An implantable glaucoma  management system is presented for the first time. Glaucoma is an incurable disease characterized by gradual visual field loss that eventually results in blindness. Studies indicate that reduction of intraocular pressure reduces the rate of disease progress. A passive parylene MEMS pressure sensor and drainage shunt comprise a complete system for the detection and alleviation of elevated intraocular pressure. Tissue anchors for securing the pressure sensor to the iris have been developed to facilitate direct and convenient optical monitoring of intraocular pressure

Chen, Po-Jui

Humayun, Munir

Meng, Ellis

Rodger, Damien

Tai, Yu-Chong

Caltech Authors - Main

Proceedings of the 3rd Annual International IEEE EMBS Special Topic
Conference on Microtechnologies in Medicine and Biology
Kahuku, Oahu, Hawaii u 12 - 15 May 2005
IMPLANTABLE PARYLENE MEMS FOR GLAUCOMA THERAPY
Ellis Meng'I Po-Jui Chen2, Damien Rodger2, Yu-Chong Tai2, and Mark Humayun3
'Department of Biomedical Engineering, University of Southern California, CA, USA
2Caltech Micromachining Laboratory, California Institute of Technology, CA, USA
'Keck School of Medicine, University of Southern California, CA, USA
Abstract-An implantable glaucoma management system is
presented for the first time. Glaucoma is an incurable disease
characterized by gradual visual field loss that eventually
results in blindness. Studies indicate that reduction of
intraocular pressure reduces the rate of disease progress. A
passive parylene MEMS pressure sensor and drainage shunt
comprise a complete system for the detection and alleviation of
elevated intraocular pressure. Tissue anchors for securing the
pressure sensor to the iris have been developed to facilitate
direct and convenient optical monitoring of intraocular
pressure.
Keywordls - Glaucoma, glaucoma drainage devices, intraocular
pressure sensor, parylene, tissue anchors
I. INTRODUCTION
Millions of people worldwide are afflicted by irreversible
vision loss attributed to glaucoma. There are often no signs
or symptoms until vision loss is severe; estimates indicate
that only half of the 3 million Americans with glaucoma are
aware they have the disease [1]. The cause of the disease is
not well understood and there is currently no cure.
Glaucoma is a chronic disease and must be treated for life.
Glaucoma is characterized by pathological changes in
the optic disc and nerve fiber layer of retina. Elevated IOP
> 22 mmHg is known to be responsible for slowly killing
the ganglion cell axons that comprise the optic nerve and is
strongly implicated in the pathogenesis of glaucoma [2].
Evidence from large, prospective studies suggests that
reducing IOP to normal levels (15.5±2.6 mmHg
(mean±SD)) reduces the rate of disease progression [3, 4].
Glaucoma management options include medical therapy,
laser surgery, incisional surgery, and glaucoma drainage
devices (GDDs). Medical therapy lowers IOP by improving
the outflow of aqueous humor (AH) or to reduce its
production. Some surgical techniques attempt to stimulate
AH outflow, however, the primary surgical strategy is to
manage glaucoma by lowering the patients' IOP through
removal of excess AH. Regardless of the technique that is
employed, accurate real-time measurements of IOP and the
ability to restore normal levels are critical in the treatment
of this disease.
Glaucoma management typically starts from
interventions that are the safest and least invasive.
Inasmuch, medical therapy is the most widely used
treatment initially. GDDs are used as a last resort in cases
of refractory glaucoma or in patients who have not
responded to previous treatment attempts. While GDDs can
potentially lower IOP effectively, ophthalmologists are
reluctant to use current GDDs due to high rates of
complications.
II. CURRENT GLAUCOMA DRAINAGE DEVICES
All modern GDDs are based on the 1969 concept of the
Molteno implant which consists of tube that shunts aqueous
humor from anterior chamber to an external sub-
conjunctival plate [5] . In the last 30-40 years, very few
innovative advances in surgical operation or implant devices
have occurred. Only two major modifications to GDDs
have been introduced: (1) addition of a valve to resist
