DOE TECHNOLOGIES DRIVE INITIAL SUCCESS OF BIONIC EYE How basic research is being leveraged to enhance quality of life for the blind Using the unique skills and resources of the U.S. Department of Energy’s (DOE) national laboratories, in partnership with leading 2009 research universities and the private sector, R&D 100 the DOE Artificial Project already Awa r d has achieved important practical progress by Winner enabling direct communication between an implanted retinal prosthesis and neural cells (See story on p. 2) that carry visual information to the brain. The project’s collaborators are working to develop the world’s most advanced retinal prosthesis. This high-density microelectronic- tissue hybrid aims to restore sight to people blinded by retinal diseases such as age-related (AMD) and (RP). However, considerable In This Issue

1 Leveraging DOE Technologies 2 2009 R&D 100 Award Winner 3 Enrollment Rises in U.S. Clinical Trials 3 Clinical Trials Ongoing Worldwide A fundus image of an implanted Argus™ II microelectrode array. 4 Increasing Resolution 4 Ensuring Surgical Reproducibility research remains in order to fully benefit The Artificial Retina Project’s challenge is to from the investments made thus far. replace the lost light-gathering function of 5 Advancing Medical Research Frontiers: A Patient Perspective Technological Challenges in the rods and cones with a video camera and Engineering a Retinal Implant to use the information captured by the cam- 6 Artificial Retina Spinoff Technologies era to electrically stimulate the part of the 8 Spotlight: Sandia National Laboratories People with AMD or RP are blind because retina not destroyed by disease. Stimulation retinal photoreceptor cells (called rods and is done with a thin, flexible metal electrode 9 PET Scans of Brain Responses cones) degenerate and lose function. Rods array that has been patterned on soft plastic and cones are specialized cells that capture 10 Novel Software System Enhances material similar to that of a contact . light and translate it into electrical signals. Image Resolution Compounding this challenge is the fact that These signals are passed through underlying 12 Progress Metrics the delicate, electrical stimulation of the retinal cells and down the optic nerve to the brain where visual images are formed. …continued on page 2 Summer 2009 project will produce a 200+ electrode device DOE ARTIFICIAL RETINA TEAM GARNERS ready for extensive preclinical testing. As a direct result of DOE basic research Coveted 2009 R&D 100 Technology Award advances, the new design will have a highly compact array (see graphic, p. 11). This array is four times more densely packed with metal contact electrodes and required wiring connecting to a microelectronic stimulator than the Argus™ II. Simulations and calculations indicate that the 200+ elec- trode device should provide improved vision for patients. Promising Advances Several pioneering technological advances in fabrication and packaging by DOE national laboratories (see sidebar, Arti- ficial Retina Team Garners 2009 R&D 100 Award, this page) have helped make the third-generation device a reality. For Researchers involved with the U.S. Department of Energy’s (DOE) Artificial example, the significantly higher electrode Retina Project have won a prestigious R&D 100 Award. The award recognizes density required new lithographic and etch- the collection of innovative technologies in engineering, microfabrication, ing techniques to pattern platinum films on material sciences, and microelectronics that has been integrated into a retinal soft polymer materials. Additionally, new prosthesis giving blind patients rudimentary vision. The multidisciplinary stacking techniques were needed to layer collaboration includes contributions from five DOE national laboratories— metals and polymers on top of each other Argonne National Laboratory, Lawrence Livermore National Laboratory, to achieve a narrower prosthesis in the sec- Los Alamos National Laboratory, Oak Ridge National tion that delivers electrical charges to the Laboratory, and Sandia National Laboratories, four electrodes. Other advances by DOE national laboratories include softening the rim of the universities—California Institute of Technology, array that is in contact with delicate retinal Doheny Eye Institute at the University of Southern neurons and improving techniques to California, North Carolina State University, and ensure none of the electrodes short-circuit. University of California, Santa Cruz, and private Because the device’s advanced electronics industry—Second Sight® Medical Products, Inc. operate in the eye’s saltwater environment, DOE’s national laboratories have spear- DOE Technologies continued from page 1 headed critical innovations in packaging. retina needs to be performed in the eye’s being targeted for electrical stimulation is These innovations include higher intercon- saltwater environment without shorting less than 5 mm by 5 mm. Consequently, as nect densities of the individual contacts out any electronic circuits. In other words, the number of electrodes increases, their and attachment to the electronic chip engineering a retinal prosthesis is some- size and spacing must decrease. while still preserving a leak-tight electrical what analogous to constructing a miniature Basic Research Payoffs connection. A novel, dual-sided integrated iPod® on a foldable contact lens that works circuit also has been developed for stacking in seawater. To date, Second Sight® Medical Products, components and interconnecting them (see Moreover, just as the resolution of graphic Inc., the project’s private-sector partner, story, Sandia National Laboratories, p. 8). images on a computer screen improves with has sponsored clinical tests approved by Research also is under way on various bio- greater pixel density, researchers assume the U.S. Food and Drug Administration for