ARN Summer 09
Transcript of ARN Summer 09
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In This Issue
1 Leveraging DOE Technologies
2 2009 R&D 100 Award Winner
3 Enrollment Rises in U.S. Clinical Trials3 Clinical Trials Ongoing Worldwide
4 Increasing Resolution
4 Ensuring Surgical Reproducibility
5 Advancing Medical Research Frontiers:A Patient Perspective
6 Articial Retina Spino Technologies
8 Spotlight: Sandia National Laboratories
9 PET Scans o Brain Responses
10 Novel Sotware System EnhancesImage Resolution
12 Progress Metrics
DOE TECHNOLOGIES DRIVE INITIAL SUCCESS OF BIONIC EYEHow basic research is being leveraged to enhance quality o lie or the blindUsing the unique skills and resources o the
U.S. Department o Energys (DOE) national
laboratories, in partnership with leading
research universities and the private sector,
the DOE Articial Retina Project already
has achieved important practical progress by
enabling direct communication between an
implanted retinal prosthesis and neural cells
that carry visual inormation to the brain.
Te projects collaborators are working to
develop the worlds most advanced retinal
prosthesis. Tis high-density microelectronic-
tissue hybrid aims to restore sight to people
blinded by retinal diseases such as age-related
macular degeneration (AMD) and retinitis
pigmentosa (RP). However, considerable
A undus image o an implanted Argus II microelectrode array.
continued on page 2
research remains in order to ully benet
rom the investments made thus ar.
Technological Challenges inEngineering a Retinal ImplantPeople with AMD or RP are blind because
retinal photoreceptor cells (called rods and
cones) degenerate and lose unction. Rods
and cones are specialized cells that capture
light and translate it into electrical signals.
Tese signals are passed through underlying
retinal cells and down the optic nerve to the
brain where visual images are ormed.
Te Articial Retina Projects challenge is to
replace the lost light-gathering unction o
the rods and cones with a video camera and
to use the inormation captured by the cam
era to electrically stimulate the part o the
retina not destroyed by disease. Stimulation
is done with a thin, exible metal electrode
array that has been patterned on so plastic
material similar to that o a contact lens.
Compounding this challenge is the act that
the delicate, electrical stimulation o the
2009
R&D 100
AwardWinner
(See story on p. 2)
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Researchers involved with the U.S. Department o Energys (DOE) Articial
Retina Project have won a prestigious R&D 100 Award. The award recognizes
the collection o innovative technologies in engineering, microabrication,
material sciences, and microelectronics that has been integrated into a retinal
prosthesis giving blind patients rudimentary vision. The multidisciplinary
collaboration includes contributions rom fve DOE national laboratories
Argonne National Laboratory, Lawrence Livermore National Laboratory,
Los Alamos National Laboratory, Oak Ridge National
Laboratory, and Sandia National Laboratories, ouruniversitiesCaliornia Institute o Technology,
Doheny Eye Institute at the University o Southern
Caliornia, North Carolina State University, and
University o Caliornia, Santa Cruz, and private
industrySecond Sight Medical Products, Inc.
Summer 2009
DOE Technologies continued rom page 1
2
retina needs to be perormed in the eyes
saltwater environment without shorting
out any electronic circuits. In other words,engineering a retinal prosthesis is some-
what analogous to constructing a miniature
iPod on a oldable contact lens that works
in seawater.
Moreover, just as the resolution o graphic
images on a computer screen improves with
greater pixel density, researchers assume
that increased electrode densities will
translate into higher-resolution images or
patients. However, the area o the retina
DOE ARTIFICIAL RETINA TEAM GARNERSCOvETED 2009 R&D 100 TEChNOLOGy AwARD
being targeted or electrical stimulation is
less than 5 mm by 5 mm. Consequently, as
the number o electrodes increases, theirsize and spacing must decrease.
Basic Research Payofso date, Second Sight Medical Products,
Inc., the projects private-sector partner,
has sponsored clinical tests approved by
the U.S. Food and Drug Administration or
the Argus I and II model systems, which
contain 16 and 60 electrodes (i.e., pixels),
respectively. In the near uture, the DOE
project will produce a 200+ electrode device
ready or extensive preclinical testing.
As a direct result o DOE basic research
advances, the new design will have a highly
compact array (see graphic, p. 11). Tis
array is our times more densely packed
with metal contact electrodes and requiredwiring connecting to a microelectronic
stimulator than the Argus II. Simulations
and calculations indicate that the 200+ elec
trode device should provide improved
vision or patients.
Promising AdvancesSeveral pioneering technological advances
in abrication and packaging by DOE
national laboratories (see sidebar, Arti-
cial Retina eam Garners 2009 R&D
100 Award, this page) have helped make
the third-generation device a reality. For
example, the signicantly higher electrode
density required new lithographic and etch-
ing techniques to pattern platinum lms on
so polymer materials. Additionally, new
stacking techniques were needed to layer
metals and polymers on top o each other
to achieve a narrower prosthesis in the sec-
tion that delivers electrical charges to the
electrodes. Other advances by DOE nationalaboratories include soening the rim o the
array that is in contact with delicate retinal
neurons and improving techniques to
ensure none o the electrodes short-circuit.