outflow and reduce hypotony and (2) increase in the end-
plate surface area to achieve lower 1OPs.
GDDs are currently limited to the treatment of
refractory glaucoma due to complications. The most
significant complication of GDDs is postoperative hypotony
(a condition where IOP is abnormally low, IOP <5 mmHg)
[6]. During the early postoperative period, there is a lack of
flow resistance prior to fibrous capsule formation around the
end-plate resulting in hypotony, flat anterior chambers,
choroidal effusions, and suprachoroidal hemorrhages.
Strategies to avoid hypotony include performing the
operation in two-stages to allow fibrous capsule formation,
tube ligature, internal tube occlusion, and the development
of valved GDDs. These solutions are not ideal and
interestingly, current valved implants do not perform as
advertised and do not eliminate the occurrence of these
complications. Furthermore, the success rate of current
GDDs decreases by 10-15% every year suggesting poor
long term performance [2].
III. MEMS GLAUCOmA THERAPY
To the best of our knowledge, no one has fabricated a
complete GDD or a passive IOP sensor using MEMS
technology. MEMS technology offers several advantages
over traditional approaches to glaucoma therapy including
highly functional microfluidic systems that can be adapted
to drug delivery and IOP management; miniaturized sensors
suitable for implantation with precise and accurate readouts
[7]; precision and batch fabrication.
The purpose of a GDD is to control and regulate IOP,
however, current GDDs are lacking in function and in
efficacy. These factors are partly attributed to suboptimal
design and nonideal biomaterial selection. By leveraging
polymer MEMS technology, all the components necessary
for a GDD can be seamlessly integrated into a miniaturized,
single-piece device that is biocompatible and minimizes
complications. Our MEMS GDD is an implantable, passive
parylene shunt to reduce and regulate IOP by controlling the
removal of excess aqueous humor from the anterior
chamber.
0-7803-8711-21051$20.00©2005 IEEE 116
Until now, MEMS pressure sensors designed for the
purpose of IOP sensing required electrical circuitry and
hermetic sealing which severely limits their implementation.
Also, tonometers fabricated using conventional techniques
are not suitable for continuous IOP monitoring and cause a
considerable amount of patient discomfort. They typically
require contact with a patient's cornea, necessitating the use
of anesthetics. We propose a new mechanical sensing
paradigm for a passive and biocompatible parylene MEMS
IOP sensor. Our sensor will be integrated with novel
parylene/silicon tissue anchors such that the sensor platform
will be implanted behind the cornea and attached to the iris
without sutures. The mechanical structure has an integrated
indicator tip that can be monitored through external optics to
track changes in IOP.
Parylene is selected as the structural material for
aforementioned components for its desirable properties,
both as a biomaterial and a MEMS material. It is a USP
Class VI material that is utilized for its biocompatibility,
biostability, and low cytotoxicity. Parylene is a proven
MEMS material [8-13] with excellent properties including
low process temperature, low defect density, transparency,
and chemical inertness. In addition, parylene technology
accommodates multi-layer processing to produce highly
functional structures and features. While biological
environrents are extremely corrosive to most MEMS
materials, parylene is not affected as it cannot be degraded
hydrolytically [14].
The combination of an implantable MEMS sensor and
drain will make it possible to closely track a patient's IOP
history and maintain IOP at normal levels. This constitutes
a novel and complete diagnostic and therapeutic system for
treating glaucoma.
IV. PARYLENE GLAUCOMA DRAINAGE DEVICE
GDDs must be designed to incorporate several
physiological parameters. Aqueous humor is produced in
the eye at 2.4±0.6 giL/min (mean±SD) and changes over the
course of a day (morning: 3.0 itL/min; afternoon: 2.4
gL/min; evening: 1.5 giL/min). The resistance of
conventional AH drainage tissues is -3-4 mmHg/ItL/min [3].
The minimal system requirements for a MEMS GDD are a
