Researchers Leverage Artificial Retina Project—
Create Spinoff Technologies

As in many frontier scientific research projects, the U.S. Department of Energy’s (DOE) Artificial Retina Project has led to cutting-edge innovations as well as 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) and one of the primary technology developers for the artificial retina.

Listed below are several of the leading-edge technologies developed for and/or as a result of the Artificial Retina Project. Full descriptions follow.

• Smart Biodetection Systems - Lawrence Livermore National Laboratory
• Electronic-Tissue Interface Devices - Lawrence Livermore National Laboratory
• Metabolic Prosthesis for Diabetics - Oak Ridge National Laboratory and University of Southern California Doheny Eye Institute (USC DEI)
• From Electrodes to Molecular Photovoltaics - Oak Ridge National Laboratory
• Microscale Enablers - Sandia National Laboratories
• Vision Simulator Image Processing Software System - California Institute of Technology
• Biocompatible Microelectronics - Lawrence Livermore National Laboratory
• PET Scans to Measure Light, Electrical Stimulation - Brookhaven National Laboratory and USC DEI
• Diamond Coating Technology - Argonne National Laboratory
• MIcrochip Development ( pdf only) - University of California at Santa Cruz

Smart Biodetection Systems

A polymer-based, field-deployable biodetection system with embedded microelectronics and radio frequency-based power and data communication. [Credit: Satinderpall Pannu, LLNL]

Ongoing research at LLNL is furthering the development of remote-sensing platforms to detect biothreats in harsh environments such as oceans, rivers, and wastewater streams. Similar to the artificial retina, these polymer-based biodetection systems contain embedded electronics and electrodes (see photo at right). But instead of stimulating retinal tissue, the electrodes can be functionalized for multiple chemical or biological agents like anthrax or small pox. Whenever those particular substances are detected—for example, in a drinking water supply or at an air monitoring station—the electrical signal changes, and the information can be sent to a local agency or the Centers for Disease Control and Prevention, alerting them to the potential threat.

Several key technologies developed for the artificial retina are enabling such advanced detection devices. Because the technology was designed for the saline environment in the eye, these sensors can tolerate harsh surroundings. Moreover, communication and power transmission occur via a radio-frequency link. Miniaturized for the artificial retina, this technology permits the deployment of multiple sensors that can relay signals to each other. Operating with very low power requirements, such a distributed network of sensors permits long-range communication capabilities with a low detection risk.

Also, the flexible substrate allows these detection devices to be molded for attachment to any curved surface. They could be affixed inside a channel, pipe, tube, or even a soldier’s helmet. In a battlefield setting, such sensors could be deployed virtually everywhere—on soldiers, tanks, planes, and Humvees—permitting communication as the sensors actively search the surrounding environment for chemical and biological threats.

Ultimately, such rugged, flexible sensors could be distributed anywhere in any situation and be counted on to work for the lifetime of an operation.

Electronic-Tissue Interface Devices
The advanced, implantable microelectronic system developed for the artificial retina has the potential to revolutionize other medical implants that could help people with combat injuries (e.g., soldiers who suffer traumatic brain injuries), spinal cord injuries, Parkinson’s disease, deafness, and many other neurological disorders.

DOE’s artificial retina demonstrates that an electronic-tissue interface is capable of communicating
with the brain to provide information that the local tissue is unable to provide because of disease or injury. By selectively stimulating neural or muscular tissue, the brain can be retrained to understand bioelectronic inputs or to control the movement of muscles or electromechanical actuators.

Portable insulin pump.

This same technology platform also could be useful for drug delivery. The flexible circuit could be adapted so that instead of carrying electrical current, it would carry fluids via microfluidic channels, Pannu says. In the case of diabetics, for example, such a smart, implantable system could serve as an artificial pancreas, continually measuring glucose levels and dispensing the appropriate amounts of insulin in response to any foods being consumed (see photo at right).

Similarly, this technology might be used to administer narcotics or pain relievers to people with chronic pain such as migraine headaches. In addition, preventative systems could be implanted in people who have been diagnosed with a particular disease or have a history of cancer in their family. If the device picks up any change in the level of a certain biomarker, an alarm would be triggered to alert the patient to see a doctor immediately. Not only could such a system improve and save lives, Pannu says, it also would cut down on healthcare costs because patients would need to see a doctor only if an issue arises.

