August 2011
Volume 52, Issue 9
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Retina  |   August 2011
Chronic Implantation of Newly Developed Suprachoroidal-Transretinal Stimulation Prosthesis in Dogs
Author Affiliations & Notes
  • Takeshi Morimoto
    From the Departments of Applied Visual Science,
  • Motohiro Kamei
    Ophthalmology, and
  • Kentaro Nishida
    Ophthalmology, and
  • Hirokazu Sakaguchi
    Ophthalmology, and
  • Hiroyuki Kanda
    From the Departments of Applied Visual Science,
  • Yasushi Ikuno
    Ophthalmology, and
  • Haruhiko Kishima
    Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan; and
  • Tomoyuki Maruo
    Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan; and
  • Kunihiko Konoma
    Vision Institution, Nidek Co., Ltd., Gamagori, Japan.
  • Motoki Ozawa
    Vision Institution, Nidek Co., Ltd., Gamagori, Japan.
  • Kohji Nishida
    Ophthalmology, and
  • Takashi Fujikado
    From the Departments of Applied Visual Science,
  • Corresponding author: Takeshi Morimoto, Department of Applied Visual Science, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan; takeshi.morimoto@ophthal.med.osaka-u.ac.jp
Investigative Ophthalmology & Visual Science August 2011, Vol.52, 6785-6792. doi:10.1167/iovs.10-6971
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      Takeshi Morimoto, Motohiro Kamei, Kentaro Nishida, Hirokazu Sakaguchi, Hiroyuki Kanda, Yasushi Ikuno, Haruhiko Kishima, Tomoyuki Maruo, Kunihiko Konoma, Motoki Ozawa, Kohji Nishida, Takashi Fujikado; Chronic Implantation of Newly Developed Suprachoroidal-Transretinal Stimulation Prosthesis in Dogs. Invest. Ophthalmol. Vis. Sci. 2011;52(9):6785-6792. doi: 10.1167/iovs.10-6971.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To investigate the feasibility of implanting a newly developed suprachoroidal-transretinal stimulation (STS) prosthesis in dogs and to determine its biocompatibility and stability over a 3-month period.

Methods.: The STS prosthesis system consisted of an array of 49 electrodes (nine were active), an intravitreal return electrode, and an extraocular microstimulator. The 49-electrode array was implanted into a scleral pocket of each of three healthy beagle dogs. Color fundus photography, fluorescein angiography, electroretinography, and functional testing of the STS system were performed postoperatively. The dogs were euthanatized 3 months after the implantation, and the retinas were evaluated histologically.

Results.: All the prostheses were successfully implanted without complications, and no serious complications occurred during the 3-month postoperative period. The fixation of the implant was stable throughout the experimental period. Fluorescein angiography showed that the entire retina, including the area on the electrode array, remained well perfused without intraocular inflammation. Electroretinograms recorded from the eyes with the prosthesis did not differ significantly from those recorded from control eyes. Functional testing of the STS system showed that this system performed well for the 3-month experimental period. Histologic evaluations showed good preservation of the retina over the electrode array.

Conclusions.: Implantation of a newly developed STS retinal prosthesis into a scleral pocket of beagle dogs is surgically feasible and can be performed without significant damage to the retina or the animal. The biocompatibility and stability of the system were good for the 3-month observation period.

Retinitis pigmentosa (RP) is one of the leading causes of blindness in the world. 1 RP is a group of hereditary retinal degenerative diseases that primarily affect the photoreceptors. 1 3 In the last stage of the disease, RP patients have little or no functional vision. 4 6 To restore some degree of visual capability to these blind patients, implantable microelectronic prostheses designed to stimulate the neural retina or the optic nerve are being developed. 7 15  
Various types of subretinal, epiretinal, and optic nerve prostheses have been designed and tested in animals 16 24 and patients. 25 35 These implants are directly attached to the retina or the optic nerve; therefore, the risk for tissue damage at the implantation site is to be expected. We believe it is preferable to have the stimulating electrodes implanted so that they do not touch the retina. 
Thus, we have designed a transretinal stimulation system with electrodes implanted in the suprachoroidal space and attached to the sclera. 36 We call this a suprachoroidal-transretinal stimulation (STS) prosthesis; the stimulating electrodes were placed on the choroidal surface, and the return electrode was placed in the vitreous body. Our group has established the surgical procedures to implant the STS electrode array into the suprachoroidal space of rabbits. 37,38 At this position, we have demonstrated that STS can stimulate retinal neurons and evoke electrical potentials from the visual cortex of rats and rabbits. 36,38 40 Moreover, we succeeded in implanting an STS electrode array transiently into RP patients, and we were able to evoke phosphenes in these patients. 41 Our group also studied the STS electrodes and an STS system device. 42,43 Finally, our group has developed an implantable STS device consisting of an electrode array, a return electrode, and an extraocular microstimulator that can be used for long-term implantation. 44  
However, many questions remain, such as the feasibility of the surgical techniques for implantation, the suitability of the shape and rigidity of the device for the tissue, the flexibility and length of the cable, and the biocompatibility and stability of the implanted devices. 
Thus, the purpose of this study was to address these questions in dogs by ophthalmic examinations, electrophysiological examinations, and histologic analyses. We shall show that our STS microelectrode array can be implanted into a scleral pocket of the beagle dog without complications and that the system is biocompatible and stable for at least 3 months. 
Materials and Methods
The STS system is manufactured by Nidek Co., Ltd. (Gamagori, Japan), and consists of an implanted system and an extracorporeal control system. 
Implanted STS System
The implanted part of the STS system consisted of an extraocular microelectronic stimulator that was placed in a hermetically sealed case, a suprachoroidal electrode array, and an intravitreal return needle electrode. The electrode array and the return electrode were connected to the extraocular stimulator by a multiwire cable. The electrode array measured 6 mm × 6 mm × 0.5 mm and consisted of 49 platinum electrodes in a 7 × 7 arrangement fixed in a clear silicone rubber platform coated with parylene. Each of the stimulating electrodes measured 0.5 mm in diameter and 0.5 mm in length. The distance between the centers of electrodes was 0.75 mm. Nine of the electrodes on the array were electrically active for this experiment. The return platinum electrode measured 6.5 mm in length and 0.5 mm in diameter. 
The stimulator had microelectronics that received signals from an external transmitter by electromagnetic induction (Figs. 1A–C). 
Figure 1.
 
