International Journal of Engineering Trends and Technology (IJETT) – Volume 7 Number 3- Jan 2014
BioMEMS For Treatment Of Glaucoma
S.Sibi#1, Aman Kumar Arora*2, Amritraj.k#3, Sumangali K*4
#School of Information Technology and Engineering,
VIT University, Vellore-632014, Tamilnadu, India.
*School of Bio Sciences and Technology,
VIT University, Vellore-632014, Tamilnadu, India.
#School of Bio Sciences and Technology,
VIT University, Vellore-632014, Tamilnadu, India.
*Assistant professor (senior),
School of Information Technology and Engineering,
VIT University, Vellore-632014, Tamilnadu, India.
Abstract— Glaucoma is characterized by pathological changes in the
optic disc and nerve fibre layer of retina. Elevated intraocular
pressure 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. Reduction of intraocular pressure reduces
the rate of disease progress.
This research paper focuses on the development of MEMS (microelectromechanical system) devices which can be implanted in the eye
to continuously monitor the intraocular pressure and thus prevent
glaucoma from occurring. The paper provides measures for the
treatment of glaucoma using different types of pressure sensors and
glaucoma drainage devices. Strain gauge pressure sensor and a SU-8
based passive radio-frequency wireless intraocular pressure sensor are
used to monitor glaucoma. The elevated pressure is drained out with
the help of different types of MEMS based implantable drainage
devices.
Keywords— MEMS, BioMEMS, Glaucoma, Treatment of Glaucoma
I INTRODUCTION
Huge number of people around the globe is affected by
permanent vision loss associated to glaucoma. There are very
less signs or symptoms till vision loss become severe. The
cause of the disease is not clearly known. The cure dose not
exists as of now. Glaucoma is characterized by pathological
changes in the optic disc and nerve fibre layer of retina.
Elevated IOP> 22mmHg (Intraocular Pressure) 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. Reduction of intraocular pressure
reduces the rate of disease progress.
Glaucoma is an optic nerve disease resulting in loss of vision.
It is often associated with increased pressure of fluid inside
the eye. The types of glaucoma are: Open-angle glaucoma,
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Close-angle glaucoma, Normal tension glaucoma and
congenital glaucoma.
The iris, cornea and lens are bathed in aqueous humor, which
is continually produced by nearby tissues. The fluid moves
out of the eye via the trabecular meshwork drainage.
Blockage in the trabecular meshwork is associated with the
angle, thus the iridocorneal angle is important.
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. Current glaucoma
monitoring involves taking laboratory based intra ocular
pressure (IOP) measurements. The measurement of
intraocular fluid flow and IOP parameters related to blockage
formation in the eye require to be continuously monitored in
Glaucoma.
When there is a resistance at the outlet regions, fluid flow is
blocked and the flow-IOP equilibrium is altered. Some of the
possible changes that could occur in the outlet region are:
1. The lens blocking the fluid inlet region.
2. A rise in pressure at the exit regions.
3. A part of the lens-iris dislocating or contracting thus
blocking the angle of drainage.
4. The cornea expanding or enlarging and thus blocking
drainage.
The changes in the eye that prompt the blockage of fluid are
known not to occur suddenly but accumulate gradually over a
period of time. When a blockage occurs, IOP rises from 15 to
nearly 25 mmHg. In severe cases, IOP has been recorded up
to 40mm of Hg and above.
Doctors treating glaucoma target controlling IOP rise and
maintenance of IOP within 12-15 mmHg as a means of
achieving proper flow regulation .IOP is measured externally
on a monthly basis using a tonometer in a clinic. The
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International Journal of Engineering Trends and Technology (IJETT) – Volume 7 Number 3- Jan 2014
condition is treated with a pharmacologic known as betablockers or adrenergic agnostics which are used to clear
blockages by regulating fluid production, inlet and exit
pressures to maintain an optimal IOP level. IOP is prone to
fluctuations and has been recorded to vary during different
times of the day. When chemicals fail to bring down IOP,
treatment is then focused on surgical removal and correction
of the structures blocking fluid drainage.
Apart from raised IOP, patients with glaucoma have been
observed to have an increased resistance to outflow of the
aqueous humor which is also expressed as facility of outflow
and is an important blockage related parameter denoted by
the symbol Cf.
Glaucoma management options include medical therapy,
laser surgery, incisional surgery and glaucoma drainage
devices (GDD). 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 patient’s 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. We now see the various ways of treatment of
glaucoma using MEMS.
II TREATMENT OF GLAUCOMA
The doctors treating glaucoma target controlling IOP rise and
maintenance of IOP within 12-15 mmHg as a means of
achieving proper flow regulation .IOP is measured externally
on a monthly basis using a tonometer in a clinic. The
condition is treated with a pharmacologic known as betablockers or adrenergic agnostics which are used to clear
blockages by regulating fluid production, inlet and exit
pressures to maintain an optimal IOP level. IOP is prone to
fluctuations and has been recorded to vary during different
times of the day. When chemicals fail to bring down IOP,
treatment is then focused on surgical removal and correction
of the structures blocking fluid drainage. Apart from raised
IOP, patients with glaucoma have been observed to have an
increased resistance to outflow of the aqueous humor which
is also expressed as facility of outflow and is an important
blockage related parameter denoted by the symbol Cf.
