control drug release is a significant component for
a successful responsive drug delivery device. The actuated valve must be
biocompatible, have low power consumption, exhibit low leakage, and have
consistent performance. Electroactive polymer (EAP) actuators made from
polypyrrole (PPy) for application in biomedical research have been
demonstrated in the literature (15-17). PPy can be synthesized by
electrochemical deposition onto a metal electrode (18). Subsequent
application of a small bias can cause the deflection (bending) of the
PPy/metal bi-layer structure due to a volume change in the PPy film as
ions move in and out of the polymer to preserve charge neutrality during
reduction and oxidation reactions:

PPy^+^(DBS^−^) + Na^+^ + e^−^ ↔ PPy^0^(DBS^−^ Na^+^).

Therefore, EAP/metal layered structures can serve as actuator valves to
open and close reservoirs *(19,* 20). The bi-layer flaps require
relatively low power consumption during operation *(*21) as compared to
the metal membrane corrosion release method *(*10). Previous work *(*21)
demonstrated a device in which 13 mm^2^ PPy/Au bi-layer flap was used as
the release valve of the drug reservoir etched in a Si wafer.

In the present study, we demonstrate an advanced release system that
features a miniaturized design, integration of the counter electrodes
with the working electrodes, and inclusion of the protective reservoirs.
The actuator valve is miniaturized to 200 microns in width. The smaller
actuator dimensions are helpful for reducing power consumption and
increasing the number of valves per system and/or the number of systems
per wafer leading to increased efficiency and lower manufacturing cost.
The drug delivery system with large array of micro-actuated valves would
allow for simultaneous use of several types of drugs. If a higher
medication dose is needed, multiple valves can be opened.
Microfabrication technology is used to integrate counter and working
electrodes on the same substrate to improve manufacturability and
control of the system.

Our present work features a sealed polydimethylsiloxane (PDMS) reservoir
functioning as both a protective system and a drug reservoir (figure 1).
An array of reservoirs with scalable capacity is designed to store
various drugs. The same array of microfabricated valves can be outfitted
with higher capacity PDMS reservoirs holding larger medication volume.

**2. Experimental Section**

*2.1 Device fabrication*

The fabrication sequence is illustrated in Figure 2. A single crystal
silicon wafer covered with a 200 nm thick thermal silicon dioxide is
used as a substrate material (figure 2(a)). Before metal deposition, the
substrate is cleaned using the RCA (5 parts of deionized water, 1 part
of NH~4~OH, and 1 part of H~2~O~2~) cleaning procedure. Gold is used as
a material for the flap leads. In order to promote the adhesion of gold,
a thin Cr layer (7 nm) is deposited before forming a 20nm thick film of
gold by vapor deposition. All the depositions are achieved by using
e-beam evaporation. In the next step, the Au layer is patterned by using
a photolithographic process. A thin layer of positive photoresist
(Shipley 1827) is deposited using spin coating at 3000 rpm for 30
seconds, followed by a soft bake at 90 °C on a hot plate for 2 minutes.
The photoresist is then exposed under UV illumination through a
patterned iron oxide mask in a Karl Suss MA 6 mask aligner and
subsequently developed in MF 319 developer. Gold etchant and chromium
etchant are subsequently used to remove the undesired metal coverage.
Finally, the remaining photoresist is stripped from the substrate by
using acetone (figure 2(b)).

The drug release opening is covered by the Au/PPy bi-layer flap. To
enable flap operation, a thin layer (150 nm) of polyimide is used to
prevent the metal layer of the flap from sticking to the substrate.
Diluted polyimide is spin-coated using two steps (500rpm for 15 sec,
3000 rpm for 100 seconds). The spun-coated polyimide is then processed
with two baking steps (soft baking at 90 °C for 90 seconds, hard baking
at 200 °C for 90 seconds). Positive photoresist (Shipley 1827) is
applied on top of the polyimide thin film and patterned using the MA6
aligner. The polyimide layer is patterned simultaneously with the
positive photoresist in the MF 319 developer. The remaining photoresist
is stripped by acetone (figure 2(c)). A second layer of Au (500 nm) is
deposited using e-beam evaporation and then patterned to form the
Au-layer of the flap (figure 2(d)).