Photographs of the STS system. (A) Internal part of the STS system. The STS electrode array (B), the return electrode (C), and the extraocular microelectronic stimulator. The electrode array measured 6 mm × 6 mm × 0.5 mm with 49 platinum electrodes in a 7 × 7 arrangement that was fixed in a clear silicone rubber platform coated with polymer. Each electrode is 0.5 mm in diameter and 0.5 mm in length. The distance between the centers of the electrodes is 0.75 mm. Nine of these 49 electrodes were active. The return platinum electrode was 0.5 mm in diameter and 6.5 mm in length (C). The stimulator had microelectronics that received the signals from an external transmitter by electromagnetic induction (A). (D) Extracorporeal part of the STS system device. The system consisted of a transmitter, a processor, and a personal computer (PC). The stimulus sets were programmed using technical computing software on a PC that sent the stimulus parameters to the processor (D, gray arrowhead). The signals and power information were then passed through the transmitter (D, E, black arrowhead) to the microstimulator (E). Scale bars: 1.0 cm (A); 3.0 mm (B); 3.0 mm (C); 1.5 cm (E).
Figure 1.
 
Photographs of the STS system. (A) Internal part of the STS system. The STS electrode array (B), the return electrode (C), and the extraocular microelectronic stimulator. The electrode array measured 6 mm × 6 mm × 0.5 mm with 49 platinum electrodes in a 7 × 7 arrangement that was fixed in a clear silicone rubber platform coated with polymer. Each electrode is 0.5 mm in diameter and 0.5 mm in length. The distance between the centers of the electrodes is 0.75 mm. Nine of these 49 electrodes were active. The return platinum electrode was 0.5 mm in diameter and 6.5 mm in length (C). The stimulator had microelectronics that received the signals from an external transmitter by electromagnetic induction (A). (D) Extracorporeal part of the STS system device. The system consisted of a transmitter, a processor, and a personal computer (PC). The stimulus sets were programmed using technical computing software on a PC that sent the stimulus parameters to the processor (D, gray arrowhead). The signals and power information were then passed through the transmitter (D, E, black arrowhead) to the microstimulator (E). Scale bars: 1.0 cm (A); 3.0 mm (B); 3.0 mm (C); 1.5 cm (E).
Extracorporeal Control System
The extracorporeal part of the STS system consisted of a transmitter, a signal processor, and a personal computer (PC). Signals from the PC are carried to the processor by a wire, and the processor changes the signals to electrical pulses that are sent through the cable to the transmitter. The transmitter, which is a coil held in position by a magnet placed beneath the extraocular stimulator, sends the signals to the stimulator by electromagnetic induction (Figs. 1D, 11E). 
Animals
Three healthy adult male beagle dogs were purchased from Kitayama Labes Co. (Ina, Japan). The dogs ranged in age from 7 to 9 months and weighed between 8 and 11 kg at the time of the implantation. All procedures conformed to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research, and the procedures were approved by the Animal Care and Use Committee of Osaka University. 
Anesthesia
The dogs were initially anesthetized with an intramuscular injection of 0.3 mL/kg medetomidine (Domitor; Orion Corporation, Espoo, Finland), 25 mg/kg ketamine HCl (Ketaral; Daiichi Sankyo Co., Ltd., Tokyo, Japan), and 2 mg/kg xylazine (Seraktal; Bayer Health Care, Tokyo, Japan) followed by an intraperitoneal injection of 0.1 mg/kg atropine sulfate (Atropin; Mitsubishi Tanabe Pharma Corporation, Osaka, Japan). 
For the surgery, anesthesia was maintained with a mixture of 0.5% to 2% isoflurane (Forene; Abbott Japan Co., Ltd., Tokyo, Japan) and N 2 O/O 2 (1:1). A heating pad was used to maintain body temperature at approximately 37°(C) The electrocardiogram was continuously monitored, and the oxygenation of the hemoglobin was monitored by pulse oximetry during surgery. 
Surgery
Implantation was made to the left eye of each dog. The surgical procedures included fixation of the extraocular stimulator on the surface of the left temporal muscle, passing the cable and electrodes into the left orbit, insertion of the microelectrode array into a deep lamellar scleral pocket, and placing the return needle electrode into the vitreous body. 
A skin incision was made sagittally between the median line and approximately 5 cm from the left ear, and the stimulator was placed on the surface of the left temporal muscle. Then a skin incision of approximately 3 cm was made at the left brow, and the SC tissue was prepared for the insertion of the electrodes. The microelectrode array and the return electrode were combined into one bundle and covered with a silicone rubber tubing (Fig. 2A), and the cable was passed under the skin of the forehead and through the brow with a customized trocar. 24,29  
Figure 2.
 