shunt and pressure-sensitive valve to remove excess AH
such that IOP is maintained between 5-22 mmHg.
A parylene shunt has been fabricated using a sacrificial
silicon technology. A shunt mold is etched into a silicon
wafer and parylene is deposited around the mold. Each
shunt is removed from the master mold and the silicon is
chemically removed. In Fig. 1, several types of shunts are
shown with one end sealed off (-8xO.5x 1 mm3 and 10 gim
thick wall). At the sealed-ends, remnants of the silicon
mold are visible. This closed end is implanted into the
anterior chamber of the eye where it comes into contact with
AH. At this end of the shunt are several regions where the
parylene has been etched down to 0.5 gum or less. When
elevated IOP is detected these thinned regions can be
punctured using a laser to allow excess AH to be released
from the anterior chamber. Flow and pressure regulation is
achieved by controlling the number of and time at which the
punctures are made along the closed end of the shunt.
Like some commercially available GDDs, this parylene
device does not prevent bi-directional flow; the laser
puncture feature does allow flexibility in initiating treatment.
Our next design will integrate a check valve to enforce one-
way flow and mechanical barbs on the exterior of the tube to
anchor the device and prevent slippage after implantation.
Preliminary evaluation of these shunts by implantation into
rabbit eyes also suggests the need for increased stiffness to
facilitate handling and surgical insertion of these delicate
tubes.
At physiological flow rates, pressure drops are
negligible for the size of our shunt. Therefore, the majority
of the pressure drop in the system will be concentrated at the
valve. In order to promote drainage of AH out of the
anterior chamber, the valve must be optimized to drain at a
flow rate equal to the production ofAH at elevated lOPs. It
must open at IOP > 22 mmHg and close when IOP < 22
mmHg to prevent hypotony. Current GDDs with valves
have not performed as advertised and are unable to perform
the shut-off function required after desired IOP levels are
met. It is suspected that once the valves open, they never
close and possibly account for some of the observed
complications. Previously, we have demonstrated parylene
valve that can be adapted to meet all the requirements for
application to GDDs [15]. A new biocompatible, pressure-
sensitive valve will based on this design will enable
advanced glaucoma management by maintaining healthy
IOP levels and achieving pressure-regulated shut-off.
RLasePulse Excess Fluid Drainage
tU g00000_-lD ffffff~~~~~~~sce fluid
(b)
Fig. L. (a) Paryiene shunts with and without thinned regions. The dark
region at the rounded tip is silicon that has been left to provide contrast for
viewing. (b) Mechanism of AH release through laser-induced punctures in
thinned regions.
117
V. SPIRAL-TUBE PARYLENE IOP SENSOR
Our mechanical pressure sensor is based on the
principle of operation of a Bourdon tube [ 16] and consists of
a centrally supported, free-standing parylene spiral-tube
formed by a long, thin-walled toroidal channel (Fig. 2). An
indicator tip is integrated at the end of the channel at the
circumference of the spiral as a means for simple optical
readout. A detailed report on the fabrication of the device is
described in [17].
The hollow spiral channel forming the sensor is sealed
at I atm as the gauge reference. When a uniform pressure
difference is generated across the channel walls, a bending
moment is created forcing an in-plane radial and angular
deformation of the tube. When the external pressure is
lower than the internal pressure in the channel, the spiral
structure unwinds. When the external pressure exceeds the
internal pressure, the spiral will further coil. This effect can
be monitored by visually tracking the movement of the
indicator tip. Deformation that results is linearly related to
the applied pressure difference and can be correlated to
environmental pressure, or in this case, IOP.
Fig. 2. SEM of passive, spiral-tube parylene IOP sensor (I mm radius) and
close-up of integrated indicator tip (6x 100 pm)
8
0 6
a) 5
54
03
a. Itesting0
'D2
X- testing03
5)0
0 5 10 15 20 25 30 35 40 45
Observed Tip Rotation (degree)
