Nanobiomaterials for bionic eye

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Nanobiomaterials for bionic eye: vision of the future

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Maryam Ghaffari1, Sina Moztarzadeh1, Fuzhan Rahmanian1, Abolfazl Yazdanpanah1, Arash Ramedani2, David K. Mills3 and Masoud Mozafari4 1

Biomaterials Group, Amirkabir University of Technology, Tehran, Iran 2Institute for Nanoscience & Nanotechnology (INST), Sharif University of Technology, Tehran, Iran 3School of Biological Sciences and the Center for Biomedical Engineering and Rehabilitation Science (CBERS), Louisiana Tech University, Ruston, LA, USA 4Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), Tehran, Iran

8.1 INTRODUCTION The study of mechanical systems that function similar to biological systems or parts of biological systems is bionics. The main objective of bionic systems and cyborg organisms has improved by using novel smart materials and advanced fabrication techniques. Recently, microelectronics and semiconductor device fabrication technique progresses have played a major role in the improvement of implantable medical devices (Sebastian mannoor, 2014). Pacemakers and bionic ears were the first medical bionic devices. The purpose is the production of a neural prosthesis capable of operating an artificial organ, a bionic eye, as well as other devices for the improvement of body function. The main problem in these evolutions is connecting the device to cellular tissue. Nanotechnology is a key to the success of this (Wallace et al., 2009). Blindness affects more than 40 million people all over the world. Visual loss in age-related macular degeneration and retinitis pigmentosa (RP)-damaged cells results in loss of photoreceptors and retinal pigment epithelial cells (Anon, 2012). After years of research, visual prostheses are being approved for experimental clinical use. These medical devices are designed to provide artificial vision for the blind by stimulating localized neural populations in one of the retinotopically organized structures of the visual pathway—typically the retina or visual cortex. This chapter provides an introduction to the pathophysiology of blindness; a preface of existing visual implants, their advantages and disadvantages; the sensory effects induced by electrical stimulation; as well as the role played by flexibility and training in clinical results (Shepherd et al., 2015). The focus of this work is nanotechnology and nanomaterials which can be used for these applications. Engineering of Nanobiomaterials. DOI: http://dx.doi.org/10.1016/B978-0-323-41532-3.00008-7 © 2016 Elsevier Inc. All rights reserved.

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Nanostructures represent a significant and largely untapped resource for diagnosis and treatment of injuries and diseases related to neural tissues. From a cell biologist’s point of view the complex electrical properties and nanoscale structural features of neural tissue necessitate a neural interface with nanoscale components. Nanoengineered materials and devices have the potential to interact with biological systems on a molecular scale, offering unprecedented levels of control over physiological activity (Mozafari, 2014; Mozafari et al., 2010; Touri et al., 2013). The large class of currently available nanomaterials contains many families of nanostructures including nanoparticles (NPs), nanowires (NWs), multi and single-walled carbon nanotubes (CNTs), polymer coatings, silicon lithographic elements, and nanodevices (Sadik et al., 2009; Capek, 2009; Vidu et al., 2014; Peralta-Videa et al., 2011). All of these nanostructures have the potential to be juxtaposed with living cells, which may offer great opportunities for cellular interfacing. Recent applications of nanotechnology in other fields such as electronics, optics, and structural composites have provided a newfound wealth of information about the electrical, optical, and mechanical properties of nanomaterials. This rise in knowledge and expertise has already started contributing toward a natural transition of nanomaterial applications from electronics to neural interfacing (Rothschild, 2010; Pera´n et al., 2012; Navarro et al., 2005).

8.2 LEARNING FROM THE NATURE 8.2.1 FOVEAL REGION OF THE RETINA AND ITS IMPORTANCE IN ACUTE VISION The fovea is a minute area in the center of the retina; it is especially capable of acute and detailed vision. The central fovea, only 0.3 mm in diameter is composed almost entirely of cones; these cones have a special structure that aids the detection of detail in the visual image. That is, the foveal cones have especially long and slender bodies, in contrast to much fatter cones located more peripherally in the retina. Also, the blood vessels, ganglion cells, inner nuclear layer of cells, and plexiform layers are all displaced to one side in the foveal region rather than resting directly on top of the cones. This allows light to pass unimpeded to the cones.

8.2.2 SITE OF SIMULATION In the human visual pathway, there are at least four potential sites of neurostimulation: the retina, the optic nerve, the lateral geniculate nucleus (LGN), and the visual cortex. Noting the relative inaccessibility of the LGN, so far stimulation of the visual cortex has shown the most promise in terms of its ability to be chronically stimulated. It is the only practical option for patients without a viable visual pathway. However, it should be noted that this procedure has its own drawbacks.

8.3 Bionic Eye

8.3 BIONIC EYE Visual prostheses can be broadly categorized into groups based on their underlying technology or the anatomical location in which the electrode array is implanted. From a technological perspective there are two basic designs. (i) Optical sensors, such as an array of photodiodes, that are implanted close to the retina. The normal optical properties of the eye focus light onto the photodiodes which convert this energy into electrical pulses designed to depolarize proximal retinal ganglion cells (RGCs). (ii) A classic sensory prosthesis that includes an external video camera, vision processor, and power supply, a transcutaneous telemetry link, an implantable stimulator connected to a lead wire, and electrode array located at the level of the retina or central visual pathway.