Photographs taken during implantation surgery and 1 month after implantation. (A) Microelectrode array and return electrode are combined into one bundle and covered with silicone rubber tubing. (B) Customized trocar and electrodes. (C) Creation of a scleral pocket. (D) Electrodes and cables are passed under an extraocular muscle. (E) Cable is sutured to the sclera. (F) Insertion of a return electrode. (G) An electrode array was inserted into the scleral pocket, and the cable was sutured to the sclera. (H) Return electrode inserted intravitreally and sutured to the sclera. (I) Extraocular microstimulator implanted on the surface of the left temporal muscle. (J) Frontal view of dog 1 month after implantation. The position of the eye is orthophoric. (K) Temporal view of dog 1 month after implantation. All wounds have healed properly, and no sign of infections or wound dehiscence can be seen. The position of the extraocular stimulator was surrounded with the white line. (L) An enucleated eye that has an electrode array implanted into the scleral pocket.
Figure 2.
 
Photographs taken during implantation surgery and 1 month after implantation. (A) Microelectrode array and return electrode are combined into one bundle and covered with silicone rubber tubing. (B) Customized trocar and electrodes. (C) Creation of a scleral pocket. (D) Electrodes and cables are passed under an extraocular muscle. (E) Cable is sutured to the sclera. (F) Insertion of a return electrode. (G) An electrode array was inserted into the scleral pocket, and the cable was sutured to the sclera. (H) Return electrode inserted intravitreally and sutured to the sclera. (I) Extraocular microstimulator implanted on the surface of the left temporal muscle. (J) Frontal view of dog 1 month after implantation. The position of the eye is orthophoric. (K) Temporal view of dog 1 month after implantation. All wounds have healed properly, and no sign of infections or wound dehiscence can be seen. The position of the extraocular stimulator was surrounded with the white line. (L) An enucleated eye that has an electrode array implanted into the scleral pocket.
The conjunctiva was opened 360° near the limbus. A tunnel was prepared in the subconjunctival space in the upper temporal quadrant, through the septum, to the brow incision by a smaller customized trocar (Fig. 2B). 24,29 The devices and cables were passed through the tunnel under the superior muscle, and the silicone rubber protector was removed to separate the microelectrode array and the return electrode. 
A scleral pocket (7 mm × 7 mm) was made in the superotemporal or superonasal quadrant approximately 10 to 12 mm posterior to the limbus (Fig. 2C). The cable connecting the array was passed under the other rectus muscles and sutured to the sclera (Figs. 2D, 2E). The other cable connected to the return electrode was also passed under the other rectus and was sutured to the sclera after the insertion of the return electrode into the vitreous cavity (Fig. 2F). 
After implantation of the electrodes (Figs. 2G, 2H), the extraocular stimulator was tightly sutured to the temporal muscle, and the incisions on the head and the brow were sutured (Fig. 2I). 
Fundus Photography and Fluorescein Angiography
Color fundus photographs were taken under general anesthesia before surgery and monthly after surgery. Fluorescein angiography (FA) was performed at 1 month and 3 months after surgery. For both procedures, the eyes were dilated with topical 2.5% phenylephrine hydrochloride and 0.5% tropicamide (Midrine P; Santen Co., Ltd., Osaka, Japan), and fundus photographs were taken with a fundus camera (TRC-50IX; Topcon Corporation, Tokyo, Japan). For FA, photographs were taken after the injection of 0.075 mL/kg of 10% sodium fluorescein solution (Fluorescite; Alcon Japan Ltd., Tokyo, Japan) into a vein. 
Electroretinography
Bright-light flash electroretinograms were recorded 3 months after the implantation of the STS electrode array. Under general anesthesia, the pupils were dilated with 2.5% phenylephrine hydrochloride and 0.5% tropicamide, and a 2.5% hydroxypropyl methylcellulose ophthalmic solution (Scopysol; Santen Co. Ltd., Osaka, Japan) was used with a corneal contact lens electrode/LED mini-Ganzfeld stimulator (WLS-20; Mayo Corporation, Nagoya, Japan). A reference electrode was inserted subdermally into the left ear, and a ground electrode was inserted subdermally into the nose. The animal was dark-adapted for 30 minutes before the electroretinographic (ERG) recordings. Responses elicited by bright flash stimuli (1.5 log cd · s/m 2 ) were amplified, band pass filtered from 0.3 to 1000 Hz, and digitized at 3.3 kHz. Five responses were averaged with an interstimulus interval of 10 seconds on a computational ERG recording system (Neuropack μ; Nihon Kohden, Tokyo, Japan). 
Functional Testing of STS System
