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where l is the heat conductivity of the medium. For example, keeping temperature rise under 1°C for a 1 cm disk in water (l = 0.58 W K−1 m−1) requires dissipating less than 23 mW of power. Blood perfusion in the eye helps to cool the tissue more efficiently, especially at temperature rises exceeding 3°C [55, 56].
7.2.6 Conclusions: Comparing the Different Approaches
Though the drawbacks of percutaneous connections are many, they will continue to be used in research environments through the foreseeable future. The electrical access afforded by percutaneous cables is invaluable when studying stimulation thresholds or reading the changing electrical properties of tissue. In addition, the development of a wireless system can be quite challenging – direct connections can greatly simplify experiments. However, any commercial prosthesis will need to incorporate a wireless power and data delivery system of some sort.
Of the three wireless system types described (RF, serial optical, and parallel optical telemetry), wireless cortical and optic nerve prostheses exclusively use radio links [8, 64, 65]. For retinal prostheses, there is as of yet no clear answer as to which system is superior. The circuit complexity of inductive systems is typically much higher than for photodiode-array based ones. Data signals must be separated from the carrier frequency, decoded, stored, and routed from the coil to individual electrodes. Photodiode array pixels receive all data simultaneously, with no need for complex wiring schemes. In addition, photodiode systems can produce DC voltage directly, whereas inductive coils produce AC current which must then be converted to DC. However, in terms of power transfer efficiency, inductive coil systems have a clear edge over photodiode systems, achieving efficiencies of greater than 65%, vs. ~30% achievable with photodiodes.
Photodiode-array based prosthetics keep the natural association between eye movements and visual perception, since they use the eye’s natural optics. A shift of the patient’s gaze directly changes what part of the visual field falls on the photodiode array. In contrast, current coil designs, as well as a serial optical telemetry with one receiving photodiode deliver visual information based solely on the orientation of a head-mounted camera; shifts in gaze do not change the visual stimuli. This could be fixed in the future by adding an eye-tracking system which controls what part of the visual field is transmitted to the stimulator. The Weiland group’s proposed eye-implanted camera [69] would also produce images which shift naturally with eye movements, although it would add significant complexity to implanted electronics.
7.3 Tissue Response to a Subretinal Implant
The sophistication of the visual system requires a prosthetic much more complex than previous electrical stimulation devices including pacemakers, cochlear implants and deep brain stimulators. Ensuring that electrodes maintain sufficiently close proximity to the target cells is an important aspect of interfacing a prosthetic with the retina.
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Visual acuity of 20/200 (the threshold of legal blindness in the United States) geometrically corresponds to a spatial frequency of three cycles per degree or ten lines per millimeter on the retina [29]. Since at least 2 pixels per cycle are required for appropriate sampling (Nyquist–Shannon sampling theorem), achieving this resolution constrains the maximum pixel size to 50 mm, or a pixel density of 400 pixels/mm2. If the electrode is to be no larger than half the size of the pixel, then the electrode diameter should not exceed approximately 25 mm. The divergence of the electric field from the electrode requires greater currents to stimulate cells at increasing distances. Since increasing separation also causes the divergent electric field to influence larger regions of the retina, this effectively reduces the specificity of neural stimulation, resolution and contrast [45]. Charge and current injection limits, determined by the electrochemical capacitance of the electrode material, also determine the maximum distance at which neurons can be stimulated. In addition, significant variation in the distance between electrodes and neurons across an implant will lead to position-dependent differences in stimulation thresholds and responses. These factors dictate that the distance between the electrodes and target cells should not exceed the electrode size [45]. In the case of 50 mm pixels with 25 mm electrodes, the separation of electrodes from cells should ideally not exceed 25 mm.
Retinal neurons can be stimulated electrically using arrays of electrodes positioned either epiretinally [22, 37, 38] or subretinally [54, 61, 75]. Although surgically more challenging, a subretinal array placement to stimulate bipolar cells has the potential advantage that the electrical stimuli can be simpler. Since the cells in the inner nuclear layer (INL) have a graded response (they do not spike), they may not require as precise stimulus timing as the spiking ganglion cells. Subretinal electrical stimulation can produce a graded response which is then converted to spiking ganglion cell output via natural signal transduction pathways [61]. Addressing the visual system earlier in the signal processing cascade may also utilize some preserved natural signal processing mechanisms between the inner retina and ganglion cells. In contrast, direct ganglion cell excitation with epiretinal electrodes bypasses inner retinal circuitry and requires significantly more complex signal processing by external elements.
In the subretinal approach, the proximity between the stimulating array and the bipolar cells can be limited by subretinal gliosis and fibrosis, whereas in the epiretinal approach, proximity is limited by the inner limiting membrane and the nerve fiber layer. Mounting the implant epiretinally presents an additional challenge: attachment via a single retinal tack often results in tens or even hundreds of microns of separation between the retina and peripheral parts of the implant [36]. In contrast, the subretinal approach appears to provide more consistent proximity to the retina along the implant [47], although the thickness of the degenerating retina may be uneven.
In the following section we present results of investigations on the effect of an implant’s material and shape on its integration with the retina.