Because the devices advanced electronics
operate in the eyes saltwater environment,
DOEs national laboratories have spear-
headed critical innovations in packaging.
Tese innovations include higher intercon-
nect densities o the individual contacts
and attachment to the electronic chipwhile still preserving a leak-tight electrical
connection. A novel, dual-sided integrated
circuit also has been developed or stacking
components and interconnecting them (see
story, Sandia National Laboratories, p. 8).
Research also is under way on various bio-
adhesives that could be used to attach the
microelectrode array to the retinal surace.
continued on page 11
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Summer 2009
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Clinical Trials Ongoing at Multiple Sites Worldwide
continued on page 4
PATIENT ENROLLMENT RISES IN U.S. PORTION OF CLINICAL TRIALSecond-generation articial retina showing promise in ongoing easibility studies
Te U.S. Food and Drug Administration has
granted approval to expand Second Sight
Medical Products Argus II Retinal Implant
easibility study. Up to 20 people in theUnited States who are blind or have severely
impaired vision because o retinitis pigmen-
tosa (RP), a genetic eye disease, will be able
to participate. As o mid-July, 30 RP patients
worldwide have been implanted with the
device (see sidebar, Clinical rials Ongo-
ing at Multiple Sites Worldwide, this page),
which incorporates advanced technolo-
gies rom the U.S. Department o Energys
(DOE) national laboratories.
In the largest visual prosthesis study todate, the Argus II continues to have a good
saety prole. Implanted patients are using
the articial retina to successully identiy
the position and approximate size o objects
and detect movement o nearby objects and
people. Tese implants also are provid-
ing subjects with sucient vision to allow
demonstrated improvement in orientation
and mobility.
Te Argus II is designed to transmit inor-
mation directly to the retina o individualsabout their physical surroundings, thereby
bypassing photoreceptor cells that have
been damaged because o RP. It consists
o a 60-electrode grid that is surgica lly
implanted and attached to the retina. Te
electrodes transmit inormation acquired
rom an external camera that is mounted
on a pair o eyeglasses. Tis device has
several advantages over the Argus I,
a 16-electrode prosthesis that showed
proo o concept with chronic stimulationdemonstrated in 6 patients or more than
5 years. Argus II advantages include more
stimulating electrodes and advanced image
processing, and its smaller package requires
less surgical time or the implant proce-
dure. Te Argus II underwent extensive
in vivo and in vitro testing prior to clinical
trials. Whi le it is designed to last a lietime,
it can be saely removed i necessary. Fur-
ther developments planned or the coming
years are expected to enable reading and
acial recognition.
Preliminary ResultsAll o the patients implanted so ar with the
Argus II system had bare light perception
or worse vision beore the surgery. Averag-
ing 56.8 years, their ages range rom 28 to
77 years. Te median surgery time or theimplant procedure in the United States is
3 hours.
Ongoing 3-year easibility studies are testing
the saety and ecacy o the device. For the
17 patients implanted with the device in the
rst 6 months, there have been no device
ailures and ew serious adverse events,
all o which were resolved with treatment.
Such events included conjunctival erosion,
hypotony, and endophthalmitis.
All 17 patients have seen phosphenes pat-
terns o light produced by electrical stimu-
lationand many are showing statistically
signicant improvements in orientation and
mobility, spatial localization, and motion
detection. Tey all are using the device out-
side the clinical setting.
Trials Enable Device ImprovementsFeedback rom the easibility studies has led
to several design improvements that are
expected to increase the Argus II systems
clinical benets. Tese data also have driven
improvements to surgical techniques by
advancing the development o an easier-to-
handle device, which is making the implanta
tion procedure more replicable (see sidebar,
Ensuring Surgica l Reproducibility, p. 4).
So ar, 12 clinical centers in 5 countries have implanted patients with the Argus II retinal
prosthesis which is intended to partially restore their sight and increase orientation and
mobility, thereby improving patients quality o lie. As o mid-July, 14 patients in the
United States and 16 patients at sites in Europe and Mexico have been implanted with
the device. These numbers continue to rise as more participants are enrolled in the trials.
All clinical centers currently are recruiting more volunteers with retinitis pigmentosa.For details on inclusion criteria, see http://clinicaltrials.gov/ct2/show/NCT00407602.
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16 electrodes 200+ electrodes 1000+ electrodes
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Preclinical testing o a retinal prosthesis with
more than 200 electrodes (see story, DOE
echnologies Drive Initial Success o Bionic
Eye, p. 1) is under way and has the potential
to signicantly improve the visual acuity
o people with RP and age-related macu-lar degeneration. Additional research and
development eforts by DOE laboratories are
expected to produce articial retinas with
more than 1000 electrodes.
Hopeul First Steps TowardMeaningul SightTe higher resolution that more advanced,
1000+ electrode prostheses potentially can
provide is key to the goal o enabling reading
o large print, unaided mobility, and acial
recognition. o date, most o the patients
with the articial retina implants use them
or orientation and large object detection.
Higher-resolution implants are expected
to enhance usage by allowing better vision
not only or mobility, but also or object
detection. With the 1000+ electrode device,
patients are expected to be able to read and
recognize aces.