To confirm the integrity and stability of the STS system, functional testing of the STS system was performed. The voltage in the microelectronic circuit of the extraocular stimulator was measured by another circuit as a comparator inside the extraocular stimulator. The maximum voltage of this circuit was 10.0 V, and we set 9.5 V as a saturation voltage. Just after implantation and then at 1, 2, and 3 months after implantation, we checked to be sure that the voltage did not exceed the saturation voltage of 9.5 V. Each of the nine active electrodes was activated with balanced, cathodic-first biphasic pulses of 200 to 1000 μA, with a duration of 0.5 ms/phase and pulse duration of 0.5 ms. The frequency of the pulses was 20 Hz for 0.5 seconds that was controlled by the extraocular stimulator driven by the extracorporeal transmitter. If the voltage in the electric circuit in the microstimulator was less than the saturation voltage, the device set the current as pass, but if the voltage exceeded the saturation voltage, the device set the current as failure. 
Next the artifacts evoked by electrical stimulation were recorded with a contact lens corneal electrode/LED mini-Ganzfeld stimulator (WLS-20; Mayo Corporation). A reference electrode was inserted subdermally into the left ear, and a ground electrode was inserted subdermally into the nose. Responses elicited by electrical stimulation were amplified and band pass filtered from 0.3 to 1000 Hz, and the responses were digitized at 3.3 kHz. One response was recorded using a computational ERG recording system (Neuropack μ; Nihon Kohden). 
Histologic Analyses
After 3 months, the animals were euthanatized with 120 mg/kg intravenous pentobarbital (Somunopentyl; Kyoritsu Seiyaku Corporation) while the animals were under general anesthesia. Both eyes were enucleated, after which the electrodes and cables were removed from the left eyes. Then the eyes were placed in 1.2% glutaraldehyde and 2% paraformaldehyde in 0.1 M phosphate buffer (PB) for 30 minutes at room temperature. Eyes were trimmed, and the eyecup with the optic nerve was postfixed in the fixative at 4°C for 24 hours. The eyecups were kept in 10% formaldehyde in 0.1 M phosphate buffer at 4°C for 24 hours. Tissues were trimmed and embedded in paraffin. Semithin sections (4.0 μm) were cut along the meridian, including the optic disc and the electrode array, and were stained with hematoxylin and eosin for light microscopy. 
Results
Results of Implantation Surgery
Results of the implantation surgery are shown in Figure 2. All prostheses were safely implanted, and no intraoperative complications were encountered. The shape of the extraocular stimulator fit the curve of the head, and the electrode array and the return electrode could be easily passed under the skin from the temporal muscle into the orbit with the customized trocar. The cable easily encircled the globe, and the electrode array and the return electrode could be easily inserted (Figs. 2G, 2H). No severe bleeding occurred during the creation of the scleral pocket and the insertion of the needle electrode. 
The position of the eyes was maintained orthophoric without proptosis (Fig. 2J). All the wounds healed properly, and no sign of infections or wound dehiscence could be seen (Fig. 2K). The fixation of the extraocular stimulator was also stable throughout the observation period in all cases (Fig. 2K). The animals moved freely in their kennels and showed no apparent alterations in behavior. 
Three months after implantation, the animals were deeply anesthetized and the eyes were enucleated. The fixation of the electrode array and the cable was examined macroscopically. The electrode array was found to be completely inserted into the sclera pocket and had not rotated on its axis (Fig. 2L). 
Postoperative FA and Ophthalmic Examinations
Immediately after surgery, moderate edema and hematomas were noticeable in the periorbital region. Conjunctival chemosis and injection were also observed in all cases. Approximately 7 days after surgery, the conjunctival chemosis, periorbital edema, and hematoma had almost completely resolved. All wounds healed properly, and no signs of infections or wound dehiscence were noticed. 
Ophthalmic examinations showed that there were no ocular complications, infections, retinal detachment, or vitreous or subretinal hemorrhages. A localized posterior subcapsular cataract was present in dog 2 that was probably caused by the needle electrode touching the lens; however, the opacification did not get worse. 
Fundus photographs of the three dogs are shown in Figure 3. In dog 1, the implanted electrode array was not detectable, and there was no obvious indication of surgical damage or side effects (Figs. 3A, 3C). In dogs 2 and 3, the notch of the electrode array and the outline of the array were detected 1 month after implantation (Figs. 3E, 3I; white and black arrowheads). In addition, pigmentation of the retina at the edge of the array distal to the cable was observed in dog 2 (Fig. 3I). The size of the pigmented area did not change throughout the 3-month observation period (Fig. 3K). 
Figure 3.
 
