**2. Outer retinal disease**

Blindness due to such outer retinal diseases as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) affect hundreds of thousands of people worldwide. In fact, it has been estimated by The Eye Diseases Prevalence Research Group and the National Eye Institute that AMD alone will affect three million people in the United States by the year 2020 [1]. In addition, the prevalence of RP has been estimated to be approximately 1 in 4000 [2]. Although the pathogeneses of these retinal photoreceptor diseases are, to date, not entirely understood, it is known that they are largely restricted to the outer retina, and that downstream circuitry, although it undergoes significant remodeling, is relatively spared [3-5]. There exist several possible approaches to thwarting the devastating effects of these diseases. Of these, the surgical, pharmacological, stem cell, and dietary approaches are promising. Laser ablation of leaky blood vessels and diets rich in antioxidants, for example, have been shown to slow the progress of AMD, but not to have any effect on its incidence. Effective pharmacologic agents, likewise, have long been elusive. Recent evidence has shown that stem cell therapy could also be a possibility for the treatment of such diseases, by possibly replacing the lost photoreceptors with stem cells capable of maturing into photoreceptors that then make connections with the rest of the retina [6]. However, such treatments, in reality, are still very far away from being used in clinical practice, and have a number of ethical and political barriers to their implementation.

In need of another possible treatment for these profound retinal diseases, in 1994 Humayun *et al.* reported the results of a pioneering study to electrically stimulate vertebrate retinas [7], a bioengineering approach that would possibly bypass the diseased photoreceptors in the visual pathway. In this study, bullfrog eyecups, as well as rabbit eyes (the rabbits were injected intravenously with sodium iodate, a chemical toxic to the retinal pigment epithelium and with other effects on photoreceptors), were stimulated with platinum electrodes. In their report, the following conclusion was made: "Surface electrical stimulation of the inner retina in normal eyes and in eyes with outer retinal degeneration can elicit a localized retinal response." This has since had a profound impact on the field of ophthalmology, by dramatically throwing an engineering solution into the mix of possible treatments for patients with devastating blindness due to outer retinal disease.

As a follow-up to this study, it was shown in 1996 by Humayun *et al.* that this seemingly simple approach of passing a carefully controlled electrical current through an electrode placed directly on the retinal surface to activate the still functional electrically excitable cells of the retina can also elicit visual percepts in humans with otherwise bare or no light-perception vision [8]. Perhaps even more important than the perception itself was the nature of the perception. Subjects did not report seeing streaks or multiple percepts of light simultaneously when stimulating from one electrode, as might be expected if the axons of the ganglion cells, as they made their way to the optic nerve in the nerve fiber layer, were being stimulated. Instead, they reported seeing discrete, highly localized percepts that seemed to correlate very well with the location of stimulation. This suggested that it was not the axons that were the most electrically excitable, but instead the cell bodies of the several retinal ganglion cells (RGCs) or the bipolar, or even possibly amacrine or horizontal cells underlying the electrode. Indeed, it has since been conjectured that it could even be the characteristic right-angle bend in the axon of the RGCs that has maximal electrical excitability [9]. No matter the case, this was the confirmation of the feasibility of an engineering approach to treat human blindness with a "retinal prosthesis."

prosthetics aimed to provide eyesight to the blind and limb movement to para- and quadri‐ plegic patients through spinal cord stimulation. These technologies can also enable integration of solid state devices with novel bioMEMS sensors in such a manner that devices previously

Blindness due to such outer retinal diseases as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) affect hundreds of thousands of people worldwide. In fact, it has been estimated by The Eye Diseases Prevalence Research Group and the National Eye Institute that AMD alone will affect three million people in the United States by the year 2020 [1]. In addition, the prevalence of RP has been estimated to be approximately 1 in 4000 [2]. Although the pathogeneses of these retinal photoreceptor diseases are, to date, not entirely understood, it is known that they are largely restricted to the outer retina, and that downstream circuitry, although it undergoes significant remodeling, is relatively spared [3-5]. There exist several possible approaches to thwarting the devastating effects of these diseases. Of these, the surgical, pharmacological, stem cell, and dietary approaches are promising. Laser ablation of leaky blood vessels and diets rich in antioxidants, for example, have been shown to slow the progress of AMD, but not to have any effect on its incidence. Effective pharmacologic agents, likewise, have long been elusive. Recent evidence has shown that stem cell therapy could also be a possibility for the treatment of such diseases, by possibly replacing the lost photoreceptors with stem cells capable of maturing into photoreceptors that then make connections with the rest of the retina [6]. However, such treatments, in reality, are still very far away from being used in clinical practice, and have a number of ethical and political barriers