A scene as it might be viewed by a person with normal vision. [Credit: National Eye Institute, National Institutes of Health]

The same scene as it might be viewed by a person with diabetic retinopathy. [Credit: National Eye Institute, National Institutes of Health]

Metabolic Prosthesis for Diabetics
In addition to age-related macular degeneration and retinitis pigmentosa, diabetic retinopathy is another leading cause of blindness. It results from poor blood circulation, particularly in the retina, which is a complicating factor of diabetes. As blood flow is restricted, retinal tissue is deprived of oxygen. Subsequently, neovascularization can occur, with abnormal or excessive blood vessels forming to compensate for the lack of oxygen. Eventually, these vessels can burst, leaking blood into the vitreous and causing blindness (see photos at right). The longer a person has diabetes, the greater his or her chances of developing this eye disease.

If oxygen could be provided to retinal tissue with poor blood flow before the onset of neovascularization, progression of this condition might be stopped and perhaps reversed. An extension of the technology developed for DOE’s artificial retina could supply the needed oxygen via a metabolic prosthesis. The first publication of this new idea, including experimental data, appeared in the February 2009 issue of IEEE Transactions on Biomedical Engineering. The procedure would involve surgically implanting a feedback-controlled, three-electrode electrolysis system that stimulates oxygen production near the retina. The electrodes would provide small amounts of current in very short, repetitive pulses that last about 200 microseconds. This would result in rapid production of oxygen and suppressed production of chlorine, a potentially harmful byproduct.

“The vitreous humor has a chemical composition very similar to seawater, and if you perform ordinary electrolysis of saltwater, you’ll make bleach and alkali, which are very harsh byproducts,” explains Elias Greenbaum, who is leading this study at Oak Ridge National Laboratory (ORNL) in collaboration with the University of Southern California (USC) and University of Tennessee. “We’ve discovered that if you perform pulsed or charge-limited electrolysis of the vitreous, it’s possible to produce oxygen and suppress the formation of chlorine.”

As reported in the IEEE paper, the three-electrode and feedback loop configuration—made possible by implanting a second cathode behind a patient’s ear—would enable a constant pH to be maintained in the area to be treated. If any pH drift occurs, it can be exported to a surface-accessible region for treatment, thereby avoiding any adverse internal irritants.

If successful, this technique could preserve the retina. Currently, neovascularization treatment is destructive. “You apply a laser to the peripheral retina, essentially destroying it to create less oxygen demand in that region in order to supply more oxygen to the central retina,” explains Mark Humayun, a vitreoretinal surgeon and associate director of research at USC’s Doheny Eye Institute. “If we can supply oxygen, we can hopefully sustain the entire retina.”

Much of what has been learned through DOE’s Artificial Retina Project—practical biomedical engineering, surgical techniques, and electrode fabrication—carries directly over to oxygenation of ischemic tissue for diabetic retinopathy. And in many respects, the surgery and electrode fabrication are simpler, and the potential for neural tissue damage is eliminated because no neural tissue is stimulated. Instead, the vitreous humor is oxygenated.

Laboratory research has demonstrated proof of principle of the metabolic prosthesis concept. The next step is to build and test a device.

From Electrodes to Molecular Photovoltaics

Eli Greenbaum studies algae being used to produce hydrogen from water in an illuminated flask. [Image: ORNL Review]

While numerous spinoff technologies have been spawned by DOE’s artificial retina, other 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 to produce oxygen and hydrogen, the energy-rich gas.

Instead of using metal electrodes to stimulate retinal neurons, a light-sensitive protein from green plants could be used because it generates 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, they trigger a charge separation that generates a voltage which might be sufficient to trigger a neural response. If these reaction centers are inserted into retinal neural cells, the resulting stimulation could be much more effective than that applied with external electrodes, where voltage is lost at the interface between the electrode and liquid interface, says Greenbaum, a physicist at ORNL.

This strategy offers other advantages as well. For one, these systems are already at the nanoscale, so a high density of them could be packed into the roughly 5 mm by 5 mm area of the retina targeted by the prosthesis for stimulation. In contrast, an equivalent number of metal electrodes would require hair-like dimensions, leading to fabrication and stability issues.

“Virtually no metal is stable when you get down to those hair-like dimensions because the electrical voltages applied to them cause corrosion and loss of metal,” Greenbaum explains.

Additionally, the lens of the eye itself could be used to capture images, eliminating the need for an external camera mounted in eyeglasses. Likewise, no battery would be needed because the voltages would be self-powered by the photosynthetic reaction centers in the retinal cells.

Greenbaum’s group has shown that these nanoscale protein structures can be harvested from plant materials and reconstituted in liposomes, with their full photovoltaic properties preserved. Liposomes are artificial membranes made of lipids that mimic the membrane composition of a living cell. Using the liposomes as delivery vehicles, the researchers have inserted these photosynthetic reaction centers into mammalian cells and elicited optical activity where there was none before.