Fundus photographs and fluorescein angiograms 1 month and 3 months after implantation in three dogs. (AD) The retina appears normal, with no evidence of the STS electrode array implanted in dog 1. (A, C) One month after implantation. (B, D) Three months after implantation. (EH) Photographs of dog 3. Although the notch of the electrode array can be seen (black arrowheads), there are no significant changes such as inflammation, retinal obstruction, and vascular damage throughout the observation period. (EG) One month after implantation. (FH) Three months after implantation. (IL) Photographs of dog 2. Although pigmentation of the retina can be seen at the implantation site (white arrowheads), there is no severe retinal damage around the array. (I, K) One month after implantation. (J, L) Three months after implantation.
Figure 3.
 
Fundus photographs and fluorescein angiograms 1 month and 3 months after implantation in three dogs. (AD) The retina appears normal, with no evidence of the STS electrode array implanted in dog 1. (A, C) One month after implantation. (B, D) Three months after implantation. (EH) Photographs of dog 3. Although the notch of the electrode array can be seen (black arrowheads), there are no significant changes such as inflammation, retinal obstruction, and vascular damage throughout the observation period. (EG) One month after implantation. (FH) Three months after implantation. (IL) Photographs of dog 2. Although pigmentation of the retina can be seen at the implantation site (white arrowheads), there is no severe retinal damage around the array. (I, K) One month after implantation. (J, L) Three months after implantation.
FA showed intact vasculature without signs of inflammation, leakage, obstruction, or formation of new vessels in the area overlying and surrounding the implant in all dogs (Figs. 3B, 3D, 3F, 3H). In dog 2, there was no detectable sign of retinal damage at the pigmented area (Figs. 3J, 3L). 
Electroretinography
The electroretinograms had normal a-wave and b-waves, and the shapes did not differ from those of electroretinograms recorded from the unoperated fellow eye 3 months after implantation in all three animals (Fig. 4, Table 1). 
Figure 4.
 
Three months after implantation. Representative electroretinograms recorded of the implanted eye (A) and fellow eye (B) of dog 1.
Figure 4.
 
Three months after implantation. Representative electroretinograms recorded of the implanted eye (A) and fellow eye (B) of dog 1.
Table 1.
 
Amplitudes and Latencies of Electroretinograms of 3 Dogs
Table 1.
 
Amplitudes and Latencies of Electroretinograms of 3 Dogs
Dog Left Eye (operated) Right Eye (unoperated)
a-Wave b-Wave a-Wave b-Wave
Amp (μV) Latency (ms) Amp (μV) Latency (ms) Amp (μV) Latency (ms) Amp (μV) Latency (ms)
1 170 44.7 264 56.7 144 45.0 225 57.6
2 233 45.0 383 69.3 270 46.5 484 70.5
3 118 45.0 244 73.8 82.7 45.3 215 71.1
Functional Testing of STS System
The voltage in the microelectronic circuit of the extraocular stimulator was less than the saturation voltage in all electrodes and in all cases throughout the observation period (data not shown). Representative stimulus artifact waveforms recorded with a contact lens electrode are shown in Figure 5. All the electrodes could deliver the electric currents (Figs. 5A, 5B). Pattern stimulation could also be performed as shown in Figures 5C to 5F. The amplitude of the artifacts was altered by the current intensity (Figs. 5E, 5F). 
Figure 5.
 
Three months after implantation. Representative waveforms of the stimulus artifacts of dog 3. Drawing of the stimulus pattern of electrodes (A) and waveforms of artifacts derived from each of nine electrodes (electrodes 1–9) sequentially. Nine waves are shown (B). Drawing of stimulus pattern (C) and waveforms of artifacts derived from three electrodes (electrodes 1, 4, 7). Three waves can be seen (D). Drawing of stimulus pattern (E) and waveforms of artifacts derived from nine electrodes with different electric current intensity (electrodes 1 [1 mA], 2 [0.9 mA], 3 [0.8 mA], 9 [0.2 mA]). Amplitudes of artifacts increase with increasing current intensity (F).
Figure 5.
 
