A Passive Refillable Intraocular MEMS Drug Delivery Device
Ronalee Lo1, Kenrick Kuwahara1, Po-Ying Li1, Rajat Agrawal2, Mark S. Humayun2, Ellis Meng1
University of Southern California
1
Viterbi School of Engineering and 2Department of Ophthalmology
1042 Downey Way, DRB-140, Los Angeles, CA 90089-1111, USA
Tel: +1-213-821-3949, Fax: +1-213-821-3897, E-mail: rlo@usc.edu

Abstract
This paper presents the first passive implantable microelectromechanical systems (MEMS) device for targeted intraoculardelivery of therapeutic compounds. In particular, this device addresses the treatment of chronic, difficult to reach diseases that
affect the retina including retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, and glaucoma. Thedevice is composed of three structural polymethyldisiloxane (PDMS) layers that are irreversibly bonded without the use of anyadhesives. These layers form an integrated drug delivery device consisting of a refillable reservoir, tube, check valve, andsuture tabs. This device requires a single implantation surgery and is capable of repeated delivery of multiple drugs.
Characterization of the refillable reservoir and check valve performance is presented. Preliminary surgical implantation resultsof a mechanical test structure are also presented.
Keywords: drug delivery, PDMS, refillable, implant, check valve

1 INTRODUCTION
The ability to precisely administer pharmaceutical solutions
to a specified target within the body, especially the eye, is an
ongoing challenge in many areas of drug delivery.
Pharmacologic management of ocular disease is particularly
difficult as many factors limit drug efficacy. Traditionalroutes of ocular administration include systemic (oral drugs),
topical (eye drops), intraocular and periocular (injections andsustained-release devices); however each of theseapproaches are less than optimal for chronic treatment ofposterior segment eye diseases. These diseases, including
retinitis pigmentosa, age-related macular degeneration,
diabetic retinopathy, and glaucoma, are the leading causes
for irreversible blindness in the world [1].
The surface of the eye is a significant physical barrier tomedications that target intraocular treatment sites. Topicaleye drops must be able to permeate through the modified
mucosal membrane that covers the cornea. Less that 5% of
the topically delivered pharmaceuticals will reach theintraocular space [2]. As a result, topical delivery isineffective and often unable to achieve the required
therapeutic levels at the treatment site. Oral medications
face similar challenges and must overcome the blood-retinal
barrier. In addition, large systemic doses applied to reachtherapeutic levels may result in unwanted side effects [1, 2].
Intraocular injections are currently the most effective methodof treatment. However, chronic diseases may require 1-3
injections per week. Patient acceptance is poor and repeatedinjections may contribute to dose related side effects such as
hemorrhage, retinal detachment, and cataract [3]. Thus,
there is a need for advanced drug delivery systems that havebroad drug compatibility, are minimally invasive, refillable,and provide accurate dosing.
Drug delivery systems/devices can be broadly categorized as(1) biodegradable or nonbiodegradable implants, (2)implantable pump systems, and (3) atypical implantablesystems [4]. Current ocular drug delivery devices fall either
in the first or last category and have had limited success;commercially available sustained-release implants require
periodic replacement and have side effects similar those
associated with injections. Specifications and performanceof existing conventionally manufactured ocular drug delivery
devices are summarized in Table 1 [3, 8].
To our knowledge, this is the first implantable intraocular
MEMS drug delivery device with refill capability. The
advantages of MEMS fabrication for producing miniaturized
and efficient drug delivery systems have already beenrealized for insulin delivery and delivery of bioactive
compounds to neural tissue [5-7].
Table 1. Summary of existing ocular drug delivery devicesDevice
Volume Dosage Rate Lifetime
104 - 208
Ganciclovir
5mg
1-2µg/hrdays
Implant
Corticosteroid
5mg
0.2µg/hr
3 years
Implants
Cyclosporine
5mg
1.3µg/day
3 - 5 years
Implants
Live Cell
N/A
0.2-1.0 g/day 7 week study
Implants
Osmotic Pump
N/A
2.5µl/hr
28 day study
System2 DEVICE DESIGN AND OPERATION
Dimensions for this ocular drug delivery device are selected
such that the overall device is minimally invasive andcomfortable for the patient. The device utilizes a passive
delivery mechanism to eliminate the need for control
electronics and thus reducing the cost of the system. In orderfor the device to be a viable treatment method for chronic
diseases, it must be refillable to allow repeated dosing formany years. Once implanted, the device must precisely andrepeatedly deliver accurate doses and hold enoughmedication for multiple doses prior to refilling (~every 2months). The device should be flexible and conform to thenatural curvature of the eye. An ocular drug delivery device
and its placement relative to the eye (subconjunctival) areillustrated in Figure 1. An illustration of the first device
prototype is shown in Figure 2.