In the next step, the Si wafer is etched through to form the drug
release aperture (figure 2(e)). A 20 micron-thick layer of positive
photoresist (AZ 4620) is spin-coated onto the back side of the
substrate. Using double side alignment, the openings on the back side of
the substrate are aligned exactly underneath the flap. The wafer is
flipped over (face down) and attached onto the holding chuck. The
etching is performed in a deep reactive ion etching (DRIE) machine
(Surface Technologies Systems (STS) MESC ICP Etcher) for 3 hours to etch
through the 500 micron thick Si wafer. The polyimide layer is also
etched out during the DRIE etching.

The drug storage reservoir/protective enclosure is made from Dow Corning
(Midland, MI) PDMS using a molding process. The base (Sylguard 184
silicone elastomer) and the curing agent (silicone resin solution) are
thoroughly mixed in a weight proportion of 10:1. Low temperature curing
(65 ºC) is performed in a convection oven. Leveler is using in order to
achieve a uniform thickness of PDMS structure. The wafer is cured for 20
min at 90 ºC to polymerize the PDMS film. The resulting PDMS structure
is carefully peeled off from the mold, and a parylene layer is deposited
on the PDMS surface by 175 ºC thermal evaporation deposition *(*22).
Waterproof epoxy glue is used to seal the PDMS reservoir onto the
silicon substrate.

*2.2 Electrochemical synthesis of the Polypyrrole film*

An e-beam evaporator is used to deposit a thin gold layer onto an
oxidized silicon wafer to make working and counter electrodes. A Fischer
Scientific silver/silver chloride electrode is used as a reference
electrode. A potentiostat (Gamry Instrument PC4/750) controlled by Gamry
Framework software is used to electrochemically polymerize pyrrole and
also to actuate the drug release valves.

To polymerize pyrrole on a gold layer, sodium dodecylbenzesulfonic salt
(NaDBS, Aldrich) and pyrrole (98% Aldrich) are mixed in deionized water
with concentrations of 0.1M each. The electrochemical polymerization is
carried out by applying a fixed potential of 0.6V (versus silver/silver
chloride electrode) on the working electrode. All experiments are
executed in a Coplin staining jar (VWR, CA).

*2.3 Electrochemical and optical detection*

Both electrochemical and optical detection methods are employed to
detect drug release from the reservoirs upon flap opening. For optical
detection, a pyranine fluorescent dye (8-Hydroxy-1, 3,
6-pyrenetrisulfonic acid, trisodium salt, Aldrich) is stored in the PDMS
reservoir and sealed against the vial. The opening and closing of the
valve is recorded by a camera under a UV light. The electrochemical
detection is performed using a test platform that includes a PMMA
substrate with a channel (6.5 cm long, 2 mm wide and 3 mm deep)
connecting 2 reservoirs (2 mm deep and 5 mm in diameter) at the ends of
the channel as shown in figure 3. The channel is filled with D.I. water
and two electrodes are positioned in the reservoirs as illustrated. A
constant 1V potential is applied to the electrodes and current changes
versus time are recorded. The PDMS reservoir is filled with 3M NaCl
solution. The drug release device is put on top of the PMMA substrate
and its release aperture is aligned with the channel.

**3. Results and Discussion**

*3.1 Fabrication*

The fabrication results for the drug release valves are shown in figures
4(a)-(f). Gold electrodes were patterned on the SiO~2~/Si substrate. The
working electrodes (metal layer of the actuated flap valves) and counter
electrodes are integrated on the same chip as shown in figure 4(a).
Polypyrrole is electrochemically deposited on the working electrodes by
applying 0.6V vs. Ag/AgCl to construct the bi-layer flaps (figure 4(b)).
Figure 4(c) is a Scanning Electron Microscope (SEM) image showing the
top view of the open flap, and figure 4(d) demonstrates the drug release
aperture as seen from the backside of the device. The aperture diameter
is 160 µm. By applying a low potential (0.6V vs. Ag/AgCl), we can obtain
a relatively uniform PPy film (figure 4(e)) as compared to the PPy film
deposited at a higher applied bias (1.0V vs. Ag/AgCl) -- figure 4(f).

*3.2. Test of the actuator valve*

3.2.1 Optical detection

The device performance is tested by actuating the valve and monitoring
the release of the fluorescent dye. The device is immersed into 0.1M
phosphate buffered saline (PBS pH=7.4) solution and its working and
counter electrodes are connected to the potentiostat. The silver/silver
chloride reference electrode is also placed into the glass jar. The
valve actions are controlled by the potentiostat by providing positive
and negative potentials. Figure 5(a) shows part of the device with four
valves and a counter electrode in the buffer solution and figure 5(b)
shows the setup under UV light. A positive voltage (1.2V vs. Ag/AgCl) is
applied to one of the valves. Figure 5(c) presents picture of the opened
valve in UV light. As the valve opens, release of fluorescent dye is
observed (circled green spot on the picture). To close the valve, a
negative voltage is applied to the flap. Figure 5(d) shows the image
after the valve is closed. The spot of intense fluorescence fades after
the flap is actuated to close the aperture again. It is verified that
the reservoir still contains fluorescent dye when the valve is actuated
to re-seal the reservoir after the release cycle. The results
demonstrate that the proposed microfabricated valve can be used as a
part of the responsive drug delivery system.