adhesives that could be used to attach the that increased electrode densities will the Argus™ I and II model systems, which microelectrode array to the retinal surface. translate into higher-resolution images for contain 16 and 60 electrodes (i.e., pixels), patients. However, the area of the retina respectively. In the near future, the DOE …continued on page 11 2 Summer 2009 Patient Enrollment Rises in U.S. Portion of Clinical Trial Second-generation artificial retina showing promise in ongoing feasibility studies The U.S. Food and Drug Administration has granted approval to expand Second Sight® Clinical Trials Ongoing at Multiple Sites Worldwide Medical Products’ Argus™ II Retinal Implant feasibility study. Up to 20 people in the United States who are blind or have severely impaired vision because of retinitis pigmen- tosa (RP), a genetic eye disease, will be able to participate. As of mid-July, 30 RP patients worldwide have been implanted with the device (see sidebar, Clinical Trials Ongo- ing at Multiple Sites Worldwide, this page), which incorporates advanced technolo- gies from the U.S. Department of Energy’s (DOE) national laboratories. In the largest study to date, the Argus™ II continues to have a good safety profile. Implanted patients are using the artificial retina to successfully identify the position and approximate size of objects and detect movement of nearby objects and So far, 12 clinical centers in 5 countries have implanted patients with the Argus™ II retinal people. These implants also are provid- prosthesis which is intended to partially restore their sight and increase orientation and ing subjects with sufficient vision to allow mobility, thereby improving patients’ quality of life. As of mid-July, 14 patients in the demonstrated improvement in orientation United States and 16 patients at sites in Europe and Mexico have been implanted with and mobility. the device. These numbers continue to rise as more participants are enrolled in the trials. The Argus™ II is designed to transmit infor- All clinical centers currently are recruiting more volunteers with retinitis pigmentosa. mation directly to the retina of individuals For details on inclusion criteria, see http://clinicaltrials.gov/ct2/show/NCT00407602. about their physical surroundings, thereby bypassing photoreceptor cells that have been damaged because of RP. It consists years are expected to enable reading and All 17 patients have seen — pat- of a 60-electrode grid that is surgically facial recognition. terns of light produced by electrical stimu- implanted and attached to the retina. The lation—and many are showing statistically electrodes transmit information acquired Preliminary Results significant improvements in orientation and from an external camera that is mounted All of the patients implanted so far with the mobility, spatial localization, and motion on a pair of eyeglasses. This device has Argus™ II system had bare light perception detection. They all are using the device out- several advantages over the Argus™ I, or worse vision before the surgery. Averag- side the clinical setting. a 16-electrode prosthesis that showed ing 56.8 years, their ages range from 28 to proof of concept with chronic stimulation 77 years. The median surgery time for the Trials Enable Device Improvements demonstrated in 6 patients for more than implant procedure in the United States is Feedback from the feasibility studies has led 5 years. Argus™ II advantages include more 3 hours. to several design improvements that are stimulating electrodes and advanced image Ongoing 3-year feasibility studies are testing expected to increase the Argus™ II system’s processing, and its smaller package requires the safety and efficacy of the device. For the clinical benefits. These data also have driven less surgical time for the implant proce- 17 patients implanted with the device in the improvements to surgical techniques by dure. The Argus™ II underwent extensive first 6 months, there have been no device advancing the development of an easier-to- in vivo and in vitro testing prior to clinical failures and few serious adverse events, handle device, which is making the implanta- trials. While it is designed to last a lifetime, all of which were resolved with treatment. tion procedure more replicable (see sidebar, it can be safely removed if necessary. Fur- Such events included conjunctival erosion, Ensuring Surgical Reproducibility, p. 4). ther developments planned for the coming hypotony, and endophthalmitis. …continued on page 4 3 Summer 2009 Clinical Trials continued from page 3 Preclinical testing of a retinal prosthesis with Increasing Resolution more than 200 electrodes (see story, DOE Technologies Drive Initial Success of Bionic Eye, p. 1) is under way and has the potential to significantly improve the visual acuity of people with RP and age-related macu- lar degeneration. Additional research and development efforts by DOE laboratories are expected to produce artificial with more than 1000 electrodes. 16 electrodes 200+ electrodes 1000+ electrodes Hopeful First Steps Toward Meaningful Sight These images approximate what patients with retinal devices ideally could see. It is hoped that increasing the number of electrodes will result in more visual perceptions The higher resolution that more advanced, and higher-resolution vision. 