Glaucoma management options include medical therapy,
laser surgery, incisional surgery and glaucoma drainage
devices(GDD). 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 patient’s 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.
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A. Glaucoma Drainage Device (GDD)
These are the devices that are surgically inserted into the eye in
order to increase the outflow of the aqueous humor. They create an
alternate pathway by channeling aqueous from anterior chamber
through a long tube to an equatorial plate inserted under the
conjunctiva.
Fig 1: A glaucoma drainage device implanted in the eye
Once the device is surgically implanted, body begins to
encapsulate the device with fibrous tissue as it considers the
GDD to be a foreign object, forming a bleb. This bleb is
extremely important in the operation of the device, because it
principal source of resistance to flow of aqueous through
device. Aqueous humor flows freely out of anterior chamber,
through tube and onto drainage plate, from where it would
spread across surface of sclera with minimal resistance. This
is a major feature which determines success or failure in an
individual. 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; precision
and batch fabrication.
The purpose of a GDD is to control and regulate IOP,
however, current GDD’s are lacking in function and in
efficacy. GDD is implantable and passive to reduce and
regulate IOP by controlling removal of excess aqueous
humor from anterior chamber.
B Intraocular Pressure Sensor For Glaucoma Management
Increased IOP and wide daily IOP variations indicate risk of
glaucoma, a widespread condition which leads to irreversible
loss of peripheral vision, and detailed information would be
invaluable towards the clinical management of glaucoma.
Since changes in IOP are correlated to changes in cornea
curvature, wearable MEMS strain gauge for the measurement
of spherical deformation of the cornea due to intraocular
pressure changes promises to provide continuous, minimally
invasive monitoring over prolonged periods. The strain gauge
developed by Leonardi et al (given in figure) is based on the
same flexible polyimide technology with embedded Pt–Ti
structures. The polyimide structure is then embedded in a soft
contact lens, which can be worn continuously during the
course of a day for uninterrupted measurement.
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Fig 2: A graph between time and contact lens output voltage
Measurements from the sensing contact lens show good
sensitivity, revealing pressure changes as low as 1.5–2 mm
Hg, and this device shows promise toward the continuous
monitoring of IOP.
The strain gauge measures the change in pressure on the eye
with blinking (eyes are closed but the eyelids are pressed
more firmly). Also evident is ocular pulsation due to the heart
rate. This pulsation is the smallest signal ever measured in
the eye and corresponds to 1.5–2 mm Hg.
C Su-8 Based Micro fabricated Implantable Inductively
Coupled Passive RF Wireless Intraocular Pressure Sensor
An implantable passive wireless pressure sensor uses an
inductively coupled wireless sensing technique, particularly
designed to monitor IOP of glaucoma patients. The
microfabricated IOP sensor consists of a planar spiral gold
coil conductor, a two-parallel-gold-plate (metal-insulatormetal) capacitor, and a SU-8 pressure sensitive diaphragm.
The IOP is fully encapsulated inside biocompatible SU-8
stacking layers to isolate IOP sensor from biological tissue
medium environment. By measuring the impedance phase
dip frequency shift from external coil, the IOP signal can be
obtained through implanted IOP sensor. The optimised size
of manually wound external coil was investigated. The
readout distance is upto 6mm from implanted sensor. The
microfabricated IOP sensor has relatively high sensitivities7035ppm/mm of Hg in air and 3370 ppm/mm of Hg in saline
medium, with pressure resolution lower than 1 mm of Hg,
which is adequate for IOP monitoring application.
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Fig 3: Fabrication process flow of wireless IOP sensor
D Implantable Parylene Mems For Glaucoma Therapy
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
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 environments are extremely
corrosive to most MEMS materials, parylene is not affected
as it cannot be degraded hydrolytically . 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.
GDDs must be designed to incorporate several physiological
parameters. Aqueous humor is produced in the eye at 2.4±0.6
µL/min (mean±SD) and changes over the course of a day
(morning: 3.0 µL/min; afternoon: 2.4 µL/min; evening: 1.5
µL/min). The resistance of conventional AH drainage tissues
is ~3-4 mmHg/µL/min. 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
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International Journal of Engineering Trends and Technology (IJETT) – Volume 7 Number 3- Jan 2014
silicon wafer and parylene is deposited around the mold.
Each shunt is removed from the master mold and the silicon
is chemically removed.
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. 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 of
AH at elevated IOPs. It must open at IOP > 22 mmHg and
close when IOP ≤ 22 mmHg to prevent hypo tony.
The mechanical pressure sensor is based on the principle of
operation of a Bourdon tube and consists of a centrally
supported, free-standing parylene spiral-tube formed by a
long, thin-walled toroidal channel. An indicator tip is
integrated at the end of the channel at the circumference of
the spiral as a means for simple optical readout. 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.
