Download Retinal diseases

Application of MEMS in Optobionics: Retinal
Implant
Beghini Alessandro
ABSTRACT
MEMS technology has been attracting
increasing attention in several medical fields for
its possible applications in curing diseases,
which were considered intractable until few
years ago. A typical application, as example,
regards the MEMS based cochlear implant,
which is meant to give hearing to deaf people
through a wireless communication device.
Moreover, MEMS accelerometer are widely
applied to detect movement, heat flow, skin
temperature, heart rate, etc...
Among all these applications, one in
particular attracts the attention of researchers: the
microchip retinal implant. Extended studies have
been conducted in several places of the world
(USA, Japan, Australia, etc…) in order to
develop a microchip able to stimulate damaged
retinal cells. This is very important for patients
affected by Retinitis Pigmentosa (RP) and Age
related Macular Degeneration (AMD).
In this research, the structure of the eye
and the basic principle of the eye’s view will be
investigated. The focus will be in particular on
the function of the retina on the process of sight
and the characteristics of the macula, the part of
the retina, which gives the highest resolution for
the images. The possible diseases and abnormal
retinal conditions will also be briefly considered,
especially
the
aforementioned
Retinitis
Pigmentosa and
Age
related Macular
Degeneration.
In the second part of the project, the
possible approaches to cure the retinal
degeneration will be analyzed (i.e.: epiretinal and
subretinal implant). In particular the study will
focus on the microdevices applied in both the
aforementioned approaches. On one side the
epiretinal system is based on a retina encoder, a
telemetry link and a stimulator device. On the
other side the subretinal implant is based on a
silicon microchip of 2mm diameter, which
contains microscopic solar cells called
microphotodiodes. These are designed to convert
the
light
energy
from
images
into
electrochemical impulses that stimulate the
remaining functional cells of the retina in
patients with AMD and RP. Moreover, it is
designed to produce visual signals similar to
those produced by the photoreceptor layer in
order to subsequently induce biological signals
in the remaining functional retinal cells.
The research will also point out the main
aspects in the microfabrication of these
microchips and the possible alternatives in the
process. Another important issue is the
biocompatibility of the various component
involved in the fabrication, with a particular
concern for the biocompatibility of silicon.
Finally, some important results from the
application of these new techniques will be
addressed. In fact, pre-clinical laboratory testing
showed that animal models with the retinal
implant responded to light stimuli with electrical
signals and sometimes brain wave signals. The
induction of these biological signals indicated
that visual responses had occurred. Besides, the
subretinal device has been implanted in some
patients with RP to study its safety and
feasibility in treating retinal vision loss. Until
now no patient has shown signs of implant
rejections, inflammation or other problems.
INTRODUCTION
Retina Physiology
The human eye is composed by several
parts but the most important is definitely the
retina, which converts light information into
neural electrical signals. These signals are
transported to the visual cortex of the brain by
the optic nerve. The visual cortex then decodes
the neural signals into a meaningful image.
The retina is composed of approximately
126 million photoreceptors (size: 2-3 m), which
provide an analog electronic signal to the
attached bipolar neural cell layer. The bipolar
cells convert the signal into electrical pulse train.
Signal processing and convergence is performed
in all neural cell layers comprising horizontal
cell, bipolar cells, amacrine cells and ganglion.
Approximately one million axons of the ganglion
cells form the optic nerve, which extends into the
visual cortex of the brain. The light passes
through the eye and through the 200 µm thin
retina neural layer before reaching the
photoreceptors (Fig. 1 in next page).
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Fig. 1: Structure of the retina.
This description of the retina is definitely
simplified, in fact there are many interneurons in
the central part of the retina section between the
photoreceptors and the ganglion cells. However,
the concepts introduced can adequately support
the scope of this research.
Retinal diseases
A group of diseases that may affect the
retina is the Retinitis Pigmentosa (RP) and the
Age-related Macular Degeneration (AMD).
These diseases are characterised by a gradual
breakdown
and
degeneration
of
the
photoreceptor cells. Depending on which type of
cell is mainly affected, the symptoms vary, and
include night blindness, lost peripheral vision
(tunnel vision) and loss of the ability to
discriminate colour. Symptoms of RP are most
often recognised in adolescents and young
adults, with progression of the disease usually
continuing throughout the individual's life. The
rate of progression and degree of visual loss are
variable.
So far, there is no known cure for RP.