1000+ electrode prostheses potentially can [Credit: California Institute of Technology] provide is key to the goal of enabling reading of large print, unaided mobility, and facial recognition. To date, most of the patients Ensuring Surgical Reproducibility with the artificial retina implants use them for orientation and large object detection. Designing a robust, biocompatible retinal prosthesis is one thing. However, another Higher-resolution implants are expected challenge lies in developing easily replicable surgical techniques to place the implant in just to enhance usage by allowing better vision the right spot on the retinal macula and keep it there. not only for mobility, but also for object Many of the maneuvers surgeons perform during implantation of the Argus™ II are standard detection. With the 1000+ electrode device, techniques any experienced retinal surgeon has used numerous times, says Mark Humayun, patients are expected to be able to read and a vitreoretinal surgeon and associate director of research at the University of Southern recognize faces. California’s Doheny Eye Institute. Introducing the electrode array into the eye and tacking Currently, “We’re replacing millions of pho- it to the retina are new tasks requiring novel, advanced approaches not within a retinal toreceptor cells with just 60 electrodes, so the surgeon’s normal arsenal. corresponding vision that these patients are Consequently, “We tried to tailor the approach to processes mimicking those that surgeons able to achieve is not as good as that of a nor- already follow,” says Humayun, who pioneered the implantation procedure. Another key to mal-sighted person,” explains Elias Green- achieving surgical reproducibility is using easy-to-handle materials whose look and feel are baum, a physicist at Oak Ridge National like those with which surgeons already are comfortable. For example, the telemetry coil is Laboratory and a member of DOE’s artificial mounted on a scleral buckle, which surgeons place around the eye for retinal detachments. retina team (see box, Increasing Resolution, “We’ve really reduced this technique more to science than art so that it can be more easily this page). Consequently, continued clinical reproduced,” Humayun says. testing is crucial for further design improve- Although still a complex procedure, “It’s a surgery that’s doable, and I think it’s very ments that would allow more implantees to reasonable that this will become a much more widely used technique,” says Lyndon da realize the goal of near-normal sight. Cruz, a vitreoretinal surgeon at Moorfields Eye Hospital in London who is participating “The clinical trial expansion for the Argus™ II in the Argus™ II clinical trials. “We feel we’re part of something that’s genuinely new, retinal prosthesis is great news,” says Stephen innovative, and cutting edge,” he adds. Rose, chief research officer for the Founda- tion Fighting Blindness. “The technology holds real promise for giving some meaning- nutritional therapies are more appropri- challenge. So too does reconstructing the ful vision to people with the most advanced ate for “rescuing” photoreceptor cells in complex synapse and neural connections. retinal degenerative diseases.” the early stages of disease by halting their In contrast, the retinal implant bypasses And for people with severe, end-stage vision decline. Once those cells are lost, stem degenerated photoreceptor cells altogether losses, the artificial retina may be the only cell transplants one day might be used and, to date, has progressed more quickly option for restoring sight. Other potential to replace them, but differentiating stem and demonstrated more success than stem treatments such as gene, pharmaceutical, and cells into photoreceptors poses a difficult cell transplants. n 4 Summer 2009 implant patient Helps Advance the Frontiers of Medical Research

A highly functioning person with a job, family, and household to tend to, Kathy B. doesn’t feel like she’s blind despite the fact that she’s had no vision for about 15 years. Nevertheless, she was excited when she recently was able to find the full moon in the dark, nighttime sky. “We were out walking, and I looked upwards, scanning my head back and forth,” Kathy B. explains. “All of a sudden, I saw a big flash, and I asked my husband, ‘Is that the moon?’” It was, and she began thinking about how long it had been since she’d last glimpsed that luminescent celes- tial body. Kathy B. is one of 14 people in the United States, 30 people worldwide, so far to receive the Argus™ II, a retinal implant with 60 electrodes being tested in clinical trials. The Kathy B. uses her retinal prosthesis to walk along a line to its termination. device is intended to provide rudimentary sight to blind people by stimulating the retina to send signals to the optic nerve and, glasses. When she started tripping over the physical plant department embossing ultimately, the brain, which perceives pat- things, she went to an ophthalmologist, and engraving campus signs and keep- terns of light and dark spots corresponding thinking it might be time for a pair of ing key records for locksmiths. She then to the electrodes stimulated. eyeglasses. As it turned out, it wasn’t that became a stay-at-home mother until the Her progress in learning how to decipher simple. For several months, nobody quite youngest of her three daughters went off to the meaning of the flashes that she’s see- knew what was happening with her eyes. college. With her husband at work all day ing has been slow but steady. How much Finally, she received a diagnosis: retinitis and her children gone, Kathy B. acquired improvement she will realize in the future pigmentosa, a hereditary retinal disease a guide dog to help her get around on her with more use of the device remains to be that initially steals a person’s peripheral own. She also learned how to read Braille determined. If her initial progress is any vision, eventually leaving only a small patch at the Braille Institute, where she took a indicator, however, it is expected that she of central vision. In some cases, even that part-time job as a receptionist. could improve considerably. can disappear. Through it all, she has maintained her “I’m grateful to be able to give [the research- “They told me I would lose my vision—that optimistic outlook. Not being able to drive ers] information that is helping to move this it would go very slowly, but they didn’t or read print