8.3.1 HISTORY In 1755, Charles Leroy discharged the static electricity from a Leyden jar into a blind patient’s body using two wires, one tightened around the head above the eyes and the other around the leg. The patient, who had been blind for 3 months, caused by a high fever, had an experience described as like a flame passing downwards in front of his eyes. This was the first successful use of an electrical device with even a flicker of visual understanding (Shepherd et al., 2015). In 1929, Foerster discovered that by electrically stimulating the occipital pole, his subject would describe the sensation of a small spot of light (Lewis et al., 2015). The idea of an electronic prosthetic device can be given to Graham Tassicker, who in 1956 explained how a photosensitive selenium cell attached behind the retina of a blind patient resulted in phosphenes (Carlson et al., 2012). In the 1960s and 1970s, Brindley and Dobelle led the field of artificial vision by implanting electrodes into the visual cortex and proving that they were capable of inducing consistent phosphenes (Lewis et al., 2015). Uematsu et al. also studied the possibility of a visual prosthesis and managed to evoke phosphenes which blinked or fluttered (Uematsu et al., 1974). Further improvement in the field was limited until the 1990s when advances in biomaterials, microfabrication, electronics, and retinal surgery led to consecutive progresses in the field (Schmidt et al., 1996). The preclinical studies performed in this decade would lead to the large number of clinical experiments in the decade from 2000 to 2010. Currently, two retinal prosthetic devices are in clinical trials with demonstrated evidences of functional vision (Eckmiller, 1997). These are the most advanced prostheses up to now: epiretinal and subretinal (Ong and Lyndon, 2012).

8.3.2 RETINAL PROSTHESES (MICROELECTRODE ARRAYS) Therapeutic options in patients suffering from blindness depend on the type of disease and trauma along the visual pathway. From the posterior segment of the

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eye to the visual cortex, retina prostheses and among them multielectrode arrays (MEAs) will be the first approach that is discussed. Retina prosthesis can be either classified based on the type of stimulators or implantation space. The main concept of implanted MEAs is based on detection of and capturing the “lightbased” image from an external camera.

8.3.2.1 Epiretinal The epiretinal prosthesis consists of three major functional units: a retina encoder, a telemetry link for power and data, and an intraocular epiretinal MEA as a stimulator device. MEAs are attached to the inner retinal surface, which stimulates the axons of the retina ganglia cells. The electrode array is mechanically attached to the inner retinal surface using one or two retinal tacks. An epiretinal approach is designed to bypass the visual processing which is naturally done by the bipolar and amacrine cells (Weiland and Mark, 2008). The most clinically advanced epiretinal prosthesis at present is the Argus II implant (Figure 8.1), which was patented by Second Sight Medical Products Inc., California in 2007, and received FDA approval for commercialization in 2013. “Argus I” was the first-generation model of the device, consisting of an intraocular epiretinal MEA measuring 250 500 mm with 16 platinum microelectrodes. The extraocular components consist of an external spectacle-mounted camera, which was used to capture images which were translated into pixilated images by a visual processing unit. Clinical trials of the Argus I have shown it to provide improvement in patient visual perceptive tasks such as object detection, counting, and discrimination and direction of object movement (Humayun et al., 2009; Fernandes et al., 2012). The second-generation Argus II retinal prosthesis

FIGURE 8.1 The ARGUS II system. (a) Schematics of the ARGUS II system and the eye. (b) ARGUS II 60 electrode array placed in the surface of the retina with tack in place. Reprinted with permission from Elsevier (copyright (Humayun et al., 2013)).

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system uses an epiretinal implant for clinical study in humans. The Argus II microelectrode consists of 60 independently controllable electrodes. In the trial the system has been implanted in 30 patients at 11 centers worldwide. Subjects are reported to have demonstrated improved motion detection, mobility, and were also able to distinguish common household objects (Roessler et al., 2009). Multicenter long-term clinical trials have proven its effectiveness, for example, being able to recognize and discriminate objects, detect motion, and discriminate patterns to a fairly reasonable degree. Some patients are even able to use the devices to navigate independently (Humayun et al., 2003), read large print (Zrenner et al., 2010), and perform some activities of daily living, which is a sign of the usefulness of the technology (Humayun et al., 2012). Despite these successes, it shows a vision acuity of approximately 20/2000 (Ahuja et al., 2011). The Argus II device received commercial approval in Europe in March 2011 (Figure 8.2). The second epiretinal prosthesis is Bionic Vision Australia (BVA). This company is working on three bionic eye devices: an early prototype with 24 electrodes, a wide-view device with 98 electrodes, and a high-acuity device with 1024 electrodes. The bionic vision system consists of a camera attached to a pair of glasses, which transmits high-frequency radio signals to a microchip implanted

FIGURE 8.2 The Argus II system. (a) The external parts of the Argus II system including glasses and the video processing unit. (b) The internal parts of the system including the electrode array and electronics case. Copyright (Dorn, 2012).

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in the eye. They are currently testing the early prototype device with three people. These tests are helping researchers learn more about how the brain will interpret information from the bionic eye. Intelligent Medical Implants is a GmbH Germany medical technology company. They are currently developing an epiretinal Learning Retinal Implant. Its operation is based on the transformation of image signals from an extraocular camera which is situated on the frame of a pair of glasses (retina encoder) into sequences of current pulses applied by implanted microelectrodes, which is placed epiretinally in the area of the macula. Clinical trials in 20 subjects have demonstrated, in a limited number of patients, that it is possible to elicit visual perceptions by electrical stimulation of the retina using the epiretinal approach (Schanze et al., 2009).

8.3.2.2 Subretinal Subretinal electrode arrays are similar to epiretinal devices in that an image is captured by a camera and converted into an electric stimulation pattern to be imposed on the remaining functional neural retina but, in the subretinal approach, the device is placed in the space between the retina and the choroid. In this position, the electrode being in close proximity to the remaining bipolar and amacrine cells requires less energy to stimulate visual percepts, taking advantage of the retinal processing which occurs in these neuronal pathways. Theoretically, a subretinal prosthesis is supported by the natural adherence forces that exist between the retinal pigmented epithelium and the sensory retina so there is no need to mechanically fixate the implant in the eye wall (Shire et al., 2009). Boston Retinal Implant Project has developed a small, hermetic, wirelessly controlled retinal prosthesis for preclinical studies in Yucatan mini-pigs. The device was implanted on the outside of the eye in the orbit, their retinal prosthesis system includes an external computer-based controller with a user interface for selecting which electrodes to drive and with what level of current. Accelerated in vitro testing of the hermetically packaged implants has shown that their newgeneration device exceeds the 5 10-year survivability requirement proposed by the FDA (Rizzo et al., 2003, 2011).