However, intensive research is currently under
way to discover the cause, prevention and
treatment. At this time, RP researchers have
identified a first step in managing RP: certain
doses of vitamin A have been found to slightly
slow the progression of the disease in some
individuals. Researches have also found some of
the genes that cause RP.
There are other inherited retinal
degenerative diseases that share some of the
clinical symptoms of RP. Some of these
conditions are complicated by other symptoms
besides the loss of vision. The most common of
these is Usher Syndrome, which causes both
hearing and vision loss. Other rare syndromes
that researchers are studying include BardetBiedl syndrome, Best Disease, Leber Congenital
Amaurosis and Stargardt Disease.
Approaches to cure retinal diseases
In order to cure retinal diseases the
possible approaches are the subretinal implant
and the epiretinal implant. These two methods
differ because they substitute different
physiological functions.
An epiretinal implant stimulates directly
the ganglion cells. The device generates spike
trains at defined sites of the retina. The epiretinal
device does not rely on the natural data
processing of the neural compartments in the
retina. Hence, the epiretinal approach requires an
encoder for mapping visual patterns onto pulse
trains as inputs for electronic stimulation.
A subretinal implant is meant to replaces
the degenerated photoreceptors with photodiodes
and electrodes. Hence, the technical implant
must provide an analog signal to the adjacent
neural layers. In this case the neural retina must
be partly intact and it must be able to maps the
visual pattern into pulse trains. The signals are
processed and converged in the functional neural
layers of the retina before they are transmitted
through the optic nerve into the visual cortex.
THE
MICROIMPLANT
EPIRETINAL
Components
The
epiretinal
device
introduced
previously is composed by three major elements:
the retina encoder, a telemetry link for power and
data transmission, and the implantable stimulator
device (Fig. 2). The image sensor, the
implantable power and data receiver as well as
the stimulator are fabricated using standard
CMOS technology.
Fig. 2: The epiretinal system and its 3
functional units.
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Description
In this device, the image is received by a
CMOS photodiode based sensor chip with light
sensitivity exceeding seven decades (>140 dB).
The photodiodes are arranged in a hexagonal
grid structure to obtain a quasi circular
symmetric spatial filter kernel.
At first, spatial filtering is performed on a
receptive field utilizing the interface of the
CMOS image sensor (this is a digital-memory
like interface). Then, a multiply-add unit carries
out hardware convolution of pixel parameters
with the filter coefficients. A chip digital signal
processor is applied for temporal filtering and to
generate spike trains. The DSP unit is also meant
to control the external telemetry data
transmission, implemented as an amplitude
modulated signal (ASK-signal) running at a
carrier frequency of 13.5 MHz. Modulated data
contain stimulation parameters, encoded spike
duration, polarity, and the electrode address.
The implantable receiver chip is powered
by the RF signal. The receiver unit carries out
rectification, clock extraction, demodulation, and
decoding of the signal. A thin polyimide cable
with embedded Platinum conductors connects
the receiver chip with the stimulator die. The
stimulator electronics provides a pulse time, a
current source and a microelectrode selector
addressing a field of 5 x 5 microelectrode pads.
The chip generates pulses with a programmable
pulse width (10 - 300 µs), pulse polarity
(including bipolar pulses), pulse current (10 100 µA) and a pulse rate (500 Hz).
Microfabrication
In order to develop the epiretinal implant,
a special micro machining process has been
developed
for
embedding
platinum
microstructures into 15 µm thin polyimide (PI)
films. The flexible PI foils serve as carrier and
insulation layers that hold the platinum/ gold/
iridium based microelectrodes, conductive lines,
and interconnection pads. Fig. 3 is sketching the
micromachining process for fabricating the PI
films with via holes, double layered conducting
tracks, and contact pads. Micromachining of PI
allows the fabrication of retina contact designs
that adhere smoothly to the concave shape of the
retina. Concentric ring electrodes were fabricated
employing a double metal layer insulated by a 5
µm PI layer.
A special microflex interconnection
(MFI) technology has been developed to
integrate bare silicon chips mechanically and
electrically on the substrate without consuming
any additional space for wiring. The MFI
technology enables high-density interconnects
with a center to center pitch of contacting pads
less than 100 µm.
The basic process of this new technology
is utilizing a common thermosonic ball wedge
bonder to form just the gold ball. This serves as a
rivet
that
technically
and
electrically
interconnects the thin PI foil with the bare chip.