In need of another possible treatment for these profound retinal diseases, in 1994 Humayun *et al.* reported the results of a pioneering study to electrically stimulate vertebrate retinas [7], a bioengineering approach that would possibly bypass the diseased photoreceptors in the visual pathway. In this study, bullfrog eyecups, as well as rabbit eyes (the rabbits were injected intravenously with sodium iodate, a chemical toxic to the retinal pigment epithelium and with other effects on photoreceptors), were stimulated with platinum electrodes. In their report, the following conclusion was made: "Surface electrical stimulation of the inner retina in normal eyes and in eyes with outer retinal degeneration can elicit a localized retinal response." This has since had a profound impact on the field of ophthalmology, by dramatically throwing an engineering solution into the mix of possible treatments for patients with devastating blindness

As a follow-up to this study, it was shown in 1996 by Humayun *et al.* that this seemingly simple approach of passing a carefully controlled electrical current through an electrode placed directly on the retinal surface to activate the still functional electrically excitable cells of the retina can also elicit visual percepts in humans with otherwise bare or no light-perception vision [8]. Perhaps even more important than the perception itself was the nature of the

only conceived of are now possible.

2 Advances in Micro/Nano Electromechanical Systems and Fabrication Technologies

**2. Outer retinal disease**

to their implementation.

due to outer retinal disease.

There are now a large variety of approaches to artificial vision, each with their own advantages and disadvantages. There is this epiretinal approach (Figure 1), in which an electrode array is placed directly on the retina from its anterior aspect. There is the subretinal approach, in which an electrode or photodiode array is placed within the layers of the retina [10], as is also shown in Figure 1 (this can be further subdivided to the *ab interno* and *ab externo* approaches, in which an incision is made within the retina or within the sclera, choriocapillaris, or RPE to insert the device, respectively). There is also the optic nerve approach, in which electrodes are placed around the optic nerve in an attempt to coarsely stimulate the afferent ganglion cell axons [11]. Finally, there are also the cortical approaches, whether they be to the visual cortex [12] or to the lateral geniculate nucleus (LGN) of the thalamus [13, 14], the first stop for information from the retina as it enters the cortex. A complete discussion of the advantages and disadvantages of each of the different approaches is beyond the scope of this text, but can be found in several good review articles on visual and retinal prostheses.

The harbinger of an epiretinal prosthesis was the successful demonstration of a prototype 16 electrode device, fabricated by Second Sight Medical Products, Inc. (Sylmar, CA, USA) in six patients [15]. While clearly not enabling such activities of daily living as newspaper reading and facial recognition, previously completely blind subjects can, for instance, differentiate between a plate, a cup, and a knife, in a high-contrast environment free from background distracters, an undeniably incredible feat of engineering and medicine. Furthermore, subjects have been shown to be able to discriminate direction of movement of parallel white bars on a black background, and can locate white squares within a quadrant of otherwise black space [16]. This implant demonstrated the technology as well as the remarkable ability for the human brain to compensate for low-resolution input. Although this had previously been demonstrat‐ ed by cochlear prostheses for patients with severe hearing impediments [17], it was unclear whether this plasticity would translate well to visual prostheses. In fact, patients have demonstrated their ability to discriminate large letters simply by *instinctively* scanning the camera mounted on their head back and forth over the image displayed in front of them, a sort of innate edge-detection mechanism, dramatically increasing the capability of the 16-electrode device on their retina. Few scientists disagree, however, that increasing the number of electrodes on the implanted array will dramatically add to the capabilities of the prosthesis as a whole in enabling the patient to better carry out activities of daily living. The prototype device is hand assembled, a fact that limits the resolution possibilities of the device. Indeed, were it still necessary to interconnect integrated circuits by hand, computers would be far less useful to us as they are today. The need exists, then, to bring microelectronics and microfabrication technology to bear on the problem of retinal prosthetic devices. The race is on to build highdensity multielectrode arrays in such a way and with such materials that the method is scalable to the needs of long term, high-density retinal stimulation. Recently, a sixty electrode version of the epiretinal prosthesis has been tested and has gained the CE Mark in Europe for sale for the treatment of retinitis pigmentosa. The FDA is now reviewing the results of these same studies for potential approval in the United States as a therapy for outer retinal blindness.

**Figure 1.** System overview and relative locations of epiretinal and subretinal implants [18].