was hard for her. Knowing, forward,” Kathy B. says. think I would go totally blind,” Kathy B. however, that her children could have this In her early twenties when she began los- recounts. “Unfortunately, I did.” disease, she believed she had to set a posi- ing her sight, Kathy B. was certain that During the first 5 years, her vision deterio- tive example for them. advancements in medical science would rated fairly quickly. She had trouble seeing “I didn’t let it affect my life,” Kathy B. says. produce a cure for her disease within 20 at night and in dim light, and soon she no “I really just went on as if I could still see.” years. Now 57, she notes, “Little did I know longer was able to drive. Then her vision To this day, she does everything she pos- then that I myself would be involved in stabilized for a time before it started getting sibly can on her own. As her husband puts medical studies.” worse again. Fifteen years after the initial it, blindness isn’t so much a disability, but Journey into Darkness diagnosis, Kathy B. was completely blind. rather an inconvenience for her. “It just Until she was 23, Kathy B. had no vision She had to give up her job at the University takes me a little bit longer to figure out problems whatsoever; she didn’t even wear of California–Irvine, where she worked in …continued on page 11 5 Artificial Retina Project Spurring Spinoff Technologies Energy, defense, and biomedical arenas stand to benefit As in many frontier scientific research projects, the U.S. Department of Energy’s (DOE) Artificial Retina Project has produced several unanticipated discoveries and spinoffs that are increasing the value of these investments. The same microelectronics and feedback mechanisms used in the artificial retina to enable neural cells to communicate with machines could be adapted to interface with other cell types such as those of plants and bacteria. Applications include remote sensors that monitor for environmental contamination, assist with environmental remediation, or counter bioterrorism. A wide range of other biomedical devices also could be enabled by this technology. “We are only looking at the tip of the iceberg right now as we move into higher-density abiotic-biotic surfaces,” says Satinderpall Pannu, group leader for advanced materials and processing technologies at DOE’s Lawrence Livermore National Laboratory (LLNL). Smart Biodetection Systems Ongoing research at LLNL is furthering the ment of multiple sensors that can relay signals development of remote-sensing platforms to to each other. Operating with very low power detect biothreats in harsh environments such requirements, such a distributed network of as oceans, rivers, and wastewater streams. sensors permits long-range communication Similar to the artificial retina, these polymer- capabilities with a low detection risk. based biodetection systems contain embedded Also, the flexible substrate allows these electronics and electrodes (see photo at right). detection devices to be molded for attach- But instead of stimulating retinal tissue, the ment to any curved surface. They could be electrodes can be functionalized for multiple affixed inside a channel, pipe, tube, or even chemical or biological agents like anthrax or small a soldier’s helmet. In a battlefield setting, pox. Whenever those particular substances are A polymer-based, field-deployable biodetection system with embedded microelectronics such sensors could be deployed virtually detected—for example, in a drinking water sup- and radio frequency–based power and data everywhere—on soldiers, tanks, planes, and ply or at an air monitoring station—the electri- communication. [Credit: Lawrence Livermore cal signal changes, and the information can be National Laboratory] Humvees—permitting communication as the sent to a local agency or the Centers for Disease sensors actively search the surrounding envi- ronment for chemical and biological threats. Control and Prevention, alerting them to the for the saline environment in the eye, these sen- potential threat. sors can tolerate harsh surroundings. Moreover, Ultimately, such rugged, flexible sensors Several key technologies developed for the artifi- communication and power transmission occur via could be distributed anywhere in any cial retina are enabling such advanced detection a radio-frequency link. Miniaturized for the arti- situation and be counted on to work for the devices. Because the technology was designed ficial retina, this technology permits the deploy- lifetime of an operation. n

Electronic-Tissue Interface Devices The advanced, implantable microelectronic serve as an artificial pancreas, continually measur- system developed for the artificial retina has ing glucose levels and dispensing the appropriate the potential to revolutionize other medical amounts of insulin in response to any foods being implants that could help people with combat consumed (see photo at left). injuries (e.g., soldiers who suffer traumatic Similarly, this technology might be used to admin- brain injuries), spinal cord injuries, Parkin- ister narcotics or pain relievers to people with son’s disease, deafness, and many other chronic pain such as migraine headaches. In addi- neurological disorders. tion, preventative systems could be implanted in DOE’s artificial retina demonstrates that an people who have been diagnosed with a particu- electronic-tissue interface is capable of com- Portable insulin pump. lar disease or have a history of cancer in their fam- municating with the brain to provide informa- ily. If the device picks up any change in the level of tion that the local tissue is unable to provide This same technology platform also could be a certain biomarker, an alarm would be triggered because of disease or injury. By selectively useful for drug delivery. The flexible circuit could to alert the patient to see a doctor immediately. stimulating neural or