Currently, Were replacing mil lions o pho-
toreceptor cells with just 60 electrodes, so thecorresponding vision that these patients are
able to achieve is not as good as that o a nor-
mal-sighted person, explains Elias Green-
baum, a physicist at Oak Ridge National
Laboratory and a member o DOEs articial
retina team (see box, Increasing Resolution,
this page). Consequently, continued clinical
testing is crucial or urther design improve-
ments that would allow more implantees to
realize the goal o near-normal sight.
Te clinical trial expansion or the Argus IIretinal prosthesis is great news, says Stephen
Rose, chie research ocer or the Founda-
tion Fighting Blindness. Te technology
holds real promise or giving some meaning-
ul vision to people with the most advanced
retinal degenerative diseases.
And or people with severe, end-stage vision
losses, the articial retina may be the only
option or restoring sight. Other potential
treatments such as gene, pharmaceutical, and
nutritional therapies are more appropri-
ate or rescuing photoreceptor cells in
the early stages o disease by halting their
decline. Once those cells are lost, stem
cell transplants one day might be used
to replace them, but diferentiating stem
cells into photoreceptors poses a dicult
Clinical Trials continued rom page 3
Designing a robust, biocompatible retinal prosthesis is one thing. However, another
challenge lies in developing easily replicable surgical techniques to place the implant in just
the right spot on the retinal macula and keep it there.
Many o the maneuvers surgeons perorm during implantation o the Argus II are standard
techniques any experienced retinal surgeon has used numerous times, says Mark Humayun,
a vitreoretinal surgeon and associate director o research at the University o Southern
Caliornias Doheny Eye Institute. Introducing the electrode array into the eye and tacking
it to the retina are new tasks requiring novel, advanced approaches not within a retinal
surgeons normal arsenal.
Consequently, We tried to tailor the approach to processes mimicking those that surgeons
already ollow, says Humayun, who pioneered the implantation procedure. Another key to
achieving surgical reproducibility is using easy-to-handle materials whose look and eel are
like those with which surgeons already are comortable. For example, the telemetry coil is
mounted on a scleral buckle, which surgeons place around the eye or retinal detachments.
Weve really reduced this technique more to science than art so that it can be more easily
reproduced, Humayun says.
Although still a complex procedure, Its a surgery thats doable, and I think its very
reasonable that this will become a much more widely used technique, says Lyndon da
Cruz, a vitreoretinal surgeon at Moorelds Eye Hospital in London who is participating
in the Argus II clinical trials. We eel were part o something thats genuinely new,innovative, and cutting edge, he adds.
challenge. So too does reconstructing the
complex synapse and neural connections.
In contrast, the retinal implant bypasses
degenerated photoreceptor cells altogether
and, to date, has progressed more quickly
and demonstrated more success than stem
cell transplants.n
Increasing Resolution
These images approximate what patients with retinal devices ideally could see. It is
hoped that increasing the number o electrodes will result in more visual perceptions
and higher-resolution vision.[Credit: Caliornia Institute o Technology]
Ensuring Surgical Reproducibility
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IMPLANT PATIENT hELPS ADvANCE ThE FRONTIERS OF MEDICAL RESEARCh
A highly unctioning person with a job,
amily, and household to tend to, Kathy B.
doesnt eel like shes blind despite the act
that shes had no vision or about 15 years.
Nevertheless, she was excited when sherecently was able to nd the ull moon in
the dark, nighttime sky.
We were out walking, and I looked
upwards, scanning my head back and
orth, Kathy B. explains. All o a sudden,
I saw a big ash, and I asked my husband,
Is that the moon? It was, and she began
thinking about how long it had been since
shed last glimpsed that luminescent celes-
tial body.
Kathy B. is one o 14 people in the United
States, 30 people worldwide, so ar to receive
the Argus II, a retinal implant with 60
electrodes being tested in clinical trials. Te
device is intended to provide rudimentary
sight to blind people by stimulating the
retina to send signals to the optic nerve and,
ultimately, the brain, which perceives pat-
terns o light and dark spots corresponding
to the electrodes stimulated.
Her progress in learning how to decipherthe meaning o the ashes that shes see-
ing has been slow but steady. How much
improvement she will realize in the uture
with more use o the device remains to be
determined. I her initial progress is any
indicator, however, it is expected that she
could improve considerably.
Im grateul to be able to give [the research-
ers] inormation that is helping to move this
orward, Kathy B. says.
In her early twenties when she began los-
ing her sight, Kathy B. was certain that
advancements in medical science would
produce a cure or her disease within 20
years. Now 57, she notes, Little did I know
then that I mysel would be involved in
medical studies.
Journey into DarknessUntil she was 23, Kathy B. had no vision
problems whatsoever; she didnt even wear
glasses. When she started tripping over
things, she went to an ophthalmologist,
thinking it might be time or a pair o
eyeglasses. As it turned out, it wasnt that
simple. For several months, nobody quiteknew what was happening with her eyes.
Finally, she received a diagnosis: retinitis
pigmentosa, a hereditary retinal disease
that initially steals a persons peripheral
vision, eventually leaving only a small patch
o central vision. In some cases, even that
can disappear.
Tey told me I would lose my visionthat
it would go very slowly, but they didnt
think I would go totally blind, Kathy B.
recounts. Unortunately, I did.
