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Bionic Eye Could Lead to Vision for AMD Sight
Loss
 April
4, 2005 - Stanford physicists and eye doctors have teamed up to design a
"bionic eye," of sorts. The researchers hope their device may someday
bring artificial vision to those blind due to retinal degeneration as in
age-related macular degeneration (AMD), the major cause of vision loss
in senior citizens over age 65, and an issue is becoming more critical as the
population ages.
Each year, 700,000 people are diagnosed with AMD,
with 10 percent becoming legally blind, defined by 20/400 vision. Many
AMD patients do retain some degree of peripheral vision.
Degenerative retinal diseases result in death of
photoreceptors--rod-shaped cells at the retina's periphery responsible
for night vision and cone-shaped cells at its center responsible for
color vision. Other than AMD sufferers there are 1.5 million people in
the world who suffer from retinitis pigmentosa (RP), the leading cause
of inherited blindness.
A design of this optoelectronic retinal prosthesis
system that can stimulate the retina with resolution corresponding to a
visual acuity of 20/80--sharp enough to orient yourself toward objects,
recognize faces, read large fonts, watch TV and, perhaps most important,
lead an independent life was published in February.
The Journal of Neural Engineering published the
work by Daniel Palanker, Alexander Vankov and Phil Huie from the
Department of Ophthalmology and the Hansen Experimental Physics
Laboratory and Stephen Baccus from the Department of Neurobiology.
They are testing their system in rats, but human
trials are at least three years away.
"This is basic research," said Palanker, a
physicist whose primary appointment is in the Ophthalmology Department.
"It's the essence of Bio-X," he said, referring to Stanford's
interdisciplinary initiative to speed biomedical research from benchtop
to bedside.
"Currently, there is no effective treatment for
most patients with AMD and RP," the researchers say in their paper.
"However, if one could bypass the photoreceptors and directly stimulate
the inner retina with visual signals, one might be able to restore some
degree of sight."
To that end, the researchers plan to directly
stimulate the layer underneath the dead photoreceptors using a system
that looks like a cousin of the high-tech visor blind engineer Lt.
Geordi La Forge wore in Star Trek: The Next Generation. It consists of a
tiny video camera mounted on transparent "virtual reality" style
goggles. There's also a wallet-sized computer processor, a solar-powered
battery implanted in the iris and a light-sensing chip implanted in the
retina.
The chip is the size of half a rice grain--3
millimeters--and allows users to perceive 10 degrees of visual field at
a time. It's a flat rectangle of plastic (eventually a silicon version
will be developed) with one corner snipped off to create asymmetry so
surgeons can orient it properly during implantation.
One design includes an orchard of pillars: One side
of each pillar is a light-sensing pixel and the other side is a
cell-stimulating electrode. Pillar density dictates image resolution, or
visual acuity. The strip of orchard across the top third of the chip is
densely planted. The strip in the middle is moderately dense, and the
strip at the bottom is sparser still. Dense electrodes lead to better
image resolution but may inhibit the desirable migration of retinal
cells into voids near electrodes, so the different electrode densities
of a current chip design allow the researchers to explore parameters and
come up with a chip that performs optimally.
Another design--pore electrodes--involves an array
of cavities with stimulating electrodes located inside each of them.
How does the system work when viewing, say, a
flower?
First, light from the flower enters the video
camera. (Keep in mind that camera technology is already pretty good at
adjusting contrast and other types of image enhancement.) The video
camera then sends the image of the flower to the wallet-sized computer
for complex processing. The processor then wirelessly sends its image of
the flower to an infrared LED-LCD screen mounted on the goggles. The
transparent goggles reflect an infrared image into the eye and onto the
retinal chip. Just as a person with normal vision cannot see the
infrared signal coming out of a TV remote control, this infrared flower
image is also invisible to normal photoreceptors. But for those sporting
retinal implants, the infrared flower electrically stimulates the
implant's array of photodiodes. The result? They may not have to settle
for merely smelling the roses.