muscular tissue, the brain be adapted so that instead of carrying electri- Not only could such a system improve and save can be retrained to understand bioelectronic cal current, it would carry fluids via microfluidic lives, Pannu says, it also would cut down on inputs or to control the movement of muscles channels, Pannu says. In the case of diabetics, for healthcare costs because patients would need to or electromechanical actuators. example, such a smart, implantable system could see a doctor only if an issue arises. n Metabolic Prosthesis for Diabetics In addition to age-related macular degenera- electrolysis system that stimulates oxygen pro- surface-accessible region for treatment, thereby tion and retinitis pigmentosa, diabetic duction near the retina. The electrodes would avoiding any adverse internal irritants. retinopathy is another leading cause of provide small amounts of current in very short, If successful, this technique could preserve the blindness. It results from poor blood circulation, repetitive pulses that last about 200 microsec- retina. Currently, neovascularization treatment is particularly in the retina, which is a complicating onds. This would result in rapid production of destructive. “You apply a laser to the peripheral factor of diabetes. As blood flow is restricted, oxygen and suppressed production of chlorine, retina, essentially destroying it to create less retinal tissue is deprived of oxygen. Subse- a potentially harmful byproduct. oxygen demand in that region in order to sup- quently, neovascularization can occur, with “The vitreous humor has a chemical composi- ply more oxygen to the central retina,” explains abnormal or excessive blood vessels forming to tion very similar to seawater, and if you perform Mark Humayun, a vitreoretinal surgeon and compensate for the lack of oxygen. Eventually, ordinary electrolysis of saltwater, you’ll make associate director of research at USC’s Doheny these vessels can burst, leaking blood into the bleach and alkali, which are very harsh byprod- Eye Institute. “If we can supply oxygen, we can vitreous and causing blindness (see photos ucts,” explains Elias Greenbaum, who is leading hopefully sustain the entire retina.” below). The longer a person has diabetes, the this study at Oak Ridge National Laboratory Much of what has been learned through DOE’s greater his or her chances of developing this (ORNL) in collaboration with the University of Artificial Retina Project—practical biomedical eye disease. Southern California (USC) and University of Ten- engineering, surgical techniques, and electrode If oxygen could be provided to retinal tissue with nessee. “We’ve discovered that if you perform fabrication—carries directly over to oxygenation poor blood flow before the onset of neovascu- pulsed or charge-limited electrolysis of the of ischemic tissue for diabetic retinopathy. And larization, progression of this condition might vitreous, it’s possible to produce oxygen and in many respects, the surgery and electrode fab- be stopped and perhaps reversed. An extension suppress the formation of chlorine.” rication are simpler, and the potential for neural of the technology developed for DOE’s artificial As reported in the IEEE paper, the three-elec- tissue damage is eliminated because no neural retina could supply the needed oxygen via a trode and feedback loop configuration—made tissue is stimulated. Instead, the vitreous humor metabolic prosthesis. The first publication of this possible by implanting a second cathode is oxygenated. new idea, including experimental data, appeared behind a patient’s ear—would enable a constant Laboratory research has demonstrated proof of in the February 2009 issue of IEEE Transactions on pH to be maintained in the area to be treated. principle of the metabolic prosthesis concept. Biomedical Engineering. If any pH drift occurs, it can be exported to a The next step is to build and test a device. n The procedure would involve surgically implant- ing a feedback-controlled, three-electrode From Electrodes to Molecular Photovoltaics While numerous spinoff technologies have been spawned by DOE’s artificial retina, other existing national laboratory technologies have helped to advance the retinal implant. One of these, from ORNL, evolved from DOE-supported research using photosynthesis in spinach and algae to split water molecules for producing oxygen and hydrogen, an energy-rich gas (see photo at right). Instead of using metal electrodes to stimulate A scene as it might be viewed by a person with retinal neurons, a light-sensitive protein from normal vision. [Credit: , National Institutes of Health] green plants could be used because it gener- ates a small electrical voltage after capturing the energy of incoming light. This technology could make future artificial retinas more efficient 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, Elias Greenbaum studies the use of algae for they trigger a charge separation that generates producing hydrogen from water in an a voltage that might be sufficient to trigger a illuminated flask.[Credit: ORNL Review] The same scene as it might be viewed by a person with diabetic retinopathy. [Credit: National neural response. If these reaction centers are Eye Institute, National Institutes of Health] inserted into retinal neural cells, the resulting …continued on page 10 Summer 2009 SPOTLIGHT SANDIA NATIONAL LABORATORIES Microscale Enablers

