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

3

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

Summer 2009

4

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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Summer 2009

5

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


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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Summer 2009

8

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).


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)

arn summer 09

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