3.2.2 Electrochemical detection

An electrochemical detection method is employed to quantify the PPy
valve performance. A constant potential (1V) is applied to two
electrodes positioned at the two ends of the channel. The ionic
concentration of solution increases after the valve is opened to release
NaCl solution (3M) into the channel[^2]. The conductivity change of the
solution can be quantified by the current measurements. As shown in
figure 6, the bi-layer flap is in the neutral (closed) state between 0
and 98^th^ second. A constant potential (1.2V) is applied to the flap at
98^th^ second. A current increase is observed from 99^th^ to 134^th^
second demonstrating that NaCl solution is issuing from the reservoir.
At 135^th^ second, a negative potential (-1.0V) is applied to reverse
flap deformation and to close the valve. The current reaches a plateau
after the valve is closed and remains constant for the duration of the
experiment. This result confirms the dye release experimental results
and demonstrates a method that can quantify the amount of solution
released from the reservoir by observation of the changes in current
measurements as more ionic liquid exits the reservoir.

*3.3 Permeability of the PDMS cap*

The protective cap that doubles as a drug reservoir is made of PDMS.
PDMS has a relatively high permeability to water. As a control
experiment, 0.108 g of PBS buffer solution is stored in the PDMS cap of
0.4 in^2^ surface area sealed on the Si wafer. By measuring the weight
of the system, the amount of the buffer solution evaporated through the
PDMS cap can be calculated. A relatively large solution loss rate of
0.008 g per day (translating roughly into 7% weight loss per day) is
observed.

To decrease PDMS permeability, parylene coating is used. A PDMS cap with
the same dimensions as in the control experiment above is coated with
parylene (film thickness is \~1.2μm). The reservoir which is sealed onto
a Si wafer stores 0.092 g of PBS buffer solution. A markedly lower
weight loss (0.001 g/day) (\~1%/day) is found. A significant reduction
of moisture vapor transmission rate is achieved by coating parylene on
the PDMS surface. The vapor transmission rate may be further reduced
through a thicker parylene coating *(22,* 23).

**4. Conclusion**

A miniaturized polypyrrole bi-layer actuator is presented in this work.
This actuator is capable of serving as the release component of the
proposed responsive drug delivery system. The detailed device
fabrication sequence is presented, and the resultant device is
demonstrated. Since both the counter and the working electrodes are
fabricated on the same substrate, the device can be made on a single
chip and its dimensions can be further reduced. By using optical
(fluorescent dye release) and electrochemical (NaCl solution release)
methods, we demonstrate that the valve can be opened and closed using a
small bias. A scalable PDMS cap that serves as a reservoir is fabricated
to protect actuator flaps and to prevent the valves from being blocked
by surrounding tissues. Parylene coating is used to reduce the
permeability of the PDMS cap. The results are encouraging since our
prototype works in PBS buffer solution, which has a similar ionic
strength, pH value and ion concentration to body fluids. Future work
will include biocompatibility studies and *in-vivo* animal tests.

**Acknowledgements**

The authors would like to thank Professor Sylvia Daunert (University of
Kentucky in Lexington, KY) and Dr. Benjamin Park for helpful
discussions. The device fabrication was done in INRF (Integrated
Nanosystems Research Facility) at University of California Irvine. This
work was supported by the U.S. National Institute of Health grant no. 1
R21 EB03072-01.

**Figure captions**

**Figure 1**. Design of the protective drug delivery system

**Figure 2.** Fabrication sequence of the drug delivery device

(a) A single crystal silicon wafer covered with a 200 nm silicon dioxide
    layer is used as a substrate

(b) Chromium and gold layers are deposited via e-beam evaporation and
    subsequently patterned

(c) A polyimide layer is spin-coated and patterned

(d) A second gold layer is deposited via e-beam evaporation and
    patterned

(e) A via is opened by using Deep Reactive Ion Etching (DRIE)

(f) A polypyrrole layer is electrochemically deposited onto the gold
    layer

**Figure 3.** Electrochemical test scheme: A PMMA chip with a channel,
two reservoirs and the drug release device on top of the channel. Two
electrodes with constant potential (1V) applied are placed in the
reservoirs. Figure 3(a) demonstrates a closed valve; in Figure 3(b) the
valve is opened.