During the rst 5 years, her vision deterio-
rated airly quickly. She had trouble seeing
at night and in dim light, and soon she no
longer was able to drive. Ten her vision
stabilized or a time beore it started getting
worse again. Fieen years aer the initial
diagnosis, Kathy B. was completely blind.
She had to give up her job at the University
o CaliorniaIrvine, where she worked in
the physical plant department embossing
and engraving campus signs and keep-
ing key records or locksmiths. She then
became a stay-at-home mother until the
youngest o her three daughters went of tocollege. With her husband at work all day
and her children gone, Kathy B. acquired
a guide dog to help her get around on her
own. She also learned how to read Braille
at the Braille Institute, where she took a
part-time job as a receptionist.
Trough it all, she has maintained her
optimistic outlook. Not being able to drive
or read print was hard or her. Knowing,
however, that her children could have this
disease, she believed she had to set a posi-tive example or them.
I didnt let it afect my lie, Kathy B. says.
I really just went on as i I could still see.
o this day, she does everything she pos-
sibly can on her own. As her husband puts
it, blindness isnt so much a disability, but
rather an inconvenience or her. It just
takes me a little bit longer to gure out
continued on page 11
Kathy B. uses her retinal prosthesis to walk along a line to its termination.
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ARTIFICIAL RETINA PROjECT SPURRING SPINOFF TEChNOLOGIESEnergy, deense, and biomedical arenas stand to beneft
As in many rontier scientic research projects, the U.S. Department o Energys (DOE) Articial Retina Project has producedeveral unanticipated discoveries and spinofs that are increasing the value o these investments.
Te same microelectronics and eedback mechanisms used in the articial retina to enable neural cells to communicate withmachines could be adapted to interace with other cell types such as those o plants and bacteria. Applications include remoteensors that monitor or environmental contamination, assist with environmental remediation, or counter bioterrorism. A wideange o other biomedical devices also could be enabled by this technology.
We are only looking at the tip o the iceberg right now as we move into higher-density abiotic-biotic suraces, says SatinderpallPannu, group leader or advanced materials and processing technologies at DOEs Lawrence Livermore National Laboratory (LLN
A polymer-based, eld-deployable biodetectionsystem with embedded microelectronicsand radio requencybased power and datacommunication. [Credit: Lawrence LivermoreNational Laboratory]
Ongoing research at LLNL is urthering the
evelopment o remote-sensing platorms to
etect biothreats in harsh environments such
s oceans, rivers, and wastewater streams.
imilar to the articial retina, these polymer-
ased biodetection systems contain embedded
lectronics and electrodes (see photo at right).
ut instead o stimulating retinal tissue, the
lectrodes can be unctionalized or multiple
hemical or biological agents like anthrax or small
ox. Whenever those particular substances are
etectedor example, in a drinking water sup-
ly or at an air monitoring stationthe electri-
al signal changes, and the inormation can be
ent to a local agency or the Centers or Disease
ontrol and Prevention, alerting them to the
otential threat.
everal key technologies developed or the arti-ial retina are enabling such advanced detection
evices. Because the technology was designed
or the saline environment in the eye, these sen-
sors can tolerate harsh surroundings. Moreover,
communication and power transmission occur viaa radio-requency link. Miniaturized or the arti-
cial retina, this technology permits the deploy-
ment o multiple sensors that can relay sign
to each other. Operating with very low pow
requirements, such a distributed network o
sensors permits long-range communication
capabilities with a low detection risk.
Also, the exible substrate allows these
detection devices to be molded or attach-
ment to any curved surace. They could be
afxed inside a channel, pipe, tube, or even
a soldiers helmet. In a battleeld setting,
such sensors could be deployed virtually
everywhereon soldiers, tanks, planes, an
Humveespermitting communication as t
sensors actively search the surrounding env
ronment or chemical and biological threat
Ultimately, such rugged, exible sensors
could be distributed anywhere in anysituation and be counted on to work or the
lietime o an operation.n
he advanced, implantable microelectronic
ystem developed or the articial retina has
he potential to revolutionize other medical
mplants that could help people with combat
njuries (e.g., soldiers who sufer traumatic
rain injuries), spinal cord injuries, Parkin-ons disease, deaness, and many other
eurological disorders.
DOEs articial retina demonstrates that an
lectronic-tissue interace is capable o com-
municating with the brain to provide inorma-
on that the local tissue is unable to provide
ecause o disease or injury. By selectively
timulating neural or muscular tissue, the brain
an be retrained to understand bioelectronic
nputs or to control the movement o muscles
r electromechanical actuators.
This same technology platorm also could be
useul or drug delivery. The exible circuit could
be adapted so that instead o carrying electri-
cal current, it would carry uids via microuidic
channels, Pannu says. In the case o diabetics, or
example, such a smart, implantable system could
serve as an articial pancreas, continually m
ing glucose levels and dispensing the appro
amounts o insulin in response to any oods
consumed (see photo at let).
Similarly, this technology might be used to
ister narcotics or pain relievers to people wi
chronic pain such as migraine headaches. In
tion, preventative systems could be implant
people who have been diagnosed with a pa
lar disease or have a history o cancer in the
ily. I the device picks up any change in the
a certain biomarker, an alarm would be trigg
to alert the patient to see a doctor immedia
Not only could such a system improve and s
lives, Pannu says, it also would cut down on
healthcare costs because patients would ne
see a doctor only i an issue arises.n
Electronic-Tissue Interace Devices
Smart Biodetection Systems
Portable insulin pump.