8.3.2.3 Intrascleral and suprachorodial There are several surgical approaches in implanting a stimulating array under development. Placing the electrode arrays behind the posterior vascular blood supply of the eye (choroid) is a more surgically accessible and stable position. The choroid segment can be divided into the intrascleral (within the outer scleral wall of the eyeball) and suprachoroidal (the area between the choroid and the sclera). Intrascleral and suprachoroidal implants will require more electrical current for stimulation than those placed in the subretinal position, because the suprachoroidal electrodes will be further away from the target ganglion cells (Fujikado et al., 2011). A Japanese team have designed a transretinal stimulation system with electrodes implanted in the suprachoroidal space and attached to the sclera which is called the suprachoroidal-transretinal stimulation (STS) prosthesis. They have

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demonstrated that STS can stimulate retinal neurons and evoke electrical potentials from the visual cortex of rats and rabbits (Morimoto et al., 2011). Their group also studied the STS electrodes and an STS system device. Finally, they have developed an implantable STS device consisting of an electrode array, a return electrode, and an extraocular microstimulator that can be used for longterm implantation (Fujikado et al., 2011). BVA validated the safety and efficacy of suprachoroidal stimulation, which led to the commencement of a phase 1 clinical trial in three RP patients in 2012. They showed that through careful optimization of stimulus parameters, it was possible to obtain reliable thresholds and phosphene percepts in all three patients, thus proving that suprachoroidal stimulation can be effective (Shivdasani et al., 2014).

8.3.3 RETINAL PROSTHESES (OPTOELECTRONIC PROSTHESES) The second method seeking to replace the function of degenerated photoreceptors directly is optoelectronic prostheses. This system involves translating the light of the image falling into the retina point by point to small currents, typically by photodiode arrays which are activated by incoming light. Commonly, the optoelectronic approaches have concentrated on subretinal stimulation, where the implant is located between the retina—most likely the bipolar cell layer, and the retinal pigment epithelium. The advantage of this location is that existing neural processing functions in the inner nuclear layer (amacrine, bipolar, and horizontal cell nuclei) may still be utilized (unlike epiretinal approaches, which are more likely to stimulate the retinal ganglion and amacrine cells directly).

8.3.3.1 Artificial silicon retina The first clinical trial of a permanently implanted retinal prosthesis was initiated by Optobionics, Inc. (USA), in 2000. The photoelectric signals produced by the microphotodiodes were designed to alter the membrane potential of contacting retinal neurons similar to natural activation of these cells to form retinotopic visual images (Chow et al., 2004). Animal models implanted with Artificial silicon retina (ASR) devices responded to light stimuli with retinal electrical signals (ERGs) and sometimes brain-wave signals (VEPs). Findings in animal models indicated that visual stimulation had occurred. The FDA approved the conduct of clinical trials and it was implanted in six patients with RP (Figure 8.3) (Chow et al., 2010). The ASR was well tolerated by all six patients after 6 18 months of follow-up. All ASRs functioned electrically, and no patient showed signs of implant rejection, infection, inflammation, erosion, neovascularization, retinal detachment, or migration. Visual function improvements occurred in all patients and included unexpected vision improvements in retinal areas distant from the implant. Phase II clinical trials in 2007 showed that natural incident light did not provide enough stimulation to activate the remaining retinal cells; thus, they failed to produce patterned stimulation and elicit phosphenes (Chader et al., 2009).

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FIGURE 8.3 Artificial silicon retina. The model used here is 2 mm in diameter and 25 µm thick and contains approximately 5000 negative intrinsic layer-positive microphotodiode pixels electrically isolated from each other and separated by 5 µm. Each pixel is 20 3 20 µm square and is fabricated with a 9 3 9-µm iridium oxide electrode deposited and electrically bonded to each pixel. The pixel current was 8 12 nA with approximately 800 foot-candles of illumination. The ASR microchip was placed within a fabricated Teflon sleeve and secured intraoperatively to a saline-filled syringe injector; it was then deposited within the retina by fluid flow. (a) The ASR’s size relative to a penny. (b) The ASR microchip (original magnification 3 36). (c) The ASR pixels (original magnification 3 1400). (d) Subretinal location of the implanted ASR microchip. Copyright (Chow et al., 2004).

8.3.3.2 Microphotodiode arrays Retina Implant AG is a medical technology start-up company founded in 2003 and affiliated with the University of Tubingen. Retina Implant AG initially developed a silicon chip with an embedded microphotodiode array (MPDA) using complementary metal-oxide semiconductor process technology (Schubert et al., 1997). The implant was used in animal models but they discovered that the energy generated from the MPDA was insufficient and requires an extraocular power supply to amplify the signals of the photosensitive pixels, which makes the

8.3 Bionic Eye

implantation procedure quite complex (Zrenner et al., 2011). Currently, they have been using a technologically improved implant, the Alpha IMS, that has been run since May 2010 in a multicenter clinical trial with blind RP patients in a number of locations. Alpha IMS is a microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiodeamplifier-electrode elements on a 9-mm2 chip was subretinally implanted in blind patients. It is the highest pixel density currently available in such a device. This prosthesis was investigated in two different studies, one of them including nine patients and the other 20 patients, that completes the monocentric part of a multicenter trial (Stingl et al., 2013a,b). They achieved the most hopeful results with the best visual acuity of 20/550 in patients. Professor Zrenner, in the conference that took place in September 2014, at the ICC, ExCel London, highlighted several key findings from these studies including: 86% of patients perceived light postimplantation; 59% of patients detected the source of the light; and nearly half of patients reported useful visual experiences including recognition of shapes or details in daily life. Alpha-IMS manufactured by Retina Implant AG recently gaining European regulatory approval for the treatment of late-stage RP.