Complex processing: The eyes have it
The eye is a complex machine. It has more than 100
million photoreceptors. "If we compare it to modern digital cameras, for
example, it will be 100 megapixels," Palanker said during an interview
in the Hansen Experimental Physics Laboratory. "We buy cameras usually
of three megapixels, maybe four."
And if electronic cameras do a good job of image
processing, the eye does a spectacular job, compressing information
before sending it to the brain through the 1 million axons that make up
the optic nerve. "We have a built-in processor in the eye," Palanker
said. "Before it goes into the brain, the image is significantly
processed."
The bottom layer of photoreceptors is where
rhodopsin--a protein pigment that converts light into an electrical
signal--exists. But as far as signal processing is concerned, the rubber
meets the road where the signal enters the inner nuclear layer, which is
populated with bipolar, amacrine and horizontal cells. These three
cellular workhorses process the signals and transfer them to the
ganglion cell layer, or "output cascade" of nerves that deliver signal
pulses to the brain.
It's best to place an implant at the earliest
accessible level of image processing, Palanker said. "The earliest
[accessible level] in degenerated retina is in the nuclear layer, and
the more you go along the chain of image processing, the more complex
the signals become."
The Stanford researchers try to utilize most of the
processing power remaining in the retina after retinal degeneration by
placing their implant on the side of the retina facing the interior of
the eye ("subretinal" placement), as opposed to several other groups in
the United States, Germany and Japan that place retinal implants on the
side of the retina facing the outside of the eyeball ("epiretinal"
placement).
Signal processing allows the eye to detect
direction of motion, perceive colors, enhance contrast and adjust to
different levels of brightness. "Our eye is an amazingly adjustable
machine," Palanker said. It operates in brightness levels that span
eight orders of magnitude, meaning it can detect both dim objects and
those 100 million times brighter, "from moonless night to bright day,"
he said.
It may seem counterintuitive that as it gets
processed by the visual system, the signal travels from the back of the
eye toward the eye's interior, rather than from the inner surface of the
retina and out the back of the eye. But metabolically active
photoreceptors need a lot of support. They are connected to a highly
pigmented layer called retinal pigment epithelium (RPE) that grows atop
a highly vascularized layer of tissue (choroid) carrying a heavy flow of
blood. If the blood supply and the RPE were inside the eye, they would
obscure light from the photosensitive cells. Explained Palanker: "That
is why it's built upside down, because those cells on top--the bipolars
and ganglions--do not require as many nutrients and as much metabolic
support as do photoreceptors."
A crucial aspect of visual perception is eye
motion. Palanker said the Stanford system provides a powerful advantage
over more basic devices now being tested in humans by a U.S. company
because, besides making the most of the eye's natural image-processing
strengths by subretinal placement of implants, the system tracks rapid
intermittent eye movements required for natural image perception.
Vankov, a physicist, designed the projection and tracking system.
"In reality, when you think you are fixating to a
certain point, your eyes are not steady," Palanker said. "You are
microscanning it all the time. So if you would be projecting an image
not through the eye, but just deliver it from the camera to the implant,
bypassing the moving eye, this will not be natural perception because
you will completely eliminate this link."
Alon Asher, a graduate student in computer science
at Tel Aviv University, spent a semester working with Palanker on the
software that links image processing to motion detection. He now
continues his work on the project from Israel. Assistant Professor of
Neurobiology Stephen Baccus, a co-author of the paper who is an expert
in retinal signal processing, advises the group about the details of
image processing.
In the Stanford system, image amplification and
other processing occur in the hardware, outside the eye. If
amplification occurred inside the implant's pixels, as it does in one
German design, there'd be no way short of surgery to make adjustments.