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A scene as it might be viewed by a person withormal vision. [Credit: National Eye Institute,
National Institutes o Health]
Te same scene as it might be viewed by aerson with diabetic retinopathy. [Credit: National
ye Institute, National Institutes o Health]
Elias Greenbaum studies the use o algae oproducing hydrogen rom water in anilluminated fask. [Credit: ORNL Review]
n addition to age-related macular degenera-
on and retinitis pigmentosa, diabetic
etinopathy is another leading cause o
lindness. It results rom poor blood circulation,
articularly in the retina, which is a complicating
actor o diabetes. As blood ow is restricted,
etinal tissue is deprived o oxygen. Subse-
uently, neovascularization can occur, with
bnormal or excessive blood vessels orming to
ompensate or the lack o oxygen. Eventually,
hese vessels can burst, leaking blood into the
itreous and causing blindness (see photos
elow). The longer a person has diabetes, the
reater his or her chances o developing this
ye disease.
oxygen could be provided to retinal tissue with
oor blood ow beore the onset o neovascu-
arization, progression o this condition might
e stopped and perhaps reversed. An extension
the technology developed or DOEs articial
etina could supply the needed oxygen via a
metabolic prosthesis. The rst publication o this
ew idea, including experimental data, appeared
n the February 2009 issue oIEEE Transactions on
iomedical Engineering.
he procedure would involve surgically implant-
ng a eedback-controlled, three-electrode
electrolysis system that stimulates oxygen pro-
duction near the retina. The electrodes would
provide small amounts o current in very short,
repetitive pulses that last about 200 microsec-
onds. This would result in rapid production o
oxygen and suppressed production o chlorine,
a potentially harmul byproduct.
The vitreous humor has a chemical composi-tion very similar to seawater, and i you perorm
ordinary electrolysis o saltwater, youll make
bleach and alkali, which are very harsh byprod-
ucts, explains Elias Greenbaum, who is leading
this study at Oak Ridge National Laboratory
(ORNL) in collaboration with the University o
Southern Caliornia (USC) and University o Ten-
nessee. Weve discovered that i you perorm
pulsed or charge-limited electrolysis o the
vitreous, its possible to produce oxygen and
suppress the ormation o chlorine.As reported in the IEEEpaper, the three-elec-
trode and eedback loop congurationmade
possible by implanting a second cathode
behind a patients earwould enable a constant
pH to be maintained in the area to be treated.
I any pH drit occurs, it can be exported to a
surace-accessible region or treatment, the
avoiding any adverse internal irritants.
I successul, this technique could preserve
retina. Currently, neovascularization treatm
destructive. You apply a laser to the periph
retina, essentially destroying it to create less
oxygen demand in that region in order to s
ply more oxygen to the central retina, explMark Humayun, a vitreoretinal surgeon and
associate director o research at USCs Dohe
Eye Institute. I we can supply oxygen, we c
hopeully sustain the entire retina.
Much o what has been learned through DO
Articial Retina Projectpractical biomedic
engineering, surgical techniques, and electr
abricationcarries directly over to oxygen
o ischemic tissue or diabetic retinopathy. A
in many respects, the surgery and electrode
rication are simpler, and the potential or netissue damage is eliminated because no ne
tissue is stimulated. Instead, the vitreous hu
is oxygenated.
Laboratory research has demonstrated proo
principle o the metabolic prosthesis conce
The next step is to build and test a device.n
From Electrodes to Molecular Photovoltaics
Metabolic Prosthesis or Diabetics
continued on pa
While numerous spinof technologies have
been spawned by DOEs articial retina, otherexisting national laboratory technologies have
helped to advance the retinal implant. One o
these, rom ORNL, evolved rom DOE-supported
research using photosynthesis in spinach and
algae to split water molecules or producing
oxygen and hydrogen, an energy-rich gas (see
photo at right).
Instead o using metal electrodes to stimulate
retinal neurons, a light-sensitive protein rom
green plants could be used because it gener-
ates a small electrical voltage ater capturing theenergy o incoming light. This technology could
make uture articial retinas more efcient than
previously believed possible.
Photosynthetic membranes, which measure
5 nanometers across, are where plants convert
light energy to chemical energy. As photons
are absorbed in specialized reaction centers,
they trigger a charge separation that generates
a voltage that might be sufcient to trigger a
neural response. I these reaction centers are
inserted into retinal neural cells, the resulting
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SPOTLIGHTSANDIA NATIONAL
LABORATORIES
Microscale Enablers
An application-specifc integrated circuit being developed or advanced artifcial retinas.
Tree-dimensional model and cross section o a dual-sided integrated circuit. Te circuitenables high-density interconnects on both top and bottom suraces.
More advanced articial retinas are relying
on miniaturized electronics or process-
ing incoming images and activating the
corresponding electrodes to communi-
cate with retinal cells and ultimately the
brain. Te goal o these devices, being
developed through a U.S. Department o
Energy (DOE) collaboration, is to continu-
ally improve their visual resolution so thatimplanted individuals eventually will be
able to read large print, recognize aces, and
move about without aid. Sandia National
Laboratories expertise in the development,
abrication, and production o microsystems
is helping to make this goal a reality.