**Figure 4.** Fabricated drug release device

(a) the design of the drug release valves with counter electrode and 8
    working electrodes on the same chip

(b) the polypyrrole coated working electrodes

(c) the top view of the release valve

(d) the backside view of the drug release aperture

(e) a relatively uniform PPy film is produced with low applied potential
    (0.6V)

(f) a low quality PPy film is produced with higher applied potential
    (1.0V)

**Figure 5.** The fluorescent dye release test

(a) the drug release device with 4 release valves

(b) the drug release device with the closed valves under UV light

(c) the valve is opened by applying a 1.2 V potential and the
    fluorescent dye release is observed

(d) the valve was closed by applying a -1.0V potential

**Figure 6.** The electrochemical detection is performed with the setup
demonstrated in Figure 3. The release of NaCl solution increases
conductivity of the liquid in the channel. After the valve is closed no
further increase in current is observed.

![](media/image1.png){width="6.0in" height="3.55in"}

**Figure 1.** Design of the protective drug delivery system

![](media/image2.png){width="5.995833333333334in"
height="3.529166666666667in"}

**Figure 2.** Fabrication sequence of the drug delivery device

\(a\) A single crystal silicon wafer covered with a 200 nm silicon
dioxide layer is used as a substrate; (b) Chromium and gold layers are
deposited via e-beam evaporation and subsequently patterned; (c) A
polyimide layer is spin-coated and patterned; (d) A second gold layer is
deposited via e-beam evaporation and patterned; (e) A via is opened by
using deep reactive ion etching (DRIE); (f) A polypyrrole layer is
electrochemically deposited onto the gold layer

![](media/image3.png){width="2.36875in" height="1.575in"}
![](media/image4.png){width="2.3625in" height="1.575in"}

\(a\) (b)

**Figure 3.** Electrochemical test scheme: A PMMA chip with a channel,
two reservoirs and the drug release device on top of the channel. Two
electrodes with constant potential (1V) applied are placed in the
reservoirs. Figure 3(a) demonstrates a closed valve; in Figure 3(b) the
valve is opened.

![](media/image5.png){width="2.716666666666667in"
height="1.9694444444444446in"}
![](media/image6.png){width="2.8930555555555557in"
height="1.9673611111111111in"}

\(a\) (b)

![](media/image7.png){width="2.625in" height="1.9701388888888889in"}
![](media/image8.png){width="2.625in" height="1.9666666666666666in"}

\(c\) (d)

![](media/image9.png){width="2.625in" height="1.9701388888888889in"}
![](media/image10.png){width="2.625in" height="1.9701388888888889in"}

\(e\) (f)

**Figure 4.** Fabricated drug release device

\(a\) the design of the drug release valves with counter electrode and 8
working electrodes on the same chip; (b) the polypyrrole coated working
electrodes; (c) the top view of the release valve; (d) the backside view
of the drug release aperture; (e) a relatively uniform PPy film is
produced with low applied potential (0.6V); (f) low quality PPy film is
produced with higher applied potential (1.0V).

> ![](media/image11.png){width="1.4055555555555554in"
> height="1.9708333333333334in"}
> ![](media/image12.png){width="2.0770833333333334in"
> height="1.9701388888888889in"}

\(a\) (b)

![](media/image13.png){width="2.2215277777777778in"
height="1.9694444444444446in"}
![](media/image14.png){width="2.223611111111111in"
height="1.9694444444444446in"}

\(c\) (d)

**Figure 5.** The fluorescent dye release test

\(a\) the drug release device with 4 release valves; (b) the drug
release device with the closed valves under UV light; (c) the valve is
opened by applying a 1.2 V potential and the fluorescent dye release is
observed; (d) the valve was closed by applying a -1.0V potential.

![](media/image15.png){width="4.940277777777778in"
height="2.7930555555555556in"}

**Figure 6.** The electrochemical detection is performed with the setup
demonstrated in Figure 3. The release of NaCl solution increases
conductivity of the liquid in the channel. After the valve is closed no
further increase in current is observed.

**References**

1\. Sengupta, S., Eavarone, D., Capila, I., Zhao, G. L., Watson, N.,
Kiziltepe, T., and Sasisekharan, R. (2005) *Nature* **436,** 568-572.