The Stanford system also makes new use of an old
trick. By co-aligning real and enhanced images, it allows patients to
utilize any remaining peripheral vision while making the most of the
implant. Virtual reality systems that allow co-alignment of real and
simulated views are already in use by pilots and surgeons, Palanker
said. "This co-alignment of additional information with the normal view
allows surgeons to see in the microscope the operating site, while the
other eye is getting a projection of, say, a CT or MRI image of the same
patient. So they can relate the information that they don't see in the
operating site to anatomic findings and know exactly where the tumor or
other problem is."
The amazing grace of physics
The new design answers major questions about what's
feasible for bionic devices. Biology imposes limitations, such as the
needs for a system that will not heat cells by more than 1 degree
Celsius and for electrochemical interfaces that aren't corrosive.
Current retinal implants provide very low
resolution--just a few pixels. But several thousand pixels would be
required for the restoration of functional sight. The Stanford design
employs a pixel density of up to 2,500 pixels per millimeter,
corresponding to a visual acuity of 20/80, which could provide
functional vision for reading books and using the computer.
Physical limitations regarding electrical
stimulation most likely make it impossible for implants to impart a
visual acuity of 20/10 (the sharpness required to see the bottom line on
an eye chart), 20/20 (the so-called standard of good vision) or even
20/40 (the level to which vision must be correctable to be eligible for
a California driver's license).
A major limiting factor in achieving high
resolution concerns the proximity of electrodes to target cells. A pixel
density of 2,500 pixels per square millimeter corresponds to a pixel
size of only 20 micrometers. But for effective stimulation, the target
cell should not be more than 10 micrometers from the electrode. It is
practically impossible to place thousands of electrodes so close to
cells, Palanker said. With subretinal implants but not epiretinal ones,
Stanford researchers discovered a phenomenon--retinal migration--that
they now rely on to encourage retinal cells to move near
electrodes--within 7 to 10 microns. Within three days, cells migrate to
fill the spaces between pillars and pores.
"If the mountain doesn't come to Muhammad, Muhammad
goes to the mountain," Palanker said. "We cannot place electrodes that
close to cells. We actually invite cells to come to the electrode site,
and they do it happily and very quickly."
Currently the researchers are testing two designs
in parallel because they aren't yet sure which will be best. One design
uses electrodes that protrude up from the chip like pillars. The pillars
allow retinal cells greater access to nutrients and let researchers
affect specific cell layers by controlling the height of the pillars.
But pillars expose more cells to current, potentially heating tissue and
increasing the chance for "cross-talk"--where many electrodes affect one
cell. The second design has electrodes recessed into pores, which
localizes currents and makes stimulation selective, perhaps allowing
researchers to stimulate single cells.
Huie, a cell biologist and histologist, implants
the chips in rats using a unique tool he and others developed. So far
his short-term rat studies show no rejection of the implants. The next
step will be longer tests in rats, as well as tests in larger animals
for which models of retinal dystrophy exist. The researchers are
currently shipping chips to Joseph Rizzo, a professor of ophthalmology
at Harvard Medical School, for implantation into pigs.
Professor Mark Blumenkranz, chair of the
Ophthalmology Department, advises the authors about surgical issues, and
Professor Michael Marmor in that department, an expert in retinal
physiology, provides advice about retinal electrophysiology. Graduate
students Ke Wang in applied physics and Neville Mehenti in chemical
engineering are currently working with Fishman of the Stanford
Ophthalmic Tissue Engineering Laboratory on carbon nanotube electrodes
and on chemical stimulation of the retinal cells. Medical student Ian
Chan continues to develop lithographic fabrication technology for the
implants. Alex Butterwick, a graduate student in applied physics, is
studying the mechanisms of cellular damage and the safe limits of
electrical stimulation.
The project is funded in part by the U.S. Air Force
and VISX Corp., which licensed the technology through Stanford's Office
of Technology Licensing. Harvey Fishman, who is not an author of the
current paper but directs the Stanford Ophthalmic Tissue Engineering
Laboratory, pioneered the project.
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