The ChallengeBiocompatible electronics packages cur-
rently used in medical devices require only
a small number o electrical interaces to
operate them. For example, pacemakersat most have our electrical contacts, and
cochlear implants or the hearing impaired
use 22 or ewer. Additionally, the volume o
these packages is typically more than 5 cm3.
By comparison, DOEs articial retina
requires a much smaller electronics package
but one to two orders o magnitude more
electrical eed-throughs to communicate
with retinal cells.
Tis density is beyond conventional packag-
ing technology. Te compact size o thearticial retinas electronics package makes
it dicult to mechanically and electrically
interconnect the microelectronics inside.
Te package also has to withstand the
human eyes harsh saline environment or
the lietime o the patient, so the electronics
have to be hermetically sealed, preventing
all transer o moisture and gases between
the components inside the package and the
human body.
Essentially, were trying to cram more
and more things into smaller and smaller
spaces, says Kurt Wessendor, an analog
circuit designer and leader o Sandias
articial retina eforts. I more electrodes,
and hence more capabilities, can be packed
into the system, the images that implanted
individuals see will be o higher resolu-
tion. Tis is the area benetted by Sandias
expertise in microsystems.
Engineering Tiny MachinesMicrosystem devices smaller than a human
hair are built on silicon waers or chips.
Tey contain electrical circuitry and
microelectromechanical systems (MEMS),which are miniature machines.
Te articial retinas custom-designed
integrated circuit (IC) is the systems brain.
Its job is to take signals rom the external
camera and convert them into stimuli that
are transerred to the electrode array. Te IC
perorms this unction via a series o inter-
connected, nanosize nodes, whose locations
on the chips surace are important because
they can minimize the wire length along
which the signal travels (see graphic above).
Te current method or achieving higher
electrode currents involves assembly with a
lot o bond wires and other interconnects,
says Sean Pearson, an IC design engineer at
Sandia. Tis makes the device tedious to
continued on page 9
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Ceramic LidMetal Annulus
Metal Annulus
Electronic CircuitSolder Ball
InteriorRegion
Electrical Vias
Ceramic Base
Ceramic andMetal Package
Summer 2009
9
build and very dicult to yield ull unc-
tionality. Consequently, he and his col-
leagues are developing a novel, dual-sided
IC to simpliy how data are routed and to
better integrate the electronics package
with the electrode array (see lower graphic,
p. 8). Were using one side to bring the
signals in and the other side to put them
out, Pearson explains.
For the electronics substrate, the research-
ers are using a Sandia-patented MEMS
technique to selectively etch away parts
o the silicon chip or add new structural
layers to create tiny eatures that cannot bemade any other way. Tis micromachin-
ing process allows wiring o the electrical
connections through the chip or access to
both sides.
By using that bottom surace, which adds
interconnect space instead o eliminating
it, were able to get higher interconnect
densities, thereby allowing the number
o electrodes on the array to be increased
without making the device bigger, says
Murat Okandan, a microsystems engineer
on the Sandia team.
Additionally, Sandia researchers are
developing state-o-the-art packagingtechnologies to assemble and integrate
the microelectronic components with the
thin-lm electrode array. Biocompatibil-
ity issues are driving much o this efort,
requiring the high-density interconnects to
be insulated with a nonconductive lm to
prevent moisture and ionic and biological
contamination rom causing device ailure
(see graphic below).
continued on page 12
PET SCANS ShOw BRAIN RESPONSES TO LIGhT, ELECTRICAL STIMULATIONA study measuring metabolic changes
in the brains o sighted people is show-
ing similar responses to both light and
electrical stimulations. Researchers at the
U.S. Department o Energys BrookhavenNational Laboratory, Doheny Eye Institute
at the University o Southern Caliornia,
and Columbia University now are taking
this study a step urther to demonstrate
that the visual cortex in patients with
retinitis pigmentosa (RP) can respond to
electrical stimulation.
Using positron emission tomography
(PE) scanning and a glucose analogue
called FDG, the researchers evaluated and
compared what happens to the visual pro-
cessing part o the brain ollowing diferent
stimuli. Eight healthy volunteers with
normal vision participated in the study.
Each underwent three PE scans on three
diferent days to represent baseline condi-
tions, responses to light stimulation, and
responses to electrical stimulation.
Light Stimulation vs. Baseline. Colored areas indicate increased (red scale) or decreased(blue scale) brain activity rom light stimulation as compared to no stimulation.
Electrical Stimulation vs. Baseline. Colored areas indicate increased (red scale) or decreased(blue scale) brain activity rom electrical stimulation as compared to no stimulation.
Prior to each scan, the volunteers sat quietly
in a darkened room or 30 minutes to dark
adapt beore receiving the FDG injection.
For the baseline scan, both eyes were blind-
olded. During the light stimulation scan,
Sandia Spotlight continued rom page 8 Dual-Use TechnologySandia has a long history o pioneering
microelectronics research, which eeds into
several deense-related systems, includingsensor technologies and satellite application
Spinofs o the Articial Retina Project
such as the si licon interconnect and higher-
density packaging o componentsare
being evaluated or potential applications in
some o these ongoing projects.