Conjunctiva

Drugdelivery
deviceFill port

Reservoir

Checkvalve
Optic nerve

Posteriorchamber

Lens

Transscleral
cannulaAnterior
chamber

reservoir to the treatment site. Suture tabs secure the device
to the eye. This first prototype also serves as a surgical test
model for future demonstration in rabbits.
The reservoir is secured to the top of the eye, while the shunt
is inserted into either the anterior or posterior chamber(Figure 3a). A specific dose of medication is dispensed fromthe device when the reservoir is manually depressed by thepatient’s finger (Figure 3b). The reservoir can be refilledwith the same or different medication without additional
surgery (Figure 3c).

(a)
(b)
(c)
Figure 3. Illustration of device operation
3 DEVICE FABRICATION
The intraocular drug delivery device is composed of three
individual structural layers of PDMS. The top layer defines
the chamber for the refillable drug reservoir. The middle
layer defines the delivery tube and check valve orifice. Thebottom layer forms the base of the device outlining therefillable chamber, delivery tube, suture tabs, and checkvalve seat. This layer contains posts that serve as (1)mechanical supports to prevent the tube or reservoir fromcollapsing and (2) the valve seat for the check valve.

Figure 1. Concept of a refillable ocular drug delivery device

Figure 2. 3D rendered image of ocular drug delivery device
The first prototype ocular drug delivery device integrates arefillable reservoir, transscleral cannula for drug delivery,
and a check valve that is located at the end of the cannula.
PDMS is selected for its flexibility and ability to reseal itself
after repeated punctures via a syringe needle. This material
selection also enables a refillable drug reservoir. The drugdelivery tube diameter is set to less than 1 mm. For incisionsof this size, the eye is able to maintain its integrity without
the aid of sutures. Support posts are contained within thetube and the reservoir to prevent the top surfaces of thedevice from collapsing when the drug is depleted. A
normally-closed check valve prevents backflow of fluids
from the eye into the device. The valve opens above acertain cracking pressure allowing drug to be dosed from theFigure 4. Exploded view of device structural layers
The top layer was fabricated using a conventionallymachined mold, whereas the middle and top layers are
molded from silicon masters that were etched using DRIE.
The silicon masters were then coated in parylene which
serves as a release layer between the PDMS and silicon.
Individual layers were then bonded together assisted byeither oxygen plasma [9] or wet chemical surface treatment.
Both methods alter the surface chemistry of PDMS fromhydrophobic to hydrophilic; this change facilitates
irreversible bonding of PDMS-to-PDMS without adhesives.
Figure 5 shows a completely assembled drug delivery
device.

and out of the check valve. Flow rate is measured by timing
fluid passage through a precision calibrated pipette. The
valve’s cracking pressure (62 kPa) and flow rate vs. appliedpressure for DI water flow are presented in Figure 9. The
check valve requires optimization to obtain operation at
physiologically-compatible cracking pressures.