8.3.3.3 Photovoltaic implants Palanker’s group at Stanford University (Palo Alto, CA, USA) is investigating the design of a two-dimensional silicon photodiode to provide: (i) proximity of electrodes to the target cells; (ii) delivery of information associated with natural eye movements; and (iii) location-dependent image processing (Palanker et al., 2005). In this way they are working on a photodiode array capable of photovoltaic conversion of pulsed near-IR illumination projected from video goggles into biphasic electrical current in each pixel, and successfully stimulated the retina. This approach helps to avoid complex wired power connections, greatly simplifies the surgical procedure, and reduces the chances of infections associated with transscleral cables used in powered implants. Each pixel has a local return electrode, which reduces the spatial spread of the electrical stimulation, therefore reducing cross-talk between pixels, achieving uniformity in stimulation thresholds, avoiding erosion of the electrodes and overheating of tissue, besides improving the spatial resolution of the implant. Each pixel contains three series-connected, trench-isolated photodiodes to increase charge injection levels (Wang et al., 2012; Mathieson et al., 2012). Palanker’s group has developed designs of protruding electrodes on the subretinal array penetrating deep into the retina after migration of the retinal cells into the empty spaces between the pillars so providing close proximity between the neural cells inside the retina and the stimulating sites of the implant. They showed that high enough resolution for useful vision cannot be achieved unless very close proximity (on the order of cellular size) between the electrodes and target cells is established along the whole interface of the implant with the retina. In the process to develop wireless photovoltaic retinal prosthesis Mandel et al. (2013) produce arrays of 0.8 3 1.2 mm in size, containing 13, 45, and 186 pixels of 280, 140, and 70 µm in width, respectively. The pixel density

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with 70 µm pixels is 209 pixels per mm2, corresponding to more than 4800 pixels over an area similar to the Argus II implant of Second Sight Inc. (5 3 5 mm). The implants were well tolerated in the subretinal space in rats, and stable over the 6 months’ follow-up with normal and degenerate retina eliciting robust cortical responses upon stimulation with pulsed near-IR light.

8.3.4 OPTIC NERVE PROSTHESES Electrical stimulation of the optic nerve as a potential site for the implementation of a visual prosthesis capable of eliciting visual percepts in an individual has been attempted. Some independent groups related variable degrees of success in promoting visual sensations through electrical stimulation of the optic nerve (Fang et al., 2006; Shandurina et al., 1996; Shandurina, 1995). In camper with retinal prosthesis the processing power of the bipolar, horizontal, and amacrine cells is lost and, therefore, much more image processing must be achieved by the optic nerve implant. Veraart’s group from the Universite´ Catholique de Louvain (Brussels, Belgium) was one of the groups attempting this method, employing the concept of a spiral nerve cuff electrode that wrapped around the nerve (Veraart et al., 1998). In 2009, two volunteers blind from RP were implanted with a spiral cuff electrode developed by Veraart and colleagues to examine the visual-evoked potentials (VEP) and electroretinograms (ERG) generated during electrical stimulation of the human optic nerve. The results showed a unique inner retinal potential generated by retrograde stimulation of the eye from the optic nerve (Brele´n et al., 2010). Thus far, they showed optic nerve prostheses were able to localize and identify basic objects (Duret et al., 2006), visual rehabilitation (Veraart et al., 2004), and had basic pattern recognition ability (Veraart et al., 2003). An alternative to the cuff electrode was proposed by the C-Sight team (Chinese Project for Sight). It was a MEA with specific configurations that inserted into the optic nerve as a neural interface to couple the encoded electrical stimuli into the axons of the ganglion cells for vision recovery (Ren et al., 2007). The feasibility of this visual prosthesis has been validated using some animal experiments but it has had less functional vision success (Sun et al., 2013; Cai et al., 2009; Li et al., 2009; Lu et al., 2013).

8.3.5 LATERAL GENICULATE NUCLEUS PROSTHESES LGN is one of the visual prostheses targeting proximal stages of the visual pathway that is positioned between the optic nerve and visual cortex. Although, LGN is the principal structure that sends visual information to the visual cortex, with input from 90% of the RGCs, relatively little is known about its stimulation due to the difficulty of surgical access to it. Pezaris et al. tried to show the feasibility of artificially creating visual percepts through electrical stimulation in the LGN (Pezaris and Eskandar, 2009; Pezaris and Reid, 2007; Vurro et al., 2014). There has been little recent research into these devices (Choi et al., 2014).

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8.3.6 CORTICAL PROSTHESES Early work on a visual prosthesis first started with the idea of developing a cortical prosthesis in 1929 (Foerster, 1929). Cortical prostheses may be a treatment option for people who have damage to their optic nerves or eyes resulting from trauma or disease. The visual cortex has a large surface area that is readily accessible by electrodes. The seminal experiments systematically stimulated the surface of the visual cortex in human subjects, and produced phosphine lights (Pollen, 1975; Brindley, 1972; Brindley and Lewin, 1968). The Intracortical Visual Prosthesis (ICVP) is an alternative way to directly stimulate the visual cortex (Schmidt et al., 1996). The Illinois’ ICVP Project has been developing its own version of an ICVP over the past two decades and undergone implantation in human subjects. Human implantation is composed of 60 stimulator modules each with 16 microelectrodes, which are activated wirelessly by signals from a video camera/computer system (Lane et al., 2011). The Utah Electrode Array is consist of 100 small-diameter silicon microneedles array which was developed by Utah researchers (Jones et al., 1992). The UEA has been used for over a decade in cat visual cortex (Warren et al., 2001), monkey motor cortex (Kelly et al., 2007), and in the temporal lobes of human subjects to record neural responses from single units and in research with epilepsy patients. The only intracortical microelectrode array that has been FDA-approved for long-term human studies is the UEA (Nordhausen et al., 1996). Normann et al. worked on the visual neuroprosthesis designed to interface with the occipital cortex (Normann et al., 1999; Normann et al., 2009). The Monash Vision Group (MVG) is the third group which has worked on cortical prostheses. They are a consortium which includes Monash University and Alfred Hospital in Melbourne. MVG designed a cortical implant with up to 11 tiles. Each tile is a miniaturized electronic system that converts radio waves into discrete stimulation pulses on 43 electrodes which would directly stimulate the V1 visual cortex. This project commenced in 2010 and is currently in the product development phase. MVG in their annual report in 2013 claimed that they would be able to deliver a first human implant in 2015.

