Development of direct neural interface (DNI) including visual prostheses absolutely requires con rmation of their long-term safety and stability. Functional evaluation by electrically evoked potentials (EEPs) is effective in this regard, although the recording system must be stable for chronic use. In addition, control of anesthetic depth is important for stable recording of the evoked potentials. The purpose of this study was to develop a chronically implanted electrode capable of recording visual evoked responses safely during repeated anesthesia over long periods, which would allow more effective safety evaluations of not only visual prostheses but also DNI. We developed two types of electrodes, and implanted them into rabbits. A general screw electrode was used for comparison with the novel electrodes. Structurally, the newly developed platinum (Pt) ball-tip screw electrode consisted of a plastic screw with smoothly surfaced Pt balls on the tip. The depth of implantation into the brain was adjustable via a threaded insert installed in the skull. The newly developed platinum/iridium (Pt/Ir) ball-tip planar multi-electrode array (MEA) comprised Pt/Ir ball electrodes placed in a two-dimensional lattice pattern, which was implanted just beneath the skull. These electrodes recorded variations in visual evoked potentials (VEPs) in response to 20 J ash stimuli over a period of 48 weeks. After 48 weeks of implantation, the ability of the electrodes to continue recording EEPs was con rmed (500 µA, 500 µs, cathodic rst biphasic). During the recording of VEPs and EEPs, stable anesthesia was maintained with iso urane (end-tidal 2.4%). The depth of anesthesia using iso urane could be adjusted safely, and allowed stable recording of evoked potentials throughout the long-term study. However, stable recording using the general screw electrode was possible only for a short period. We also obtained stable latency and N 1 amplitude readings over the 48 weeks using the newly developed electrodes, and successfully recorded EEPs after the 48-week period. These results suggest that the novel electrodes work well over the entire duration of the study, and may allow assessment of long-term safety and stability of not only visual prostheses, but also other devices utilizing brain machine interfaces or direct neural interfaces.

The chemical speciation 1,2 and simultaneous determination 3 of metal ions have been increasingly needed in areas such as clinical chemistry, environmental pollution and industrial control. Iron is present as bivalent and trivalent states in the natural environment. The changes between these two forms of iron are important in various biological 4 and geochemical 5 processes. Thus, the development of a simultaneous method for iron(II), iron(III) and thus the total iron is still desired. The redox potential of a system involving metal ions is modified by complexation of metal ions with a suitable ligand.6 Vydra and Pribil 7,8 reported on the effect of 1,10-phenanthroline (phen) on the redox reaction of cobalt(II) with iron(III) and developed a method for the potentiometric titration of cobalt(II) with iron(III) in the presence of this ligand. By using this phenomenon, we have recently proposed novel redox systems, which are applicable to potentiometric titrimetry for the determination of metal ions. [9][10][11][12][13] In the presence of phen or 2,2′-bipyridine (bpy), a remarkable potential break is observed in the titration of vanadium(IV) with iron(III), cobalt(II) with vanadium(V) and cobalt(II) with chromium(VI). 11 Furthermore, we have reported on the successive potentiometric titration of chromium(VI) and iron(III) with cobalt(II) in the presence of phen. 12We also developed a new flow-injection spectrophtometric method for the simultaneous determination of vanadium(IV) and vanadium(V), based on the effect of phen and diphosphate on the redox potential of the Fe(III)/Fe(II) system. 14 In this paper, the successive potentiometric titration of chromium(VI) and iron(III) 12 is further developed, that is, successive potentiometric titration of iron(II) and iron(III) with cobalt(II) is presented. The redox potential of the Cr(VI)/Cr(III) system is higher than that of the Fe(III)/Fe(II) system at low pH. Thus, iron(II) was oxidized to iron(III) by adding excess chromium(VI) as an oxidizing agent before the titration. Then, non-reacted chromium(VI) and total iron were titrated with cobalt(II) in the presence of phen. The present method can determine iron(II) and iron(III) in the range 3×10 -4 -1×10 -3 mol dm -3 ; the relative standard deviations of this method were 0.66 and 0.81% for four determinations of 5×10 -4 mol dm -3 iron(II) and 1×10 -3 mol dm -3 iron(III), respectively. The method was successfully applied to the determination of total iron in standard iron-ore samples and to the successive determination of iron(II) and iron(III) in a Mosan iron-ore sample issued by The Japan Iron and Steel Federation. Experimental ReagentsAn iron(II) standard solution (0.01 mol dm -3 ) was prepared daily by dissolving 0.098 g of iron (II) A novel potentiometric titration of iron(II) and iron(III) is proposed. The method is based on the effect of 1,10-phenanthroline (phen) on the redox reactions of chromium(VI) and iron(III) with cobalt(II). In the presence of phen the conditional redox potential of the Co(III)/Co(II) syst...

We have developed retinal prosthetic devices based on suprachoroidal-transretinal stimulation (STS). The effectiveness and safety of such novel devices are con rmed by in vitro and in vivo tests based on scienti c knowledge. Animal testing is especially important because it demonstrates the total safety of the device. We successfully developed a long-term evaluation system with automatic stimulation and measurement of electrochemical characteristics in freely moving rabbits. This system allows evaluation of long-term safety and change in electrochemical characteristics. In addition, we conducted a pilot evaluation of the safety of STS using bullet-shaped electrodes in rabbits. No obvious injuries were observed in all examinations. However, the array moved away from the retina in a few rabbits. Visual and electrical evoked potentials (EEPs) were recorded after three-month implantation. The function of the retinal neurons around the electrode is assumed to be maintained because EEPs were observed after three-month stimulation. However, the evoked potentials become indistinct with time in some rabbits. The development of implantable recording electrode capable of long-term evaluation is necessary for assessing the function of retina exposed to electrical stimulation. Long-term safety and change in electrochemical characteristics can be con rmed easily using this system. No histological difference was observed between the active and inactive electrodes, suggesting that the amount of charge used in the study can be safely injected. The charge injection capacity (CIC) of these electrodes provides an indication of the safety threshold for STS. The electrode array should have a curvature to t the eyeball to avoid movement of the array away from the retina. The electrode height is slightly greater compared to the sclera thickness. Accordingly, methods to enhance the CIC vs. geometrical surface area are required if the electrode height is reduced. We were able to obtain an indication of the required performance for the stimulation electrode based on the safe charge injection for STS (CIC of approximately 90 μC/cm 2 in PBS) and establish a system capable of evaluating safety and durability of retinal prostheses for long-term stimulation.

We developed a visual prosthesis based on suprachoroidal transretinal stimulation (STS) using electrodes with femtosecond-laser-induced porosity (FLiP electrodes). A current of 1.5 mA (1.25 times higher than that of a device under development) was applied by STS in six rabbits for 6 months to evaluate the long-term changes in the electrochemical properties of FLiP electrodes in vivo. The long-term stability of the FLiP electrodes was determined by in vitro and in vivo evaluations. The performance of the electrodes did not deteriorate after the long-term application of electrical stimulation in vivo. As no difference was observed between the in vivo electrochemical performance of the electrodes to which the stimulation current was and was not applied during the experiment, it is confirmed that the FLiP electrodes exhibit sufficient safety performance under long-term stimulation both in vivo and in clinical use. However, variations in the characteristics of the electrodes owing to the manufacturing method of the FLiP electrodes were observed. This variation should be reduced during the manufacturing process to avoid side effects owing to unexpected electrochemical behavior in clinical use. This result is useful in understanding the long-term safety testing results of STSbased retinal prostheses with FLiP electrodes.

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