Fig. 3: Microfabrication of flexible 15 µm
thin polyimide film.
Surface mount devices (SMD capacitor,
SMD diodes) and a receiver coil for signal and
data
transmission
were
soldered
to
corresponding contact pads on the PI foil.
Complete epiretinal devices have been built on
flexible foils using the MFI technology and
hybrid assemblies.
Parylene was used to protect the
electronic components. A mold was designed to
house the complete device in medical graded
silicone with the shape of an intraocular lens at
the signal receiving end (Fig. 4).
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Fig. 4: An epiretinal implant packaged in
silicone.
THE
MICROIMPLANT
SUBRETINAL
Description
The subretinal implant is based on the
studies of Chow V. and Chow A. who suggested
to place a silicon based microphotodiode array
(MPDA) in the subretinal space. The device
resembles the function of degenerated
photoreceptor. Therefore, the retina must be only
partially degenerated in order the device to work.
Each photodiode cell generates a photovoltaic
charge which is transferred to the adjacent
microelectrode for stimulation of the bipolar
cells.
Ultra thin and flexible devices have been
designed as well as CMOS-based chips with
different pixel sizes and electrode configurations.
Several prototypes have been developed holding
between 2000 – 5000 photodiode microelectrode
cells on a single device (Fig. 5).
Fig. 5: Schematic cross section of a
microphotodiode (MPD) and SEM micrograph
of the MPD chip surface.
Microfabrication
Microphotodiode arrays (MPDA) are
manufactured on a silicon wafer using CMOS
process technology. The first device produced
was essentially a single photosensitive pixel,
approximately 3 mm in diameter. The current
microphotodiode array includes a regular array
of individual photodiode subunits, each
approximately 20×20 µm2 and separated by 10
µm
channel
stops.
The
resulting
microphotodiode density is approximately
1,100/m2. Across the different generations
examined, the implants have decreased in
thickness, from ~250 µm (earlier devices), to
approximately 50 µm (devices currently used).
Because implants are designed to be powered
solely by incident light, there are no connections
to an external power supply or other device. In
their final form, devices generate current in
response to a wavelength range of 500 to 1100
nm.
The device is obtained starting with the
deposition on the silicon wafer of a passivation
layer of silicon oxide. This consists of a thin
layer of high temperature oxide and about 0.5µm
of
TEOS
(tetra-ethyl-ortho-silicate).
Subsequently, microelectrodes are fabricated
onto the wafer.
Firstly, a photoresist layer is applied and
micropatterned. Then, contact holes are etched
into the passivation layer in order to provide for
an electrical connection of the microelectrodes to
the microphotodiodes. A layer of titanium nitride
is applied and finally micropatterned by lift-off
to release the microelectrodes.
Grooves for chip separation are etched in
the front part of the wafer. Individual chips are
obtained by grinding the wafer from the rear side
up to a final thickness of 30 to 70µm. Chip
diameter is typically 1 to 3mm, thickness 30 to
70 µm. Even though electrical active chips are
fabricated using standard CMOS process
technology,
non-standard
processes
are
necessary to obtain individual implantable
microchips. Titanium is sputtered at high
pressure in a nitrogen atmosphere to obtain
nanoporous titanium nitride (TiN) stimulation
electrodes on the implant. The TiN deposition
enhances electrode surface area by a factor of up
to 100 which is a critical prerequisite for
efficient charge transfer from chip to the retinal
tissue.
Photodiode cells have been fabricated in
various MPD area sizes: 20 x 20 µm2, 100 x 100
µm2, and 200 x 200 µm2 holding monopolar and
bipolar microelectrode configurations.
The key issue for stimulating retina cells
with technically generated photocurrents is an
optimum capacitive coupling to the bipolar cells.
Several contact layers (p-doped a- Si:H,
microcrystalline
Si,
metal-induced
crystallization) have been investigated which
provide high perpendicular conductivity with
reduced lateral parasitic losses to the surrounding
tissue.
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Experimental Results
The
studies
conducted
on
electrostimulation have elucidated that a pure
photovoltaic current is not sufficient to provide
charge capacities for stimulating the bipolar
cells. Therefore, an additional energy input is
provided by near-infrared radiation or radio
frequency power transmission.
The devices have been implanted in pigs
and rabbits to prove the biocompatibility, general
function and local stability of the implants. The
inner retina architecture is well preserved,
however in vivo experiments revealed a decay of
the passivation layer of the device when
implanted for more than six month (Fig. 6).