For more information on this spinoff topic, see articles from Discovery and Spie.

Microscale Enablers

More advanced artificial retinas are relying on miniaturized electronics for processing incoming images and activating the corresponding electrodes to communicate with retinal cells and ultimately the brain. The goal of these devices, being developed through a U.S. Department of Energy (DOE) collaboration, is to continually improve their visual resolution so that implanted individuals eventually will be able to read large print, recognize faces, and move about without aid. Sandia National Laboratories’ expertise in the development, fabrication, and production of microsystems is helping to make this goal a reality.

The Challenge
Biocompatible electronics packages currently used in medical devices require only a small number of electrical interfaces to operate them. For example, pacemakers 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 packaging 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 the components inside the package and the human body.

“Essentially, we’re trying to cram more and more things into smaller and smaller spaces,” says Kurt Wessendorf, an analog circuit designer and leader of Sandia’s artificial retina efforts. If more electrodes, and hence more capabilities, can be packed into the system, the images that implanted individuals see will be of higher resolution. This is the area benefitted by Sandia’s expertise in microsystems.

Engineering Tiny Machines

Figure 1. An application-specific integrated circuit being developed for advanced artificial retinas. A four-way switch allows each incoming signal to go to one of four places as an output, enabling more electrodes to be stimulated. Click on image to enlarge.

Microsystem devices smaller than a human hair are built on silicon wafers or chips. They contain electrical circuitry and microelectromechanical systems (MEMS), which are miniature machines.

The artificial retina’s custom-designed integrated circuit (IC) is the system’s brain. Its job is to take signals from the external camera and convert them into stimuli that are transferred to the electrode array. The IC performs this function via a series of interconnected, nanosize nodes, whose locations on the chip’s surface are important because they can minimize the wire length along which the signal travels (see figure 1 at right).

Figure 2. Three-dimensional model and cross section of a dual-sided integrated circuit. The circuit enables high-density interconnects on both top and bottom surfaces. Click on image to enlarge.

“The current method for achieving higher electrode currents involves assembly with a lot of bond wires and other interconnects,” says Sean Pearson, an IC design engineer at Sandia. “This makes the device tedious to build and very difficult to yield full functionality.” Consequently, he and his colleagues are developing a novel, dual-sided IC to simplify how data are routed and to better integrate the electronics package with the electrode array (see figure 2 at right). “We’re using one side to bring the signals in and the other side to put them out,” Pearson explains.

For the electronics substrate, the researchers are using a Sandia-patented MEMS technique to selectively etch away parts of the silicon chip or add new structural layers to create tiny features that cannot be made any other way. This micromachining process allows wiring of the electrical connections through the chip for access to both sides.

“By using that bottom surface, which adds interconnect space instead of eliminating it, we’re able to get higher interconnect densities,” thereby allowing the number of electrodes on the array to be increased without making the device bigger, says Murat Okandan, a microsystems engineer on the Sandia team.

Figure 3. High-density hermetic electronics packaging with a dual-sided electronic circuit. Click on image to enlarge.

Additionally, Sandia researchers are developing state-of-the-art packaging technologies to assemble and integrate the microelectronic components with the thin-film electrode array. Biocompatibility issues are driving much of this effort, requiring the high-density interconnects to be insulated with a nonconductive film to prevent moisture and ionic and biological contamination from causing device failure (see figure 3 at right).

Dual-Use Technology
Sandia has a long history of pioneering microelectronics research, which feeds into several defense-related systems, including sensor technologies and satellite applications. Spinoffs of the Artificial Retina Project—such as the silicon interconnect and higher-density packaging of components—are being evaluated for potential applications in some of these ongoing projects.

“The kind of exposure seen in the eye is not unlike the harsh, corrosive environments in which many defense-related components are required to survive for many years,” Wessendorf says. Moreover, “We’re always looking at miniaturizing and increasing function, and these efforts will help in those directions.”

Sandia National Laboratories is operated by Sandia Corporation, a Lockheed Martin company, for the U.S. Department of Energy’s National Nuclear Security Administration.

A novel software system not only processes incoming images in real time but also enhances what retinal implant recipients perceive

Typical palette of Artificial Retinal Implant Vision Simulator (ARVIS) image-processing modules that are applied in real time to the video camera stream driving the artificial retina. [Credit: California Institute of Technology]. Click on image to enlarge.

The human retina is not just a detector of light that sends optical information to the brain. It also performs complex image processing to provide the brain with optimized visual information. Replacing diseased photoreceptors with the electrodes of an artificial retina thus not only reduces the number of pixels, it also disrupts this necessary image processing.