Three months after implantation. Representative waveforms of the stimulus artifacts of dog 3. Drawing of the stimulus pattern of electrodes (A) and waveforms of artifacts derived from each of nine electrodes (electrodes 1–9) sequentially. Nine waves are shown (B). Drawing of stimulus pattern (C) and waveforms of artifacts derived from three electrodes (electrodes 1, 4, 7). Three waves can be seen (D). Drawing of stimulus pattern (E) and waveforms of artifacts derived from nine electrodes with different electric current intensity (electrodes 1 [1 mA], 2 [0.9 mA], 3 [0.8 mA], 9 [0.2 mA]). Amplitudes of artifacts increase with increasing current intensity (F).
Histologic Analyses
Sections from two implanted and control eyes showed no obvious changes in the structure of the retina and the choroid beneath the electrode array in dogs 1 and 3 (Figs. 6A, 6C). Although the notch of the electrode array was not visible in dog 1, the electrode array was completely inserted in the scleral pocket (Fig. 6A). On the other hand, pathologic changes were detected in the retina of dog 2. Although the changes were limited to the edge of the array, the retinal and choroidal architecture was destroyed because of the mechanical pressure of the array (Figs. 6B, 6D; black arrowheads). However, there was no obvious damage at other regions of the retina beneath the array (Figs. 6B, 6D; black arrows). 
Figure 6.
 
Light microscopic photographs of the retina and sclera of the implanted eyes. (A, C) Photographs of the retina and sclera around the electrode array of dog 1. There is no obvious change in the structure of the retina and the choroid around the array. Magnifications: (A) ×40; (C) ×400. (B, D) Photographs of the retina and sclera around the array of dog 2. Local damage to the retina and choroid at the site of the implanted electrode array can be seen (arrowheads); however, other areas of the retina on the array are intact (arrows). Magnifications: (B) ×40; (D) ×400. Scale bars: (A, B) ×500 μm; (C, D) 100 μm. (asterisk) Edge of the array distal to the cable.
Figure 6.
 
Light microscopic photographs of the retina and sclera of the implanted eyes. (A, C) Photographs of the retina and sclera around the electrode array of dog 1. There is no obvious change in the structure of the retina and the choroid around the array. Magnifications: (A) ×40; (C) ×400. (B, D) Photographs of the retina and sclera around the array of dog 2. Local damage to the retina and choroid at the site of the implanted electrode array can be seen (arrowheads); however, other areas of the retina on the array are intact (arrows). Magnifications: (B) ×40; (D) ×400. Scale bars: (A, B) ×500 μm; (C, D) 100 μm. (asterisk) Edge of the array distal to the cable.
Discussion
Our results showed that it is possible to implant our STS device into the deep lamellar scleral space of beagle dogs without intraoperative or postoperative complications and that the system was biocompatible with the tissue and remained stable for 3 months. This is the first report of successful implantation of an STS device consisting of electrodes and an extraocular microstimulator and demonstrates that this device operated normally for the 3-month experimental period. 
Feasibility of Implanting STS System Device
The surgery was successful in all cases and led to stable placement of the prosthesis over the 3-month period. Although the device was designed to be implanted into humans, the shapes of the microstimulator and the electrodes fit the anatomy and tissues of the dog very well. It was not difficult to pass the electrodes from the head region to the eye, though our internal device was divided into electrodes and extraocular microstimulator because we used a customized trocar similar to that used by Gekkeler et al. 24 and Besch et al. 29 The electrodes and cables were first enclosed in a silicone cover and passed through the trocar to the surface of the eye. The length of the cable was sufficient, and its flexibility was good for the implantation surgery. 
In one animal, the retina at the edge of the electrode array distal to the cable was histologically degenerated, though this degeneration did not spread. Because the scleral incision was made only to the surface of the outer choroid, the local circulation of the choroid at the edge of the array might have been damaged. This taught us that it is critical to control the depth of the scleral pocket to avoid retinal and choroidal damage. 
Biocompatibility and Stability of STS Device
No major undesirable reactions such as cellular proliferation, inflammation, or retention of subretinal fluid in the retina beneath the electrode array occurred during the experimental period. These results are similar to our findings in rabbits. 38,39 ERG studies showed no significant decline of retinal function compared with the electroretinograms in the control eyes, indicating good biocompatibility of the implanted STS system in dogs. 
We also checked whether the voltage in the circuit in the microstimulator was greater than the saturation voltage to examine the stability of the STS device. Although the voltage evoked by each of the nine electrodes was less than the saturation voltage, we could not measure the actual voltage from nine electrodes because of the recording system. Therefore, we could not detect any significant difference in the amplitude of the voltage among these electrodes to check which electrode made good contact with the tissue or whether it was damaged. 
We recorded the artifacts evoked by electrical pulses and considered these electrical changes as an indication of the function of an STS system, as did Yamauchi et al., 45 because it was difficult to record the electrical-evoked potentials on the surface of the visual area of the brain. These results indicated good stability of the STS system device after implantation. 
Comparison with Other Retinal Prostheses
It has still not been determined which approach—epiretinal, subretinal, optic nerve, or suprachoroidal—will provide the best functional outcomes. To avoid the invasive surgery required to implant the epiretinal, subretinal, and optic nerve electrodes, we chose the suprachoroidal position for the electrode array. Subretinal implantation requires more complex surgery and requires a transscleral approach. With this method, the electrode array would have to pass through the choroid to the subretinal space, and it is possible that this would result in ocular complications such as retinal detachments, choroidal hemorrhages, and endophthalmitis. The epiretinal prosthesis is not difficult to place on the retina; however, the epiretinal implants and cables must pass through the pars plana and vitreous and be placed directly on the retina. Therefore, vitreous hemorrhage, retinal detachment, endophthalmitis, and retinal damage can develop. The optic nerve prosthesis requires complex surgery because it is necessary to insert the electrodes into the optic nerve, and the number of electrodes is limited by the size of the orbital space. 
On the other hand, the surgical technique for implantation of the STS system is relatively simple and is less invasive because the electrode array is implanted into the deep lamellar scleral space away from the retina. In addition, the surgical difficulties of removing or replacing the electrodes are less traumatic than those necessary for the other types of prostheses. However, the estimated spatial resolution for the STS prosthesis is approximately 1° of visual angle, 36 which is not as good as that of subretinal stimulation or epiretinal stimulation. 38,39  
Although the threshold current by STS is slightly higher than that for the other types of prostheses, 41 the current is within the safe limits for long-term stimulation. 27 In addition, Shivdasani et al. 46 suggested that it was possible to reduce voltage requirements for the STS system by selecting the proper electrical parameters. 
STS Device
Our electrode array had 49 potential electrodes, but only nine were active in this study. We are developing a complete STS device with 49 active electrodes. We plan to implant this STS device into animals and to observe the animals for a longer period. 
Conclusion
In conclusion, the aim of this study was to determine the feasibility of implanting our STS system into animals with larger eyes and to determine compatibility and stability over a 3-month period. We successfully implanted a newly developed STS prosthesis in the deep lamellar scleral space of beagle dogs. The implanted STS prosthesis was biocompatible and remained stable for at least 3 months. Further investigations are needed to rule out any influence of chronic electrical stimulation provided by this STS system on its biocompatibility and stability for a longer term follow-up. 
Footnotes
 Supported by Health Sciences Research Grants (H19-sensory-001) from the Ministry of Health, Labor and Welfare and by the Strategic Research Program for Brain Sciences from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Footnotes
 Disclosure: T. Morimoto, None; M. Kamei, None; K. Nishida, None; H. Sakaguchi, None; H. Kanda, None; Y. Ikuno, None; H. Kishima, None; T. Maruo, None; K. Konoma, Nidek Co., Ltd. (E); M. Ozawa, Nidek Co., Ltd. (E); K. Nishida, None; T. Fujikado, None
The authors thank their project partners Kouji Oosawa, Eiji Yonezawa, Yasuo Terasawa, and Tohru Saitoh (Vision Institution, Nidek Co., Ltd.) for their help. 
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Figure 1.
 