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.
E Artificial Nano-Drainage Implant For Glaucoma
Treatment (ANDL)
This technique involves replacing the functionality of
diseased drainage pathway for aqueous humor outflow (i.e.,
trabecular meshwork). By enhancing aqueous humour
outflow, artificial drainage implant will lead to decrease in
IOP and a halt in progression of glaucoma. A nano-drainage
implant consists of a micro porous membrane connected to
an integrated polymeric shaft inserted through sclera into
anterior chamber, thereby, allowing a bypass route for
aqueous
humor
outflow.
Initial studies of aqueous humor perfusion through such
membranes showed protein plugging as a result of
hydrophobic interactions. Myocilin, a strong hydrophobic
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protein was identified as the cause of that obstruction. The
nano-filtration implant design could easily and safely be
inserted into a glaucomatous eye and could immediately and
predictably lower the IOP. Nano pore of 200nm or less in
diameter can effectively prevent bacterial penetration. Tiny
porous size will contribute to protein absorption and clogging
unless a non-fouling biocompatible material is coated on the
surfaces. An integrated packaging technique has to be
utilized to connect filtration membrane to polymeric shaft for
easy implantation procedure.
Fig 4: Fabrication process of ANDL
F Minimally Invasive Parylene Dual-Valved Flow Drainage
Shunt For Glaucoma Implant
Enabled by the dual-check valve operation, a paryleneenabled microvalved shunt implant can physically drain extra
intraocular fluid and regulate IOP within normal range of 1520mm of Hg. Improved surgical features, in addition to
microfluidic components, such as parylene- tube carrier and
anchors, are also incorporated in such device to realize
minimally invasive suture-less implantation, suitable for
practical in-vivo use.
With the optimized micromachining and post-fabrication
process procedures, developed implant is first check-valved
GDD, which is passive, consumes no additional power and
functions without any circuit involved to pursue it’s medical
application.
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International Journal of Engineering Trends and Technology (IJETT) – Volume 7 Number 3- Jan 2014
impanation. The slit between valve and parylene microtube was
sealed by epoxy. After epoxy dried, valve tube assembly was
inserted into DuPont Teflon FET capillary tube and photoresist
was used to seal gap between FET tube and valve tube structure.
FET tube was cut into 2 inch segments in advance and integrated
valve tube assembly was attached to one end of capillary tube.
Whole setup was baked to dry in conventional oven at 100*C.
After photoresist dried, each assembly was connected to testing
setup. Bench-top testing setup used compressed nitrogen to apply
pressure to water.
Fig 5: Full GDD System consisting of dual valve micro-flow regulation
system
The complete implant comprises a dual-valve microflow
regulation system in tube with integrated anchors. Dual backto-back microvalves with one normally closed(NC) but open
at 20mm Hg and normally open(NO) but closed beyond
50mm Hg are designed. Few holes are designed on strictionbonding parts where epoxy can be used to further ensure
bonding strength and to prevent parylene from delamination
after repeated operations. To accommodate two microvalves,
hollow tubes made of thick parylene are utilized and length is
chosen as 6mm long. The fluid can flow from NC valve to
NO valve before the pressure reaches limit of NO valve,while
opposite direction iis forbidden due to closed NC valve.
G Ex-Vivo Implantation Study Of Minimally Invasive GDD
The GDD is designed to treat glaucoma patients by draining
out their extraneous aqueous humor out of anterior chamber
utilizing MEMS micro-fluidic normally closed (NC) check
valve. NC check valve is encapsulated in protective tubing
made from parylene C, which has been proven to be
biocompatible in implantation. A new packaging and benchtop testing procedure is established to characterize integrated
GDD prior to it’s implantation into enucleated porcine eyes.
Pre-implanted characterization curve demonstrates cracking
pressure of 10-20mm Hg of NC check valve.
The NC check valve remains closed as long as aye pressure is
lower than designed cracking pressure. It restricts eye fluid
from leaking out of anterior chamber, which otherwise causes
hypotony. Owing to the inherent structure of NC valve, fluid
coming from opposite way will be rejected, protecting
anterior chamber from any unwanted fluid flowing in.
Cracking pressure can be controlled by many parameters
such as height of stiction part of parylene, parylene thickness,
tether numbers and geometry of tethers. Flow rate is defined
by size of opening orifice and opening gap of parylene
membrane.
The chip with valves was first dipped into acetone water to strip
off protective photoresist. Each valve is released from chip by
breaking silicon connection part. The NC check valve was then
inserted with parylene side facing interior of parylene micro tube
in order to prevent damaging parylene membrane during
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Fig 6: Fabrication process of NC check valves
III CONCLUSION
Though there are a lot of ways treating glaucoma. The real
important question is “is there a cure?” If there is a cure then
it would be really be a great medical breakthrough. The most
promising method of cure seems possible from the studies of
Dr.Drooper of UCLA medical institute. The treatment for
glaucoma has increased tremendously over the years but
finding the cure is more important.
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