More advanced artificial retinas are relying on miniaturized electronics for process- ing incoming images and activating the An application-specific integrated circuit being developed for advanced artificial retinas. corresponding electrodes to communi- cate with retinal cells and ultimately the “Essentially, we’re trying to cram more The artificial retina’s custom-designed brain. The goal of these devices, being and more things into smaller and smaller integrated circuit (IC) is the system’s brain. developed through a U.S. Department of spaces,” says Kurt Wessendorf, an analog Its job is to take signals from the external Energy (DOE) collaboration, is to continu- circuit designer and leader of Sandia’s camera and convert them into stimuli that ally improve their visual resolution so that artificial retina efforts. If more electrodes, are transferred to the electrode array. The IC implanted individuals eventually will be and hence more capabilities, can be packed performs this function via a series of inter- able to read large print, recognize faces, and into the system, the images that implanted connected, nanosize nodes, whose locations move about without aid. Sandia National individuals see will be of higher resolu- on the chip’s surface are important because Laboratories’ expertise in the development, tion. This is the area benefitted by Sandia’s they can minimize the wire length along fabrication, and production of microsystems expertise in microsystems. which the signal travels (see graphic above). is helping to make this goal a reality. Engineering Tiny Machines “The current method for achieving higher The Challenge Microsystem devices smaller than a human electrode currents involves assembly with a Biocompatible electronics packages cur- hair are built on silicon wafers or chips. lot of bond wires and other interconnects,” rently used in medical devices require only They contain electrical circuitry and says Sean Pearson, an IC design engineer at a small number of electrical interfaces to microelectromechanical systems (MEMS), Sandia. “This makes the device tedious to operate them. For example, pacemakers which are miniature machines. …continued on page 9 at most have four electrical contacts, and cochlear implants for the hearing impaired use 22 or fewer. Additionally, the volume of these packages is typically more than 5 cm3. By comparison, DOE’s artificial retina requires a much smaller electronics package but one to two orders of magnitude more electrical feed-throughs to communicate with retinal cells. This density is beyond conventional packag- ing technology. The compact size of the artificial retina’s electronics package makes it difficult to mechanically and electrically interconnect the microelectronics inside. The package also has to withstand the human eye’s harsh saline environment for the lifetime of the patient, so the electronics have to be hermetically sealed, preventing all transfer of moisture and gases between Three-dimensional model and cross section of a dual-sided integrated circuit. The circuit the components inside the package and the enables high-density interconnects on both top and bottom surfaces. human body. 8 Summer 2009 PET Scans Show Brain Responses to Light, Electrical Stimulation A study measuring metabolic changes in the brains of sighted people is show- ing similar responses to both light and electrical stimulations. Researchers at the U.S. Department of Energy’s Brookhaven National Laboratory, Doheny Eye Institute at the University of Southern California, and Columbia University now are taking this study a step further to demonstrate Light Stimulation vs. Baseline. Colored areas indicate increased (red scale) or decreased that the visual cortex in patients with (blue scale) brain activity from light stimulation as compared to no stimulation. retinitis pigmentosa (RP) can respond to electrical stimulation. Using positron emission tomography (PET) scanning and a glucose analogue called FDG, the researchers evaluated and compared what happens to the visual pro- cessing part of the brain following different stimuli. Eight healthy volunteers with Electrical Stimulation vs. Baseline. Colored areas indicate increased (red scale) or decreased normal vision participated in the study. (blue scale) brain activity from electrical stimulation as compared to no stimulation. Each underwent three PET scans on three different days to represent baseline condi- Prior to each scan, the volunteers sat quietly For the baseline scan, both eyes were blind- tions, responses to light stimulation, and in a darkened room for 30 minutes to dark folded. During the light stimulation scan, responses to electrical stimulation. adapt before receiving the FDG injection. …continued on page 12

Sandia Spotlight continued from page 8 Murat Okandan, a microsystems engineer Dual-Use Technology build and very difficult to yield full func- on the Sandia team. Sandia has a long history of pioneering tionality.” Consequently, he and his col- Additionally, Sandia researchers are microelectronics research, which feeds into leagues are developing a novel, dual-sided developing state-of-the-art packaging several defense-related systems, including IC to simplify how data are routed and to technologies to assemble and integrate sensor technologies and satellite applications. better integrate the electronics package the microelectronic components with the Spinoffs of the Artificial Retina Project— with the electrode array (see lower graphic, thin-film electrode array. Biocompatibil- such as the silicon interconnect and higher- p. 8). “We’re using one side to bring the ity issues are driving much of this effort, density packaging of components—are signals in and the other side to put them requiring the high-density interconnects to being evaluated for potential applications in out,” Pearson explains. be insulated with a nonconductive film to some of these ongoing projects. prevent moisture and ionic and biological For the electronics substrate, the research- “The kind of exposure seen in the eye is not contamination from causing device failure ers are using a Sandia-patented MEMS unlike the harsh, corrosive environments (see graphic below). technique to selectively etch away parts in which many defense- of the silicon chip or add new structural Ceramic Lid Electrical Vias Interior related components are layers