Photographs of the STS system. (A) Internal part of the STS system. The STS electrode array (B), the return electrode (C), and the extraocular microelectronic stimulator. The electrode array measured 6 mm × 6 mm × 0.5 mm with 49 platinum electrodes in a 7 × 7 arrangement that was fixed in a clear silicone rubber platform coated with polymer. Each electrode is 0.5 mm in diameter and 0.5 mm in length. The distance between the centers of the electrodes is 0.75 mm. Nine of these 49 electrodes were active. The return platinum electrode was 0.5 mm in diameter and 6.5 mm in length (C). The stimulator had microelectronics that received the signals from an external transmitter by electromagnetic induction (A). (D) Extracorporeal part of the STS system device. The system consisted of a transmitter, a processor, and a personal computer (PC). The stimulus sets were programmed using technical computing software on a PC that sent the stimulus parameters to the processor (D, gray arrowhead). The signals and power information were then passed through the transmitter (D, E, black arrowhead) to the microstimulator (E). Scale bars: 1.0 cm (A); 3.0 mm (B); 3.0 mm (C); 1.5 cm (E).
Figure 1.
 
Photographs of the STS system. (A) Internal part of the STS system. The STS electrode array (B), the return electrode (C), and the extraocular microelectronic stimulator. The electrode array measured 6 mm × 6 mm × 0.5 mm with 49 platinum electrodes in a 7 × 7 arrangement that was fixed in a clear silicone rubber platform coated with polymer. Each electrode is 0.5 mm in diameter and 0.5 mm in length. The distance between the centers of the electrodes is 0.75 mm. Nine of these 49 electrodes were active. The return platinum electrode was 0.5 mm in diameter and 6.5 mm in length (C). The stimulator had microelectronics that received the signals from an external transmitter by electromagnetic induction (A). (D) Extracorporeal part of the STS system device. The system consisted of a transmitter, a processor, and a personal computer (PC). The stimulus sets were programmed using technical computing software on a PC that sent the stimulus parameters to the processor (D, gray arrowhead). The signals and power information were then passed through the transmitter (D, E, black arrowhead) to the microstimulator (E). Scale bars: 1.0 cm (A); 3.0 mm (B); 3.0 mm (C); 1.5 cm (E).
Figure 2.
 