8.3.7 POST-ELECTRODE PROSTHESES “Post-electrode” is a term used by Greenbaum to describe a new generation of visual prosthesis which is a more biologically compatible method for neuron stimulation (Greenbaum and Evans, 2011). The principle underlying this approach is using light to activate neurons that cause depolarization of the neural membrane, leading to generation of an action potential, which then propagates along the axon of the neuron to the brain. This new generation of visual prostheses provides a unique opportunity to develop a noninvasive device with better spatial resolution and specific cellular targeting. Here, we briefly introduce two main techniques in post-electrode prostheses.

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8.3.7.1 Neurotransmitter stimulation Neurotransmitter application is a possible alternative method to provide visual perception in comparison with other methods based on electrical stimulation as mentioned earlier. Since neurotransmitters normally shape visual responses, visual prostheses based upon the spatially and temporally controlled delivery of neurotransmitters to the retina seem more effective and natural. Raymond Iezzi, Assistant Professor of Ophthalmology at Kresge Eye Institute, Wayne State University, Detroit, for the first time proposed a neurotransmitter-based retinal prosthesis which can modulate RGC responses (Iezzi and Finlayson, 2011; Iezzi et al., 2003). The concept involves an epiretinal visual prosthetic implant that will mimic normal chemical signaling between neurons in the retina so improving the resolution and variety of visual percepts. Iezzi’s group is developing its “uncage and release device” employing microfluidic channels (Finlayson and Iezzi, 2010; Raza et al., 2003).

8.3.7.2 Optogenetic techniques The new generation of visual prostheses are a design based on the expression of a light-sensitive ion channel or protein in retinal ganglion or bipolar cells to return functional vision. Since the discovery of Channelrhodopsin-2 (ChR2) as a lightactivated ion channel by Negal et al. in 2002, there has been an explosion toward using this ion channel in neural circuits (Nagel et al., 2003). This ion channel is a nonselective ion channel that transports sodium and potassium across the cell membrane. By engineering this ion channel interfaces it is possible to stimulating neurons that can be gated directly by light. For the first time, Boyden et al. in 2005 used the protein ChR2 to create light-sensitive action potentials (Boyden et al., 2005) and as the process was renamed optogenetics(Deisseroth et al., 2006). Anding et al. showed that ChR2 satisfies several major criteria for its use as a light sensor in retinal neurons. They demonstrated that expression of ChR2 in surviving inner-retinal neurons of a mouse with photoreceptor degeneration can restore the ability of the retina to encode light signals and transmit the light signals to the visual cortex (Bi et al., 2006). In similar research, Degenaar et al. (2009) subcloned the fusion protein ChR2-YFP into a plasmid and transferred it to rat hippocampal neurons as a model for RGCs. Neuron clusters expressing ChR2 protein were grown on glass dishes and electrophysiological responses were investigated. Recently, Reutsky-Gefen et al. have proved that a reliable holographic excitation pattern causes effective excitation of ChR2-expressing RGCs (optogenetic stimulation) with millisecond temporal precision and singlecell resolution. A holographic feature combined with an optogenetic approach might become a promising way to have a high-acuity vision restoration device (Reutsky-Gefen et al., 2013). Over recent years, optogenetic techniques in visual prostheses have become to a steadily expanding research field (Mace´ et al., 2014; Polosukhina et al., 2015; Doroudchi et al., 2011).

8.4 Challenges in the Design and Fabrication of a Bionic Eye

8.4 CHALLENGES IN THE DESIGN AND FABRICATION OF A BIONIC EYE Despite great successes in the design of a bionic eye, remaining serious challenges are a reminder that they can be classified into: those resulting from inherent characteristics of the microelectrode and those due to the cell electrode interface. In the main, dealing with the above concerns must be done according to following criteria. (i) Cytotoxicity and biocompatibility of materials that are implanted in the targeted tissue. In fact, long-term biocompatibility must be a concern to avoid additional surgery (Majji et al., 1999). (ii) For decreasing inflammatory and foreign body responses the additional miniaturization of the traditional stimulation electrodes is crucial, however the field of vision is related to the dimension of stimulation electrodes. (iii) Mechanical mismatch at the device cell interface is one of the key factors causing chronic inflammation. (iv) Delivering visual information in real time (Fornos et al., 2008). (v) Biostability which means a stable physiologic interface at the device and a neuron without degradation over the long term period (Polikov et al., 2005). (vi) Flexibility in the artificial retina device to conform to the shape of the retina for reducing eye damage during normal eye motion. (vii) Targeting individual neurons. (viii) On one hand, a large number of electrodes propose higher resolution in visual perception but due to limited size of the device the electrodes must be smaller, on the other hand, miniaturization of electrodes increases impedance at the electrode cell interface. Higher impedance means higher voltage (more than stimulation threshold) to stimulate the neurons, which increases energy consumption and causes heat damage to the surrounding tissue. Furthermore, lower impedance is crucial to maintain signal quality and effective charge displacement for stimulation (McConnell et al., 2009). (ix) Electrode’s higher charge injection limit. A hgher charge injecting limit means higher current can be applied on the stimulation electrodes safely without driving irreversible chemical reactions (Merrill et al., 2005). (x) Capacitive charge stimulation. During charge injection between electrode and extracellular fluid (electrolyte) the reaction can be Faradaic or capacitive. In a Faradaic reaction, electrons transfer across the electrode electrolyte interface and induce irreversible reduction oxidation reactions, such as metal corrosion, water hydrolysis, or release of toxic chemical reaction products that can damage both the electrode and the tissue. In a capacitive reaction, redistribution of charged species in the electrolyte cause charging and discharging of the electrode double layer (ionic current) and there is no electron transfer across the electrode tissue interface. In this way no electrochemical reaction take places in the electrode tissue interface. (xi) Minimizing the space between artificial stimulation and target neurons which facilitates smooth exchange of information between them (Cogan, 2008). (xii) Resistance of material to sterilization procedures. Several studies have been directed to explore strategies to overcome the above issues to achieve useful vision. Nanobiomaterial and nanostructure have spectacular roles in these researches.