Refillable reservoir

Check valve

Vent8 . 8 8 81 mm

Suture tabsRegulator

Transscleral cannulaFigure 5. Assembled PDMS ocular drug delivery device

Drug Delivery Device

WaterReservoir

4 RESULTS AND DISCUSSIONValve

4.1 Refillable Reservoir
Currently, the entire top layer of the reservoir serves as arefill port. Optical images of cross-sections of a single
needle insertion point through silicone septa using noncoring (20 and 30 gauge) and coring (30 gauge) needles werecompared (Figure 6). It is clear that a non-coring needle isable to take advantage of the self-sealing nature of thePDMS and does not remove material when puncturing
PDMS.

Pressure
MeterN2Metering
Valve

VolumeCalibrated
Pipette(a)(b)
Figure 8. (a) Experimental apparatus for determining checkvalve performance and (b) fixture for holding the device

500 μm500 μm500 μm(a)(b)(c)
Figure 6. Optical images of cross sections at puncture sites
for non-coring (a) 20 gauge and (b) 30 gauge needles andcoring (c) 30 gauge needle
4.2 Check Valve
Dyed fluid was injected into the reservoir to verify that theassembled layers were reliably sealed. Pressure was applied
to the reservoir and fluid flow was optically monitored as it
moved down the tube and out of the check valve (Figure 7).

1 mm
Figure 7. Time lapse images of check valve operation
The operating characteristics of the check valve weredetermined by clamping the device in a custom testing
apparatus and attaching the fixture to a water chamberpressurized by a nitrogen cylinder (Figure 8). In such amanner, pressurized water is forced through the delivery tube

Figure 9. DI water flow rate vs. applied pressure for theintegrated check valve (Mean±SE, n=4)
4.3 Surgical Implantation
The prototype device was utilized as a surgical test model formechanical characterization from both surgical handling andoperation perspectives. The device was implanted into an
enucleated porcine eye. First, the reservoir portion wassecured to the eye wall using the suture tabs and then the
tube was directed into the anterior chamber through a small
incision at the limbus (Figure 10). Based on preliminary
surgical results, the device geometry requires adjustment tofacilitate the implantation surgery.
Various device
geometries are being considered and will be evaluated inenucleated porcine eyes. In vivo experiments in rabbits areplanned to demonstrate drug delivery.

in vivo demonstration of ocular drug delivery and applicationof this drug delivery concept to treat conditions in otherphysiological systems.
ACKNOWLEDGEMENT
This work was supported in part by the Engineering
Research Centers Program of the NSF under Award Number
EEC-0310723 and Bausch & Lomb. The authors would liketo thank Tuan Hoang, Mei Nickles, Tun Min Soe, LilianTran, and Joy Wong for their contributions to this work.

Delivery tubeReservoir
1 mmFigure 10. Drug delivery device implanted in enucleatedporcine eye
5 FUTURE WORKThe concept for the second generation device is shown in
Figure 11 and will conform to the eye contours and integrate
flow regulating components that will deliver specific andrepeatable dose volumes.
It will also incorporate
geometrical changes suggested by ophthalmic surgeons tofacilitate implantation. The edges of device will be roundedin order to distribute stress and minimize dead volume. The
refill port will be relocated to maximize accessibility afterthe device is implanted. Other materials for the refill port
and device body are being investigated to further extend
lifetime and mechanical robustness under surgical handling.
A surgical procedure utilizing phenylephrine, a quick-acting
dilating agent, to validate device functionality in vivo will bedeveloped. Future versions will also explore electronicallycontrolled pumping to achieve drug delivery.
Reservoir

Suture holes
Support posts

Check valve

Figure 11. Exploded and assembled views of second
generation device.
6 CONCLUSION
This device is the first reported passive MEMS refillable
intraocular drug delivery device. Its miniature size and refillfeature promises more effective drug treatment for chroniceye diseases. This multi-layer PDMS device requires only asingle implantation surgery and can be repeatedly refilledwith the same or different medications. Characterization of
the device and preliminary surgical implantation results ofthe mechanical model are presented. Future work includes

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