Te kind o exposure seen in the eye is not
unlike the harsh, corrosive environments
in which many deense-
related components are
required to survive or manyyears, Wessendor says.
Moreover, Were always
looking at miniaturizing and
increasing unction, and
these eforts will help in
those directions. nSandia National Laboratories is
operated by Sandia Corporation, a
Lockheed Martin company, or the
U.S. Department o Energys National
Nuclear Security Administration.
High-density hermetic electronics packaging with a dual-sided electronic circuit.
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ypical palette o Articial Retinal Implant Vision Simulator(ARIVS) image-processing modules that are applied in realtime to the video camera stream driving the articial retina.[Credit: Caliornia Institute o echnology]
Summer 2009
10
Spinof Technologies continued rom page 7
SEEING IS PROCESSINGA novel sofware system not only processes incoming images in real time but also enhanceswhat retinal implant recipients perceive
Te human retina is not just a detector o
light that sends optical inormation to the
brain. It also perorms complex image pro-cessing to provide the brain with optimized
visual inormation. Replacing diseased
photoreceptors with the electrodes o an
articial retina thus not only reduces the
number o pixels, it also disrupts this neces-
sary image processing.
o restore that lost unction, researchers
at the Caliornia Institute o echnol-
ogys Visual and Autonomous Exploration
Systems Research Laboratory under the
direction o Wolgang Fink are developingsoware to pre-process the inormation
rom implant patients miniature cameras
beore it is ed to their retinal prostheses.
Dubbed the Articial Retinal Implant
Vision Simulator (ARIVS), this soware
system provides real-time image processing
and enhancement to improve the limited
vision aforded by the camera-driven device.
Te preservation and enhancement o
contrast diferences and transitions, such as
edges, are especially important compared topicture details like object texture.
Since predicting exactly what blind subjects
may be able to perceive is dicult, ARIVS
ofers a wide variety o image processing
lters. Tey include contrast and brightness
enhancement, grayscale equalization or
luminance control under
severe lighting condi-
tions, user-dened gray-scale levels or reducing
the data volume trans-
mitted to the visual pros-
thesis, blur algorithms,
and edge detection (see
graphic at right). Tese
lters are not unlike what
a person experiences in a
regular eye exam during
which a battery o tests
is perormed to deter-mine the proper eyeglass
prescription. In this case,
retinal implant recipi-
ents can choose among
these diferent lters tourther ne tune, optimize, and customize
their individual visual perception by actively
manipulating parameters o individual
image-processing lters or altering the
sequence o these lters.
An incomparably greater challenge existsin predicting how to electrically stimulate
the retina o a blind subject via the retinal
prosthesis to elicit a visual perception that
matches an object or scene as captured by
the camera system that drives the prosthesis.
Tis requires the ecient translation o the
camera stream, pre-processed by ARIVS,
into patterns o electrical stimulation o
retinal tissue by the implanted electrode
array. Te Caltech researchers on the U.S.
Department o Energys team are address-
ing this challenge by developing and testing
multivariate optimization algorithms basedon evolutionary principles. Tese algo-
rithms are used to modiy the electrical
stimulation patterns administered by the
electrode array to optimize visual percep-
tion. Operational tests with Argus I users
currently are under way.n
stimulation could be much more efective
than that applied with external electrodes,
where voltage is lost at the interacebetween the electrode and liquid interace,
says Greenbaum, a physicist at ORNL.
Tis strategy ofers other advantages as
well. For one, these systems are already at
the nanoscale, so a high density o them
could be packed into the roughly 5 mm
by 5 mm area o the retina targeted by the
prosthesis or stimulation. In contrast, an
equivalent number o metal electrodes
would require hair-like dimensions, lead-
ing to abrication and stability issues.
Virtually no metal is stable when you
get down to those hair-like dimensionsbecause the electrical voltages applied to
them cause corrosion and loss o metal,
Greenbaum explains.
Additionally, the lens o the eye itsel could
be used to capture images, eliminating the
need or an external camera mounted in
eyeglasses. Likewise, no battery would be
needed because the voltages would be sel-
powered by the photosynthetic reaction
centers in the retinal cells.
Greenbaums group has shown that these
nanoscale protein structures can be har-
vested rom plant materials and reconsti-
tuted in liposomes, with their ull photo-voltaic properties preserved. Liposomes
are articial membranes made o lipids
that mimic the membrane composition o
a living cell. Using the liposomes as deliv-
ery vehicles, the researchers have inserted
these photosynthetic reaction centers
into mammalian cells and elicited optical
activity where there was none beore. n
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Fabricated 200+ thin-lm electrode array.Te metal traces ormingthe electrodes in thearticial retina areless than a micrometerthickless than 1%the thickness o ahuman hair.
Summer 2009
11
Advancing Medical Research continued rom page 5
DOE Technologies continued rom page 2
how to do something or get somewhere, she
explains.
Relearning SightKathy B. had been blind or nearly 15 years
when she heard about the Argus II clinical
trials. Deciding that at this point in her lie
she had nothing to lose, she opted or the
surgery when she ound out she was a suit-
able candidate.