To restore that lost function, researchers at the California Institute of Technology’s Visual and Autonomous Exploration Systems Research Laboratory under the direction of Wolfgang Fink are developing software to pre-process the information from implant patients’ miniature cameras before it is fed to their retinal prostheses. Dubbed the Artificial Retinal Implant Vision Simulator (ARIVS), this software system provides real-time image processing and enhancement to improve the limited vision afforded by the camera-driven device. The preservation and enhancement of contrast differences and transitions, such as edges, are especially important compared to picture details like object texture.

Since predicting exactly what blind subjects may be able to perceive is difficult, ARIVS offers a wide variety of image processing filters. They include contrast and brightness enhancement, grayscale equalization for luminance control under severe lighting conditions, user-defined grayscale levels for reducing the data volume transmitted to the visual prosthesis, blur algorithms, and edge detection (see graphic at right). These filters are not unlike what a person experiences in a regular eye exam during which a battery of tests is performed to determine the proper eyeglass prescription. In this case, retinal implant recipients can choose among these different filters to further fine tune, optimize, and customize their individual visual perception by actively manipulating parameters of individual image-processing filters or altering the sequence of these filters.

An incomparably greater challenge exists in predicting how to electrically stimulate the retina of 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. This requires the efficient translation of the camera stream, pre-processed by ARIVS, into patterns of electrical stimulation of retinal tissue by the implanted electrode array. The Caltech researchers on the U.S. Department of Energy’s team are addressing this challenge by developing and testing multivariate optimization algorithms based on evolutionary principles. These algorithms are used to modify the electrical stimulation patterns administered by the electrode array to optimize visual perception. Operational tests with Argus™ I users currently are under way.

Designing Biocompatible Microelectronics

The artificial retina team at Lawrence Livermore National Laboratory includes: Front row (left) Julie Hamilton and (right) Terri Delima. Back row, from left to right: Phillipe Tabada, Satinderpall Pannu, and William Benett.

Pioneering work with polymer-based microfabrication methods at Lawrence Livermore National Laboratory (LLNL) is feeding into the primary component of the Artificial Retina Project—namely, development of a flexible, biocompatible microelectrode array.

A key LLNL technique for making thin metal lines “allows us to pack many more electrodes into a much smaller device than previous models,” says Satinderpall Pannu, who is leading the LLNL effort. This technique, coupled with integrated-circuit and wireless technologies, drives the Department of Energy’s advanced retina prosthesis. The current goal is to develop an array with hundreds of electrodes.

Micrometer Sizing
As part of LLNL’s Center for Micro- and Nano-Technology, Pannu and his team are applying their expertise to microelectromechanical systems (called MEMS) that integrate micrometer-sized mechanical elements, sensors, actuators, and electronics through microfabrication technology.

The metal traces forming the electrodes and electronics in the array are less than a micrometer thick, less than 1% the thickness of a human hair. Embedded in such soft, moldable substrates as silicone, the array conforms easily to the curved shape of the retina.

A closeup view of the neural microelectrodes that make up the artificial retina array.

Pannu’s group also is developing methods for integrating complementary metal oxide silicon (called CMOS) electronics into the retinal prosthesis to reduce its overall size and complexity.

These electronics send electrical signals to microelectrodes to stimulate the retina, a function normally generated by the eye’s photoreceptor cells. In blind people suffering from retinitis pigmentosa and age-related macular degeneration, however, this process has broken down. The microelectrode array mimics the function of the photoreceptor cells by electrically stimulating the remaining healthy bipolar and ganglion cell layers.

Additionally, LLNL’s expertise is being tapped to develop advanced ocular surgical tools that will allow surgeons to place the microelectrode array precisely on the retina with minimal tissue damage.

Dual-Use Technology
Many of the technological advances forming the basis of this research stem from LLNL’s role as a national security laboratory. “This project is a great example of LLNL’s multidisciplinary approach to science,” says Cherry Murray, LLNL’s deputy director of Science and Technology.

Previously, LLNL researchers used silicone as a substrate for microfluidic devices such as biosensors to detect and identify chemical and biological pathogens in waterways. Since silicone is a biocompatible material, more recent work has focused on developing processes for embedding metal microelectrodes and electronics within silicone for use in biomedical devices.

Advanced ocular surgical tools developed at LLNL are used to tack the thin-film electrode array into the retinal tissue.

“We’re leveraging a lot of the technologies we’ve developed for biodetection systems onto the retinal prosthesis, and vice versa,” Pannu explains.