to create tiny features that cannot be Region required to survive for many made any other way. This micromachin- Metal Annulus years,” Wessendorf says. ing process allows wiring of the electrical Electronic Circuit Moreover, “We’re always connections through the chip for access to Solder Ball looking at miniaturizing and both sides. Metal Annulus increasing function, and “By using that bottom surface, which adds Ceramic Base these efforts will help in interconnect space instead of eliminating Ceramic and those directions.” n it, we’re able to get higher interconnect Metal Package Sandia National Laboratories is densities,” thereby allowing the number operated by Sandia Corporation, a Lockheed Martin company, for the of electrodes on the array to be increased High-density hermetic electronics packaging with a dual- sided electronic circuit. U.S. Department of Energy’s National without making the device bigger, says Nuclear Security Administration. 9 Summer 2009 Seeing Is Processing A novel software system not only processes incoming images in real time but also enhances what retinal implant recipients perceive The human retina is not just a detector of luminance control under light that sends optical information to the severe lighting condi- brain. It also performs complex image pro- tions, user-defined gray- cessing to provide the brain with optimized scale levels for reducing visual information. Replacing diseased the data volume trans- photoreceptors with the electrodes of an mitted to the visual pros- artificial retina thus not only reduces the thesis, blur algorithms, number of pixels, it also disrupts this neces- and edge detection (see sary image processing. graphic at right). These To restore that lost function, researchers filters are not unlike what at the California Institute of Technol- a person experiences in a ogy’s Visual and Autonomous Exploration regular eye exam during Systems Research Laboratory under the which a battery of tests direction of Wolfgang Fink are developing is performed to deter- software to pre-process the information mine the proper eyeglass Typical palette of Artificial Retinal Implant Vision Simulator from implant patients’ miniature cameras prescription. In this case, (ARIVS) image-processing modules that are applied in real retinal implant recipi- time to the video camera stream driving the artificial retina. before it is fed to their retinal prostheses. [Credit: California Institute of Technology] Dubbed the Artificial Retinal Implant ents can choose among these different filters to Vision Simulator (ARIVS), this software camera stream, pre-processed by ARIVS, further fine tune, optimize, and customize system provides real-time image processing into patterns of electrical stimulation of their individual visual perception by actively and enhancement to improve the limited retinal tissue by the implanted electrode manipulating parameters of individual vision afforded by the camera-driven device. array. The Caltech researchers on the U.S. image-processing filters or altering the The preservation and enhancement of Department of Energy’s team are address- sequence of these filters. contrast differences and transitions, such as ing this challenge by developing and testing edges, are especially important compared to An incomparably greater challenge exists multivariate optimization algorithms based picture details like object texture. in predicting how to electrically stimulate on evolutionary principles. These algo- Since predicting exactly what blind subjects the retina of a blind subject via the retinal rithms are used to modify the electrical may be able to perceive is difficult, ARIVS prosthesis to elicit a visual perception that stimulation patterns administered by the offers a wide variety of image processing matches an object or scene as captured by electrode array to optimize visual percep- filters. They include contrast and brightness the camera system that drives the prosthesis. tion. Operational tests with Argus™ I users enhancement, grayscale equalization for This requires the efficient translation of the currently are under way. n

Spinoff Technologies continued from page 7 would require hair-like dimensions, lead- Greenbaum’s group has shown that these stimulation could be much more effective ing to fabrication and stability issues. nanoscale protein structures can be har- than that applied with external electrodes, “Virtually no metal is stable when you vested from plant materials and reconsti- where voltage is lost at the interface get down to those hair-like dimensions tuted in liposomes, with their full photo- between the electrode and liquid interface, because the electrical voltages applied to voltaic properties preserved. Liposomes says Greenbaum, a physicist at ORNL. them cause corrosion and loss of metal,” are artificial membranes made of lipids that mimic the membrane composition of This strategy offers other advantages as Greenbaum explains. a living cell. Using the liposomes as deliv- well. For one, these systems are already at Additionally, the lens of the eye itself could ery vehicles, the researchers have inserted the nanoscale, so a high density of them be used to capture images, eliminating the these photosynthetic reaction centers could be packed into the roughly 5 mm need for an external camera mounted in into mammalian cells and elicited optical by 5 mm area of the retina targeted by the eyeglasses. Likewise, no battery would be activity where there was none before. n prosthesis for stimulation. In contrast, an needed because the voltages would be self- equivalent number of metal electrodes powered by the photosynthetic reaction centers in the retinal cells. 