At rst, Kathy B. didnt see anything. Ten
occasionally shed see a ash o light. Now,
she sees percepts whenever theres a strong
contrast between light and dark, indicating
that something is there. Trough testing atthe clinical site and using the device on her
own, shes learning to interpret what these
percepts mean.
Everyone tells me to be patient, that
this will take awhile, she says.
Shes not expecting much, certainly
not any miracles. Still, Its always a
nice surprise to actually be able to do
something I havent been able to dolike sorting laundry, Kathy B. says.
Against the light-colored carpet in her
home, shes able to pick out dark-col-
ored clothing rom light-colored cloth-
ing, separating it into piles. Likewise,
i shes walking down a sidewalk bor-
dered by grass, she can walk straight
down it as she picks up percepts rom
the edge o the darker grass.
With her articial retina, Kathy B. can see a doorrom 20 eet away and walk to it.
Her retinal prosthesis enables Kathy B. toidentiy which direction a bright bar ismoving across a dark computer screen.
Soware upgrades to the unit are making it
easier or her to see the edges o objects, suchas doors or windows, as well as the direction
o lines on a computer screen.
She also sees movement. Te light will
move, so i a car goes by, I can tell which way
it went, Kathy B. explains. Similarly, when
she watches a basketball game on V, or
example, she can discern which way a player
is running down the court. I cant see the
person, but I eel like Im more involved
in the game to even be able to pick up the
movement, she says.Additionally, the implant is helping her at
work. I she hears something, she can glance
up, scan, and get a ash, indicating that
someone is at her desk. I cant see the out-
line o the persons body, but I can ask them
i they need help because I know theyre
there, she says.
Looking AheadKathy B. was the rst person in her amily to
be diagnosed with retinitis pigmentosa. Her
younger brother was next. So ar, theyre the
only two in her amily with the disease.
While her daughters have been spared to
date, uture grandchildren might not be.
Tats why I really want to be part o this,
she says. Im denitely excited or the utur
I think eventually this is going to be good.I nd it pretty amazing to have this much
hardware in my eye and not eel anything;
my eye eels perectly normal, she adds.n
Work in Progress
As the DOE Articial Retina Project
moves orward, prospects or additional
progress include developing a device
with 1000 or more electrodes that canbe scaled up using the knowledge gained
in creating the 200+ model. Various
advances and spinofs rom this work
already are beginning to pay of in other
biomedical applications as well as in a
wide range o hybrid surveillance sys-
tems, including environmental sensors,
and or plant and bacteria studies (see
story, Articial Retina Project Spurring
Spinof Technologies, p. 6). n
Engineering a retinal prosthesis is somewhat analogous
to constructing a miniature iPod on a foldable
contact lens that works in seawater.
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Related WebsitesDoheny Eye Institutewww.usc.edu/hsc/doheny/
Second Sight Medical Products, Inc.www.2-sight.com
Biomimetic MicroElectronic Systemsbmes-erc.usc.edu
Genome Management Information SystemOak Ridge National Laboratory1060 Commerce Park, MS 6480Oak Ridge, TN 37830, U.S.A.
Postmaster: Do Not ForwardAddress Correction Requested.Return Postage Guaranteed.
FIRST CLASS MAILU.S. POSTAGE
PAID
OAK RIDGE, TN
PERMIT NO. 3
Ofce o ScienceBiological and Environmental Research Program
ArtifcialRetina.energy. gov
12
Progress Metrics. Te U.S. Department o Energy (DOE) has spent approximately $63 mil-lion to date (FY2009) on the Artifcial Retina Project, with annual unding averaging~$7 million between 2001 and 2009. During this time, 16- and 60-electrode devices havebeen developed and implanted, and major research is under way to develop a 200+ elec-trode device. See sidebar, Increasing Resolution, on p. 4 to understand the level o visioneach o these devices provides. DOE unding or the project is scheduled to end in 2010.
Prepared or the U.S. Department oEnergy Ofce o Science by the GenomeManagement Inormation System (GMIS)at Oak Ridge National Laboratory, 1060Commerce Park, MS 6480, Oak Ridge,TN 37830. Telephone: 865.574.0597.
Kris Christen, Writer and EditorHolly Haun, EditorShirley Andrews, Graphic DesignerMarissa Mills, Web Editor
Special thanks to:
Lindy Yow, Science Project DirectorDoheny Eye InstituteUniversity o Southern Caliornia
Sponsor Contacts
Dean Cole, [email protected]
Send announcements and suggestions oruture issues to Dean Cole.
PET Scans continued rom page 9
the persons right eye was exposed to light
ashes rom a computer monitor. For the
electrical stimulation experiment, a ber
electrode was placed on the right eye and
a stream o electrical pulses with the same
duty cycle was delivered. Te results show
similar activation and inactivation patterns
between the light and electrical stimulations
(see upper graphics, p. 9).
Extending the study to RP patientsimplanted with retinal prostheses, the
researchers will analyze what happens to
the visual part o the brain over time as the
device is used more by patients. Ultimately,
the researchers hope to use the results to
examine the efect o cortical reorganiza-
tion in retinal degenerative diseases.
Te original work was unded by the
U.S. Department o Energy, and the
RP patient work is being unded by the
National Science Foundation (NSF grantnumber: 0917458). n
Award Winner (See p. 2)