Future applications for the flexible electrode array go beyond the artificial retina. LLNL researchers are working to integrate this technology into next-generation devices such as the cochlear implant for hearing. The array also might be used one day to stimulate the deep brain for treating such diseases as Parkinson’s and chronic depression, and the spinal cord to relieve chronic pain.

“Our hope is that this technology will evolve into a general-purpose neural electrode array,” Pannu says, “helping to restore eyesight in blind people and revolutionizing treatment for all kinds of neurologically based diseases.”

LLNL is managed by the University of California for the U.S. Department of Energy’s National Nuclear Security Administration.

PET Scans Show Brain Responses to Light, Electrical Stimulation

A study measuring metabolic changes in the brains of sighted people is showing 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 that the visual cortex in patients with 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 processing part of the brain following different stimuli. Eight healthy volunteers with normal vision participated in the study. Each underwent three PET scans on three different days to represent baseline conditions, responses to light stimulation, and responses to electrical stimulation.

Pet scans showing brain activity in response to light (upper) stimulation and electrical (lower) stimulation. Click on image to enlarge.

Prior to each scan, the volunteers sat quietly in a darkened room for 30 minutes to dark adapt before receiving the FDG injection. For the baseline scan, both eyes were blindfolded. During the light stimulation scan, the person’s right eye was exposed to light flashes from a computer monitor. For the electrical stimulation experiment, a fiber electrode was placed on the right eye and a stream of electrical pulses with the same duty cycle was delivered. The results show similar activation and inactivation patterns between the light and electrical stimulations.

Extending the study to RP patients implanted with retinal prostheses, the researchers will analyze what happens to the visual part of the brain over time as the device is used more by patients. Ultimately, the researchers hope to use the results to examine the effect of cortical reorganization
in retinal degenerative diseases.

The original work was funded by the U.S. Department of Energy, and the RP patient work is being funded by the National Science Foundation (NSF grant number: 0917458).

Researchers John Carlisle (left) and Orlando Auciello (right) are developing an ultrathin biocompatible coating for the device.

Creating Diamond Coatings for the Retinal Implant

Argonne National Laboratory (ANL) plays a critical role in the success of the electrode implants used in the Artificial Retina Project. That’s where researchers Orlando Auciello and colleague John Carlisle are using their patented ultrananocrystalline diamond (UNCD) technology to apply a revolutionary new coating to the retinal prosthetic device. The new packaging promises to provide a very thin, ultrasmooth film that will be far more compact and biocompatible than the bulky materials used to encase the earlier prototypes (models 1 and 2).

“It’s like wearing a skin instead of a space suit,” says Mark Humayun (Doheny Eye Institute at the University of Southern California), leader of the Artificial Retina Project.

An Ultrathin Diamond Coating

UNCD is a form of carbon that captures many of the properties of diamond and can be deposited on a wide variety of surfaces in thin layers. The diamond grains used in the coating are only 2 to 5 nanometers in size (a nanometer is about 10,000 times narrower than a human hair). These films are as hard as single-crystal diamond, the hardest known material on earth. Unlike natural diamond, however, its properties can be adjusted and optimized for a given application.

Considered to be a platform technology, UNCD has numerous potential beneficial applications in such areas as medicine, transportation, and industrial production. It is chemically inert (nonreactive) and compatible with biological tissues, traits that make it useful in retinal prosthetic implants as well as other biodevices such as an artificial pancreas. Additionally, the material is a superb electrical insulator but also can be made to be highly conductive, and this conductivity can be tuned. This work has led to the use of UNCD for biosensors that use electrochemical reactions to detect biomolecules.

Parts of the UNCD technology received a 2003 R&D 100 award, an honor given to the most innovative developments that occur in a particular year. The technology has been licensed to Advanced Diamond Technologies (Champaign, Il.), a company founded by Carlisle and Auciello.

From the National Labs to the Public

A goal of the national laboratories is to provide benefits to industry and the public by moving discoveries into everyday use, a process called technology transfer. This practice leads to benefits for everyone and demonstrates the value of using tax dollars to support early-stage scientific research. In recognition of their efforts toward that end, Carlisle and Auciello received the 2006 Award for Excellence in Technology Transfer from the Federal Laboratory Consortium.

The nation’s first national laboratory, ANL conducts basic and applied scientific research across a wide spectrum of disciplines, ranging from high-energy physics to climatology and biotechnology. Since 1990, Argonne has worked with more than 600 companies and numerous federal agencies and other organizations to help advance America’s scientific leadership and prepare the nation for the future.

Argonne is managed by the University of Chicago for the U.S. Department of Energy’s Office of Science.