10 Summer 2009 Advancing Medical Research continued from page 5 “Everyone tells me to be patient, that this will take awhile,” she says. She’s not expecting much, certainly not any miracles. Still, “It’s always a nice surprise to actually be able to do something I haven’t been able to do” like sorting laundry, Kathy B. says. Against the light-colored carpet in her home, she’s able to pick out dark-col- ored clothing from light-colored cloth- ing, separating it into piles. Likewise, Her retinal prosthesis enables Kathy B. to if she’s walking down a sidewalk bor- identify which direction a bright bar is With her artificial retina, Kathy B. can see a door moving across a dark computer screen. from 20 feet away and walk to it. dered by grass, she can walk straight down it as she picks up percepts from how to do something or get somewhere,” she the edge of the darker grass. someone is at her desk. “I can’t see the out- explains. line of the person’s body, but I can ask them Software upgrades to the unit are making it if they need help because I know they’re Relearning Sight easier for her to see the edges of objects, such there,” she says. as doors or windows, as well as the direction Kathy B. had been blind for nearly 15 years Looking Ahead when she heard about the Argus™ II clinical of lines on a computer screen. Kathy B. was the first person in her family to trials. Deciding that at this point in her life She also sees movement. “The light will be diagnosed with retinitis pigmentosa. Her she had nothing to lose, she opted for the move, so if a car goes by, I can tell which way younger brother was next. So far, they’re the surgery when she found out she was a suit- it went,” Kathy B. explains. Similarly, when only two in her family with the disease. able candidate. she watches a basketball game on TV, for While her daughters have been spared to At first, Kathy B. didn’t see anything. Then example, she can discern which way a player date, future grandchildren might not be. occasionally she’d see a flash of light. Now, is running down the court. “I can’t see the “That’s why I really want to be part of this,” she sees “percepts” whenever there’s a strong person, but I feel like I’m more involved she says. “I’m definitely excited for the future; contrast between light and dark, indicating in the game to even be able to pick up the I think eventually this is going to be good. that something is there. Through testing at movement,” she says. the clinical site and using the device on her Additionally, the implant is helping her at “I find it pretty amazing to have this much own, she’s learning to interpret what these work. If she hears something, she can glance hardware in my eye and not feel anything; percepts mean. up, scan, and get a flash, indicating that my eye feels perfectly normal,” she adds. n

DOE Technologies continued from page 2 Work in Progress “Engineering a retinal prosthesis is somewhat analogous As the DOE Artificial Retina Project to constructing a miniature iPod® on a foldable moves forward, prospects for additional contact lens that works in seawater.” progress include developing a device with 1000 or more electrodes that can be scaled up using the knowledge gained Fabricated 200+ thin- in creating the 200+ model. Various film electrode array. The metal traces forming advances and spinoffs from this work the electrodes in the already are beginning to pay off in other artificial retina are biomedical applications as well as in a less than a micrometer thick—less than 1% wide range of hybrid surveillance sys- the thickness of a tems, including environmental sensors, human hair. and for plant and bacteria studies (see story, Artificial Retina Project Spurring Spinoff Technologies, p. 6).n 11 Prepared for the U.S. Department of Energy Office of Science by the Genome Management Information System (GMIS) at Oak Ridge National Laboratory, 1060 Commerce Park, MS 6480, Oak Ridge, TN 37830. Telephone: 865.574.0597. Kris Christen, Writer and Editor Holly Haun, Editor Shirley Andrews, Graphic Designer Marissa Mills, Web Editor Special thanks to: Lindy Yow, Science Project Director Doheny Eye Institute University of Southern California Progress Metrics. The U.S. Department of Energy (DOE) has spent approximately $63 mil- lion to date (FY2009) on the Artificial Retina Project, with annual funding averaging Sponsor Contacts ~$7 million between 2001 and 2009. During this time, 16- and 60-electrode devices have Dean Cole, Ph.D. been developed and implanted, and major research is under way to develop a 200+ elec- [email protected] trode device. See sidebar, “Increasing Resolution,” on p. 4 to understand the level of vision Send announcements and suggestions for each of these devices provides. DOE funding for the project is scheduled to end in 2010. future issues to Dean Cole.

PET Scans continued from page 9 the person’s right eye was exposed to light researchers will analyze what happens to Office of Science flashes from a computer monitor. For the the visual part of the brain over time as the Biological and Environmental Research Program electrical stimulation experiment, a fiber device is used more by patients. Ultimately, ArtificialRetina.energy. gov electrode was placed on the right eye and the researchers hope to use the results to a stream of electrical pulses with the same examine the effect of cortical reorganiza- Related Websites duty cycle was delivered. The results show tion in retinal degenerative diseases. Doheny Eye Institute similar activation and inactivation patterns The original work was funded by the www.usc.edu/hsc/doheny/ between the light and electrical stimulations U.S. Department of Energy, and the Second Sight® Medical Products, Inc. (see upper graphics, p. 9). RP patient work is being funded by the www.2-sight.com Extending the study to RP patients National Science Foundation (NSF grant Biomimetic MicroElectronic Systems implanted with retinal prostheses, the number: 0917458). n bmes-erc.usc.edu

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Award Winner (See p. 2)

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