Fig. 3. Observed tip rotation in water under applied pressure.
Sensor operation has been verified in air, isopropyl
alcohol (IPA), and water. Observed tip rotation is visually
recorded with the aid of optical magnification as the
environmental pressure is increased. The results for water
are shown below (Fig. 3). Measured sensitivities are
0.22 '/mmHg (+ 9% variation in rotation angles) in IPA and
0.13 '/mmHg in water (± 15% variation). Sensitivity of the
pressure sensor can be tuned by changing the number of coil
turns. Increased sensitivity can be achieved by increasing
the number of coil turns, decreasing the thickness of the
tube walls, and increasing the aspect-ratio profile of the tube.
Preliminary implantation studies in rabbits indicate that
the spiral-tube structure lacks the necessary mechanical
robustness to survive surgery. Currently, efforts to further
reduce the overall device size and integration of a protective
cap are underway to facilitate implantation. In addition to
improving device reliability, design optimization is being
investigated to increase sensitivity.
VI. SUTURE-LESS TISSUE ANCHORS
Implantable devices require mechanical attachment to
the biological environment. This is typically achieved by
sutures, tacking, or stapling at the expense of increasing
overall implant size through the addition of anchoring sites.
Given the spatial constraints in the eye and to minimize
damage, it is desirable to implant and secure our sensor and
GDD without needing sutures.
The logical choice for placement of the IOP sensor to
facilitate optical readout would be behind the transparent
cornea on the iris. In order to monitor movement of the
indicator tip, the sensor should be securely attached to the
iris. The surface topology of the iris consists of numerous
folds resembling hills and valleys that can accommodate
alternative mechanical attachment methods. We fabricated
and implanted two tissue anchoring prototypes consisting of
Velcro-like arrays of parylene-covered silicon posts on the
irises of rabbit eyes (Fig. 4).
Fabrication of the posts can be integrated with the IOP
sensor process. To enhance the adhesion of parylene,
anchors are patterned and etched at future post sites
following [18]. Posts are then defined and etched using
DRIE in a silicon substrate. Finally, the entire structure is
coated with a biocompatible parylene layer.
The etched columnar anchors securely fastened silicon
plates to rabbit irises. The plates remained fastened even
after vigorous shaking imposed on the eye by the surgeon.
The force required to dislodge anchored structures will be
determined. Currently, these structures are being integrated
on the backside of an IOP sensor substrate and will be used
to hold the entire platform in place for visual inspection of
IOP. Similar anchoring structures may also be applied to
mechanically attach the GDDs.
118
Top Bottom
Fig. 4. (a) 3D illustration of IOP sensor on a silicon platform (1.5 mm
.75 mm) with initegrated tissue anchors underneath. (b) Fabricated
anchors slhowing differenit layotuts and views (top and side). The circular
anclhor in thie top lefe is 250 sun in diameter and 250 pum long. The square
anchors measure 250 pun on a side and the radial arrns in the lower left
photo are 8 smi in width.
VII. CONCLUSION
Implantable parylene MEMS for complete management
of glaucoma. including monitoring and therapy. are
presented. Preliminary results of implanted svstem
components into rabbits are extremely promising. Current
work in progress includes careful examination of
biocompatibility and implantation challenges and
optimization of system components for application in
humans.
ACKNOWLEDGEMENT
This work was supported in part by the Engineering
Research Centers Program of the NSF under Award
Number EEC-0310723 and by a fellowship from the
Whitaker Foundation. We would like to thank Mr. Trevor
Roper for assistance in fabrication. Dr. Murat Tunc for
perfonning surgical implantations. and Dr. Tuan Hoang for
help with proofreading.
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Implantable parylene MEMS for glaucoma therapy

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Implantable parylene MEMS for glaucoma therapy

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