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8.5 NANOBIOMATERIAL POINT OF VIEW Nanoscale materials show unique mechanical, electrical, and optical properties in comparison with other microscopic or macroscopic structures (Mozafari and Moztarzadeh, 2010; Mozafari et al., 2010). These distinctive properties, beside nanoscale dimension, can provide the opportunity in the fields of biomaterial science and bioengineering to mimic the biological situation in a more sophisticated way (Ramedani et al., 2014; Yazdanpanah et al., 2012). Widespread clinical application of nanobiomaterials in neural prostheses demonstrated well cell prosthesis interactions, structural integrity, long-term biostability, biocompatibility, and ability to be multifunctional (Heim et al., 2012; De Vittorio et al., 2014). Furthermore; one key point to minimize initial injury and control the inflammatory response is to reduce the prosthesis dimensions, which can be achieved with nanoscale materials (Mozafari et al., 2013; Thelin et al., 2011). In the case of passive ocular implants like contact lenses, intraocular lenses, and vitreous substitutes, many studies have been achieving excellent results (for a recent review see Balaji (2011)). In this chapter we focus on visual prostheses which can be described as active ocular implants. We have already mentioned several times that the fundamental aim of visual perception is based on stimulation of neurons in the visual pathway, which can be electrical, chemical, or through light. As a result, modifying these stimulations to analogous stimulations at the molecular level will mimic the biological seeing pathway. Thus, in the case of applied neuroscience such as visual prostheses, the subject of this chapter, there is new hope to reach nanoscale resolution with the aid of nanobiomaterials and nanotechnology. Various applicable approaches, such as nanoporous, NP, nanoflake, NW, and nanocrystalline, have already been introduced in the field of visual prostheses which will be discussed here.

8.5.1 NANOPOROUS, NANOFLAKES, AND NANOPARTICLES The nature of the interface between electrode and neural tissue determines the ability of the electrode to provide the appropriate and functional communication with the neural tissue. Gold, platinum, iridium oxide, titanium dioxide, and titanium nitride are commonly used for neural electrodes. Although; they are inert under biological environment they need extra surface modification to increase the surface area for reducing the interfacial impedance in micrometer-sized electrodes. In addition, the charge injection limit of this kind of metal and metal compound electrodes is lower than the charge density required to stimulate the neurons (Mozafari et al., 2011; Mozafari, 2014). Nanoporous electrodes were proposed as a candidate to address the deficiency of conventional electrodes in neuroprosthetic application. Attard (1997) proposed an electrochemical reaction to create a well-defined long-ranged mesoporous Pt film. The increased specific surface area caused lower impedance. Design of the 3D-nanoporous Pt films on a

8.5 Nanobiomaterial Point of View

MEA by Park et al. showed in vitro lower interfacial impedance and high charge injection capability for neural stimulation. In addition, the nanoporous structure has stable mechanical properties for long implantation (Park et al., 2010). Also, gold nanostructure electrodes show enhanced electrical performance for neural signaling besides long-term biostability (Kim et al., 2008). Kim et al. (2010) modified microelectrodes to create flake nanostructure on the gold electrode surface. This geometrical change increased the effective surface area of the electrode, as a result reducing electrode electrolyte interface impedance and subsequently enhancing signal-to-noise ratio. Stimulation of hippocampal neurons of rats demonstrated that nanoflake electrode structures can evoke neurons with a lower stimulation voltage level. Ha¨mmerle et al. (2002) compared the biostability of two microphotodiodes in vitro and in vivo to replace degenerated photoreceptor cells in the retina. For long-term performance of chronic implants, biostability is an especially important factor. One of the semiconductor chips was designed with planar titanium/gold (Ti/Au) and the other with a nanoporous titanium/titaniumnitride (Ti/TiN) electrode. The Ti/TiN electrode showed superior charge transfer capacity and did not show any gross damage of the electrode during 16 months. Biological application of inorganic NPs is not limited to imaging, biosensing, drug delivery, killing tumors cells, and DNA analysis (Jafarkhani et al., 2012; Xu et al., 2006). The optoelectronic properties of semiconducting NPs allow them to perform the task photovoltaically in the biological environment. The semiconductor and metal NPs are optically excited and show a broad range of absorption and narrow excitation spectra. Voltage-gated ion channels in the cell membrane can be influenced by temporary dipole moment from optical excitation of NPs. This phenomenon can either initiate an actin potential or silence it (Malvindi et al., 2008). Winter et al. (2005) produced the CdS quantum dot films that optically excited and induced a sufficient-strength electric field to stimulate the ion channels of cortical cells. Despite the initial promising results, they cannot provide interface longevity and cell biocompatibility. In a similar study, light electroactive NP films were made from HgTe stabilized with thioglycolic acid. The photoelectric current generation in this kind of NP film is totally different from optogenetic approaches or a bulk semiconductor device. Their results demonstrated that the resistive coupling mechanism dominated at the electrode cell interface (Pappas et al., 2006). Like other studies, chronic biostability and maintained interface are still significant concerns.