Titanium nitride electrodes proved to be
biostable over an implantation period exceeding
18 months. Biostable passivation and packaging
will be a major concern in on-going experiments.
Fig. 6: Micrograph comparing surfaces
of the MPDA before and after 10 month of
implantation in the rabbit eye.
The next generation of the subretinal
device will integrate up to three active
microchips on a flexible polyimide foil with
embedded platinum or gold conductors.
The polyimide foil is microfabricated
employing the same technology illustrated in
Fig. 3. Chips will comprise a photodiode array, a
transducer for IR energy supply, and an active
stimulation chip with microelectrodes.
The chips will be soldered and glued to
the flexible PI foil. This device is currently in the
design phase.
BIOCOMPATIBILITY
Long-term
biocompatibility,
as
mentioned previously, is one of the most
important issues to be solved in order to put for a
long period of time a retinal implant into a
human eye.
Immune reactions in the form of rejection
are not likely to be a major problem given the
"immune-privilege" enjoyed by the eye and the
availability of inert materials. Chronic
inflammation and cellular reactions that occur in
response to the physical presence of the foreign
body are of much greater concern. Responses of
Müller cells could scar the retinal surface and
exert tractional forces that could detach the
retina. Indeed, surface scarrings has been
observed in the experiments with electrode
placement on the retina. The future research
should be directed towards minimisation of
postoperative reactions by using inert materials
with a mechanical design that avoids significant
tissue distortion.
Stabilising the electrode matrix on the
surface of the retina is an especially formidable
problem. Penetrating electrodes could be used to
help maintain stable positioning of the matrix
and the electrodes would be closer to the retinal
ganglions. Violation of the retinal surface,
however, could cause destructive tissue reactions
and thus the wisdom of using penetrating
electrodes is doubtful. The matrix could instead
be fixed using biocompatible adhesives, e.g.
fibrin adhesives. Electrochemical toxicity can
kill neurons. When charge is passed through
metal (or metal-doped) electrodes the creation of
toxic by-products is nearly unavoidable. Here the
only goal yet available is damage control. The
problem can be lessened by minimising charge
and utilising accurately balanced biphasic pulses.
One can also make the electrodes of preferred
metals like iridium and use different surface
coatings that substantially increase the surface
area of the electrodes. Although histological
evidence of neuronal damage is commonly
found, patients still benefit from the prosthesis.
EPIRETINAL AND SUBRETINAL
MICROIMPLANT: PROS AND CONS
As illustrated in this research both
approaches, epiretinal and subretinal, have
advantages and disadvantages.
The epiretinal design, for example, does
not rely on the presence of intact neurons for
signal processing when imposing spike patterns
on the ganglion cells. This is an advantage
especially when retinal neurons have already
been damaged in an advanced state. However,
the generation of receptive fields through
ganglion cell stimulation has still to be tried
under in-vivo conditions with the developed
system.
The subretinal systems looks more
interesting because of its simpler structure which
results in a lower number of technical
5
components needed for its operation. The
epiretinal systems requires the external camera,
which has to follow the movements of head or
eye, and the encoder unit, which will be tuned by
the patient. The operation of subretinal system
cannot be influenced from outside, once it is
implanted. This may be an advantage or a
disadvantage, depending on the quality of the
surgical operation. It is easier to integrate a
higher number of electrode sites onto the
subretinal device. Current designs will have a
number of 2000 electrode sites at a distance of
approximately 70 µm. In comparison, the current
epiretinal device is controlling only 24
microelectrodes. It is planned to increase twice
the number of electrode sites in future designs by
a factor of ten, yielding comparable electrode
numbers as the subretinal device. The technical
challenge is quite substantial in regard to heat
dissipation of electronic components and to
physically addressing the sites.
CONCLUSION
This research has shown how the
importance of the retinal implant, both epiretinal
and subretinal, is growing in the possible
applications to cure eye diseases.
However, it should be also pointed out
that the implemented systems are far from
nature’s sophistication. More than 100 million
photoreceptors receive the incoming light in
healthy eyes. About 1 million ganglion cells
produce signals that lead to the perception of
meaningful images. An approach with 20 or
2000 electrodes will always be crude.
Besides, even if the advances in genetic
and tissue engineering have the potential to
outperform a pure technical retina implant in the
far future, this project has proven that a retinal
implant is technically feasible today utilizing the
recent advances in MEMS technology.
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