2\. Li, Y. W., Shawgo, R. S., Tyler, B., Henderson, P. T., Vogel, J. S.,
Rosenberg, A., Storm, P. B., Langer, R., Brem, H., and Cima, M. J.
(2004) *Journal of Controlled Release* **100,** 211-219.

3\. Khademhosseini, A., and Langer, R. (2006) *Chemical Engineering
Progress* **102,** 38-42.

4\. Razzacki, S. Z., Thwar, P. K., Yang, M., Ugaz, V. M., and Burns, M.
A. (2004) *Advanced Drug Delivery Reviews* **56,** 185-198.

5\. Kempen, D. H. R., Lu, L. C., Kim, C., Zhu, X., Dhert, W. J. A.,
Currier, B. L., and Yaszemski, M. J. (2006) *Journal of Biomedical
Materials Research Part A* **77A,** 103-111.

6\. Keegan, M. E., Royce, S. M., Fahmy, T., and Saltzman, W. M. (2006)
*Journal of Controlled Release* **110,** 574-580.

7\. Samati, Y., Yuksel, N., and Tarimci, N. (2006) *Drug Delivery*
**13,** 105-111.

8\. Martanto, W., Moore, J. S., Kashlan, O., Kamath, R., Wang, P. M.,
O\'Neal, J. M., and Prausnitz, M. R. (2006) *Pharmaceutical Research*
**23,** 104-113.

9\. Zahn, J. D., Deshmukh, A., Pisano, A. P., and Liepmann, D. (2004)
*Biomedical Microdevices* **6,** 183-190.

10\. Santini, J. T., Richards, A. C., Scheidt, R., Cima, M. J., and
Langer, R. (2000) *Angewandte Chemie-International Edition* **39,**
2397-2407.

11\. Madou, M. J., and He, K. Q. (2000) *Abstracts of Papers of the
American Chemical Society* **220,** U364-U364.

12\. Low, L. M., Seetharaman, S., He, K. Q., and Madou, M. J. (2000)
*Sensors and Actuators B-Chemical* **67,** 149-160.

13\. Deo, S., Moschou, E., Peteu, S., Eisenhardt, P., Bachas, L., Madou,
M., and Daunert, S. (2003) *Analytical Chemistry* **75,** 207A-213A.

14\. Soppimath, K. S., Aminabhavi, T. M., Dave, A. M., Kumbar, S. G.,
and Rudzinski, W. E. (2002) *Drug Development and Industrial Pharmacy*
**28,** 957-974.

15\. Smela, E. (2003) *Advanced Materials* **15,** 481-494.

16\. Pettersson, F., Jarger, E.W.H., Inganas, O. (2000) Poster of
*IEEE-EMBS Special topic conference on Microtechnologies on Medicine and
Biology, Lyon, France*.

17\. George, P. M., Lyckman, A. W., LaVan, D. A., Hegde, A., Leung, Y.,
Avasare, R., Testa, C., Alexander, P. M., Langer, R., and Sur, M. (2005)
*Biomaterials* **26,** 3511-3519.

18\. Wallace, G. G., Spinks M. G., Kane-Maguire L. A. P., Teasdale, R.
P. (2003) *Conductive Electroactive Polymers*.

19\. Roemer, M., Kurzenknabe, T., Oesterschulze, E., and Nicoloso, N.
(2002) *Analytical and Bioanalytical Chemistry* **373,** 754-757.

20\. Daunert, S., Moschou, E. A., Ehrick, J. D., Peteu, S. F., Deo, S.
K., Ball, J. C., Bachas, L. G., and Madou, M. J. (2002) *Abstracts of
Papers of the American Chemical Society* **224,** U117-U117.

21\. Xu, H., Wang, C., Wang, C., Zoval, J., and Madou, M. (In press)
*Biosensors and Bioelectronics*.

22\. Shin, Y. S., Cho, K., Lim, S. H., Chung, S., Park, S. J., Chung,
C., Han, D. C., and Chang, J. K. (2003) *Journal of Micromechanics and
Microengineering* **13,** 768-774.

23\. Yang, X., Grosjean, C., and Tai, Y. C. (1999) *Journal of
Microelectromechanical Systems* **8,** 393-402.

[^1]: ^\*^ Corresponding author, e-mail: <mmadou@uci.edu>

[^2]: When valve is closed, the measured current is
    26$\pm$`<!-- -->`{=html}1 nA.