8.5.2 NANOWIRES In neural stimulation application, NWs have emerged as one of the significantly improved electrical couplings between cells and electrodes for building a functional interface to neurons (Robinson et al., 2012). Thus, using NW microelectrode arrays in visual prostheses would enable precise control over the size and configuration of the stimulation because of providing high-aspect-ratio microelectrodes, high surface area, and similarity in size of NWs and natural nanostructures

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of biological tissue (Merritt and Justus, 2008). In addition, microelectrode array embedded in a tissue must be fluid-impermeable to avoid short-circuiting or corrosion in electronic prostheses. Whalen et al. which worked on Argus I and II, patented a NW microelectrode array in 2012 (Whalen et al., 2012). In the process of manufacturing NW microelectrodes, nanochanneled aluminum oxide substrates are first manufactured and at the last step of manufacturing the platinum is electrodeposited into nanochannels to form the NWs. Other biocompatible metals, metal alloys, or metal oxide compositions, like platinum oxide, iridium, iridium oxide, platinum iridium alloys, tantalum and tantalum oxide, carbon, rhodium, and ruthenium, can be substituted by platinum. Their design can effectively be fluidimpermeable. High visual acuity needs more electrodes and high-resolution microelectrode arrays have more complexity in wiring. Silicon nanowire fieldeffect transistor switches integrated with a microelectrode array can significantly reduce wiring problem (Lee et al., 2014). Khraiche et al. have developed ultrahigh-sensitivity photodetector technology with the aide of semiconductor vertical NWs for visual prosthesis (Khraiche et al., 2013). The semiconductor silicon NW array was manufactured from silicon epitaxial wafer (p 1 /p-/p 1) by nanoimprinting technique. In general, light with enough energy can generate an electron hole pair so the electrical conductivity of semiconductors is changed. In NWs, similar phenomena happen and the originally insulated NWs become electrically conductive, depending on the intensity of light. Their results showed that the semiconductor silicon NW array is capable of replacing retinal photoreceptors due to high sensitivity as a photo detector. It has near-single-photon sensitivity. In addition, the array can be modified by tailoring the size and spatial distribution of the NWs (Khraiche et al., 2011).

8.5.3 NANOCOATINGS There are several reasons, which were summarized above, for using coatings with a nanostructured surface on metal electrode and metal compounds in medical bionic devices. In particular, the use of CNTs, conductive polymers, hydrogels, and conductive hydrogels, could greatly enhance biocompatibility, charge injection capacity, and decrease the electrode impedance (Abidian and Martin, 2009). In addition, the loose structure of polymer provides a greater mechanical modulus match that decreases foreign body reactions and scar tissue formation. CNTs are discussed Section 8.5.4. Among conductive polymer polypyrroles, poly(ethylene dioxythio- phene) (PEDOT) and parylene and various modifications of them have been studied as coating materials for neuroprosthetic electrodes. Conductive polymer is usually composed of NPs, NWs, nanofibers, or nanotubes. In this way, there are various methods applicable to coat electrodes based on the type of coating materials. Electrochemical deposition and physical vapor deposition are the most common methods (Heim et al., 2012). Green et al. (2013) demonstrated the PEDOT potential to charge transfer benefited by Pt electrode array coated by PEDOT for bionic eye application. The high surface area has the potential to

8.5 Nanobiomaterial Point of View

increase the charge injection limit compared to Pt both in vitro and in vivo. As a result, charge densities are safely delivered to the tissues and may decrease power supplies of implant electronics. A high charge injection limit, on one hand, might be due to loss of structure and highly effective surface area of the polymers that facilitated ion diffusion and exchange between electrode and electrolyte. On the other hand, Loudin et al. (2009) studied the charge injection limits of three different electrodes: platinum, activated iridium oxide film (AIROF) electrodes, and sputtered iridium oxide film (SIROF). Sine AIROF electrodes have approximately twice the area of the SIROF electrodes; AIROF showed greater charge injection. These studies show the importance of nanoscale interactions in increasing visual prostheses resolution. Biologically, for chronic application of visual prostheses, neuron survival in contact with electrodes must be provided. Attachment and differentiation of chick cortical neurons significantly increased next to nanoscale multilayer coating of polyethyleneimine-laminin on a silicon electrode (He and Bellamkonda, 2005). The Abidian group at Michigan University fabricated soft, low-impedance and high-charge-density microelectrodes that have ability to release antiinflammatory drug with the aid of a PEDOT nanotube coating. Since cellular reactive responses increase the electrode tissue impedance due to the foreign-body reaction, controlled release of antiinflammatory drugs improves electrical properties (Zarbin et al., 2015). They continued their studies to investigate the effect of nanoscale morphology on neurite outgrowth (Abidian et al., 2010). Light activation of neuron studies can serve as a model system for providing an opportunity to enhance contemporary approaches in visual prosthesis. One of the main routes that is commonly used to optically activate neurons is through employing extracellular electrodes that are coated with a photosensitive thin film. In this way, conductive polymer, photoconductive silicon, and quantum dots are more often investigated. Since light excitation of retinal tissue can be achieved by these materials, an active surface must be create between these materials and neural cells. As a result, the thin film layer must be favorable for cell adhesion and proliferation. In this way, surface nanoscale morphology is determinant (Cramer et al., 2013). Ghezzi et al. (2011) spin-coated the organic photovoltaic blend onto a glass substrate precoated with indium-tin oxide. Recently they demonstrated that the poly(3-hexylthiophene) (P3HT) film was capable of depolarizing neurons via a photoexcitation process to restore light sensitivity in degenerated retina (Ghezzi et al., 2013).

8.5.4 CARBON NANOMATERIALS From the perspective of material science, an electrode array and its interface characteristics with the neurons either in the retina or visual pathway, determine the quality of visual perception in visual prostheses. The desired features at the interface include a large number of distinct contacts as well as low impedance. Carbone base nanostructure materials, such as CNT and graphene, have been suggested as a potential electrode material for neural stimulation. They have large