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7.3.1 Flat Implants
SU-8, a photo-curable epoxy, was used to manufacture devices to investigate tissue response to subretinal implants. SU-8 polymers are ideal for this purpose because they can be coated with materials commonly used in retinal prostheses, can form high aspect-ratio structures and are soft enough to be easily sectioned, in situ, on a conventional microtome to histologically evaluate the implant–retina interface. Three different coating materials have been compared: silicon oxide, parylene-C, and iridium oxide.
The Royal College of Surgeons (RCS) rat is a commonly studied model of retinal degeneration and is ideal for subretinal implantations of these devices because of its sufficiently large eyes and vascularized retina [32]. All implantations were performed at 45–60 days of age; at this stage the photoreceptor cells have largely degenerated. The implants were placed in the subretinal space using a custom implantation tool that protects the implant from mechanical damage during insertion [9]. The implant is delivered trans-sclerally through a small incision behind the pars plana; the retina is detached from the RPE by injecting BSS with a 30-gauge cannula. Implant placement was evaluated after each surgery by fundus examination.
Figure 7.2a illustrates the normal wild type rat retina, and Fig. 7.2b shows RCS retina at 45 days of age (P45). Figure 7.2c demonstrates a flat SU-8 implant in the subretinal space of a P45 RCS rat 6 weeks after surgery. Changes in the degenerating retina are easily seen comparing 7.2b to 7.2a; in Fig. 7.2b, the outer segments have disintegrated and there is significant thinning of the outer nuclear layer (ONL) though the inner nuclear, inner plexiform, and ganglion cell layers are generally well preserved.
As shown in Fig. 7.2c, two types of tissue reaction to the subretinal implant are evident: gliosis and fibrosis. Differentiation of retinal pigment epithelial (RPE) cells into long fibrotic membranes that encapsulate the foreign body is called fibrosis – this
Fig. 7.2 Histological sections depicting (a) wild type rat retina, (b) RCS rat retina 45 days post natal (P45), and (c) RCS rat retina with a flat SU-8 implant in the subretinal space 6 weeks post-op. A fibrotic seal running along the length of the implant is denoted with the left arrow. A region of gliosis separating the implant from the INL by 40 mm is shown by the right arrow. Scale bar is 50 mm. Figure reprinted from [9], with permission
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Fig. 7.3 Comparison of typical tissue responses to flat implants with different coatings 6 weeks post-op. (a) SiO2 coating appears to induce significant fibrosis over the implant. (b) IrOx causes a mild gliosis above to the implant, pointed by an arrow. (c) Parylene-c coating allows the INL to settle down very close to the implant. The INL is separated from the upper surface of the implant by only 15–30 mm. Scale bar is 50 mm. Figure reprinted from [9], with permission
dark stained layer apposed to the implant is denoted by an arrow in Fig. 7.2c. The lightly stained reaction in the inner nuclear layer (INL), denoted by an arrow in Fig. 7.2c, is the hypertrophy of glial cells processes and is called gliosis. Fibrosis and gliosis can separate the INL from the surface of the implant by approximately 40 mm.
The silicon oxide coating (Fig. 7.3a) induced significant fibrosis around the implant. Generally, the iridium oxide and parylene coatings (Fig. 7.3b, c) were well tolerated with only a mild gliotic response, resulting in 15–30 mm separation from INL somata.
7.3.2 Chamber Implants
The tendency of retinal cells to migrate into the voids of three-dimensional implants can be used to provide closer apposition between the implant and the inner nuclear layer [44]. The vertical movement of the retina is hypothesized to be largely due to the movement of glial processes into the voids. Retinal neurons appear to be pulled along with retinal glia – this movement occurs within 72 h after implantation [17]. The ability of these structures to maintain a stable interface and suppress severe fibrosis is discussed below.
Chamber structures were fabricated with an array of wells (40 × 40 × 20 mm tall) in an SU-8 substrate (Fig. 7.4a, b). These devices were implanted into the subretinal space of RCS rats. A representative histological section of the retina, 6 weeks postimplantation, is shown in Fig. 7.5. In general, INL cell bodies migrate through apertures larger than 20 mm (right three chambers). In some chambers with apertures greater than 20 mm a retinal microvasculature developed [9].
Computational molecular phenotyping (CMP) analysis was used to distinguish superclasses and classes of neurons and glia, determine their status, examine morphological circuitry changes in response to retinal degeneration, and document any influence the implant may have upon these processes [25, 26]. Within the time
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Fig. 7.4 SEM of three-dimensional implant structures. (a) Two microfabricated layers of the SU-8 chamber structures prior to adhesion to the basal membrane. Chamber sizes are 40 and 20 mm, and aperture sizes are 20 and 10 mm. (b) High magnification view of the chamber array. The 10 and 20 mm apertures can be seen clearly in the center of the 40 mm chambers. (c) Implant with an array of SU-8 pillars at three densities, with center-to-center distances of 60, 40 and 20 mm. (d) High magnification SEM of the pillar array. Pillars are 10 mm in diameter and 65 mm in height. All scale bars in this figure are 100 mm. Figure reprinted from [9], with permission
Fig. 7.5 The chamber structure implanted into P45 RCS rat subretinally for 6 weeks. The three chambers on the right have 20 mm apertures, the two on the left are 10 mm. This is an example of a typical section where cell bodies have migrated through the wider apertures while only processes migrated through 10 mm apertures. Artifactual folds are marked with a *. Scale bar is 50 mm. Figure reprinted from [9], with permission