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surface areas, extremely high conductance and large specific capacitance (Cs) that reduces the electrode impedance.The Fishman’s laboratory at Stanford University was the first to propose vertically self-assembled, conductive, multiwall CNT to penetrate into retinal tissue without breakage or incompatibility (Wang et al., 2003). Later they presented vertically aligned multiwalled CNTs as pillars for electrical stimulation of primary neurons (Wang et al., 2006). Because of the high charge injection ability of the CNT electrode (1 1.6 mC/cm2), small electrodes can be used without faradic reactions. Their approach is critical to develop safe stimulation and miniaturized visual prostheses. Another approach to enhance visual resolution is applying CNT to improve the typically metal-based electrodes in stimulation microelectrodes. Some techniques are based on growing CNT on a substrate or applying chemical vapor deposition (CVD). Gabay et al. (2007) presented novel microfabricated CNT electrodes. The array was fabricated from highly dense CNT mats coated on conductive titanium nitride. The array showed enhanced electrochemical properties and biocompatibility. Based on the Gaby microelectrode, Eleftheriou et al. (2012) compared the CNT microelectrode arrays with commercially available titanium nitride (TiN) electrodes in prolonged repetitive stimulation of RGCs. Their electrophysiological data demonstrated a decrease in the impedance between the electrode and its biological target, delivering dense current pulses strong enough to activate RGCs through very small electrodes, without causing damage at the retina electrode interface. Based on their results and similar studies (Gabriel et al., 2009; Shoval et al., 2009) CNT could be considered as a promising material in visual prostheses. David-Pur et al. (2014) developed a flexible neuronal microelectrode device with the aid of CNT to provide a seamless integration circuit between the microelectrode and retina tissue. Luo et al. (2011) used a pure CNT to electrochemically deposit on Pt microelectrodes with poly(3, 4-ethylenedioxythiophene) (PEDOT) to enhance electrode stability for chronic stimulation. Samba et al. (n.d.) compared composite PEDOT CNT electrodes with titanium nitride (TiN) electrodes. The results showed that PEDOT CNT requires a lower voltage threshold and lower charge injection to stimulate retinal neurons presynaptic to the ganglion cells. Graphene, due to its electric conductivity and biocompatibility, was investigated by Park et al. as an electrode for neural stimulation. The results demonstrated that the nanostructure of graphene films can deliver electric currents to cells via capacitive charge injection without a faradic reaction (Park et al., 2011).

8.5.5 NANOCRYSTALLINE AND ULTRANANOCRYSTALLINE Ganesan et al. (2010) designed a novel high-density and penetrating electrode array for retinal stimulation. In their design, an electrically insulating polycrystalline diamond sheath surrounded the conductive channel that kept the electrode chip in a close to the retina cells. Electrode material and structure need to penetrate the retina to minimize the space between artificial stimulation and target

8.6 Conclusions

neurons. In the BVA epiretinal implant, electrical insulating diamond was utilized as a capsule for the implant’s compartment. Before that, Xiao et al. (2006) proposed ultrananocrystalline diamond as an insulated and bioinert coating for a retinal microelectronic device. Electrically conductive novel nanobiomaterials bring new insight into the electrical stimulation of the retina. New fabrication of a 3D microelectrode array with synthetic conducting diamond was proposed by Bergonzo et al. (2011). Nanodiamond was seeded on the substrate according to the pattern considered for a microelectrode. They achieved a higher range of charge injection limit in comparison with Pt microelectrodes. These studies known as MEDINAS Project (Rousseau et al., 2013). In fact, polycrystalline, nanocrystalline and ultrananocrystalline diamond can be produced by codeposition of a dopant such as nitrogen. Nanocrystalline diamond (NCD) also known as diamond-like carbon is a novel nanobiomaterial with crystal dimension less than 5 nm (Auciello and Sumant, 2010). Garrett et al. (2011) grew ultrananocrystalline diamond as an electrode in the presence of nitrogen. In the next step, nitrogen-doped ultrananocrystalline diamond (N-UNCD) was electrochemically anodized to form an iridium oxide coating on its surface. The electrodes shown enhanced the charge injection limit to the values that can stimulate neurons without water hydrolysis. A further advancement in this area was the introduction of completely diamond-based microelectrodes without the necessity to form the coating. They demonstrated that with tailoring growth conditions, the N-UNCD microelectrode array without coating can be effectively utilized for electrical stimulation of ganglion cells (Hadjinicolaou et al., 2012).

8.6 CONCLUSIONS In the 1970s, cochlear implants were branded as “an aid to lip reading.” For 30 years they increased expectations and improved the patient baseline from deaf adults to both deaf adults and children (Shannon, 2012). We can expect the same conditions for visual implants in the following decades. Briefly, there are significant technical challenges that must be investigated before visual implants can be used in clinical applications. The possible electrode locations involve the epiretinal, subretinal, suprachoroidal, and visual cortex, each having strengths and weaknesses (Attard, 1997). Safety, stability, and effectiveness are different in each electrode location and there are few long-term data in humans to specify the range of applications for each location. In the future, the combinations of electrodes in different sites may provide peripheral vision with a wider field of view. There is a tendency for larger numbers of electrodes, but there is no evidence that more electrodes is related to better performance. Performance will also be related to the ratio of electrodes that generate visual percepts, the spatial separation and size of electrodes, and the size of the perceptual space that is related to the whole

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array (Wagemans et al., 2012). The optimal number and spacing of electrodes in the visual cortex is different as the cortical retinotopic map of the macula is expanded relative to the macula itself (Eckhorn et al., 2006). Understanding control mechanisms of the percepts generated by stimulation and insuring that the total stimulation is at a safe level are also problems for the future (Zeng et al., 2008). Stimulation of electrodes at fixed positions on the retina generate phosphenes that seem to move through space as the eye moves relative to the head (Pezaris and Eskandar, 2009). Another challenging issue may be the fitting and training of patients to use devices with a large number of electrodes (Dagnelie, 2012). Production of these devices is confined by the physical properties of the materials. Electrical and mechanical properties show key limitations. The material should be highly conductive and also mechanically strong and flexible. Considering the challenges outlined above it may be also the opening to fully redesign the electrodes. The final aim of visual implants is to improve the quality of life of blind patients by enhancing their abilities. Accepting these challenges, visual implants are destined to allow significant improvements in clinical applications (Merabet, 2011). The future of neural interfaces is in the use of both traditional methods and also nanoscale materials and devices. The nanobiomaterials can revolutionize the current technologies used to stimulate neural tissues. The future improvement of nanostructured coatings will also cause significant enhancement of charge injection capacity and reduction of interface impedance (Abidian and Martin, 2009; Aregueta-Robles et al., 2014).

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