Photographs taken during implantation surgery and 1 month after implantation. (A) Microelectrode array and return electrode are combined into one bundle and covered with silicone rubber tubing. (B) Customized trocar and electrodes. (C) Creation of a scleral pocket. (D) Electrodes and cables are passed under an extraocular muscle. (E) Cable is sutured to the sclera. (F) Insertion of a return electrode. (G) An electrode array was inserted into the scleral pocket, and the cable was sutured to the sclera. (H) Return electrode inserted intravitreally and sutured to the sclera. (I) Extraocular microstimulator implanted on the surface of the left temporal muscle. (J) Frontal view of dog 1 month after implantation. The position of the eye is orthophoric. (K) Temporal view of dog 1 month after implantation. All wounds have healed properly, and no sign of infections or wound dehiscence can be seen. The position of the extraocular stimulator was surrounded with the white line. (L) An enucleated eye that has an electrode array implanted into the scleral pocket.
Figure 2.
 
Photographs taken during implantation surgery and 1 month after implantation. (A) Microelectrode array and return electrode are combined into one bundle and covered with silicone rubber tubing. (B) Customized trocar and electrodes. (C) Creation of a scleral pocket. (D) Electrodes and cables are passed under an extraocular muscle. (E) Cable is sutured to the sclera. (F) Insertion of a return electrode. (G) An electrode array was inserted into the scleral pocket, and the cable was sutured to the sclera. (H) Return electrode inserted intravitreally and sutured to the sclera. (I) Extraocular microstimulator implanted on the surface of the left temporal muscle. (J) Frontal view of dog 1 month after implantation. The position of the eye is orthophoric. (K) Temporal view of dog 1 month after implantation. All wounds have healed properly, and no sign of infections or wound dehiscence can be seen. The position of the extraocular stimulator was surrounded with the white line. (L) An enucleated eye that has an electrode array implanted into the scleral pocket.
Figure 3.
 
Fundus photographs and fluorescein angiograms 1 month and 3 months after implantation in three dogs. (AD) The retina appears normal, with no evidence of the STS electrode array implanted in dog 1. (A, C) One month after implantation. (B, D) Three months after implantation. (EH) Photographs of dog 3. Although the notch of the electrode array can be seen (black arrowheads), there are no significant changes such as inflammation, retinal obstruction, and vascular damage throughout the observation period. (EG) One month after implantation. (FH) Three months after implantation. (IL) Photographs of dog 2. Although pigmentation of the retina can be seen at the implantation site (white arrowheads), there is no severe retinal damage around the array. (I, K) One month after implantation. (J, L) Three months after implantation.
Figure 3.
 
Fundus photographs and fluorescein angiograms 1 month and 3 months after implantation in three dogs. (AD) The retina appears normal, with no evidence of the STS electrode array implanted in dog 1. (A, C) One month after implantation. (B, D) Three months after implantation. (EH) Photographs of dog 3. Although the notch of the electrode array can be seen (black arrowheads), there are no significant changes such as inflammation, retinal obstruction, and vascular damage throughout the observation period. (EG) One month after implantation. (FH) Three months after implantation. (IL) Photographs of dog 2. Although pigmentation of the retina can be seen at the implantation site (white arrowheads), there is no severe retinal damage around the array. (I, K) One month after implantation. (J, L) Three months after implantation.
Figure 4.
 
Three months after implantation. Representative electroretinograms recorded of the implanted eye (A) and fellow eye (B) of dog 1.
Figure 4.
 
Three months after implantation. Representative electroretinograms recorded of the implanted eye (A) and fellow eye (B) of dog 1.
Figure 5.
 
Three months after implantation. Representative waveforms of the stimulus artifacts of dog 3. Drawing of the stimulus pattern of electrodes (A) and waveforms of artifacts derived from each of nine electrodes (electrodes 1–9) sequentially. Nine waves are shown (B). Drawing of stimulus pattern (C) and waveforms of artifacts derived from three electrodes (electrodes 1, 4, 7). Three waves can be seen (D). Drawing of stimulus pattern (E) and waveforms of artifacts derived from nine electrodes with different electric current intensity (electrodes 1 [1 mA], 2 [0.9 mA], 3 [0.8 mA], 9 [0.2 mA]). Amplitudes of artifacts increase with increasing current intensity (F).
Figure 5.
 
Three months after implantation. Representative waveforms of the stimulus artifacts of dog 3. Drawing of the stimulus pattern of electrodes (A) and waveforms of artifacts derived from each of nine electrodes (electrodes 1–9) sequentially. Nine waves are shown (B). Drawing of stimulus pattern (C) and waveforms of artifacts derived from three electrodes (electrodes 1, 4, 7). Three waves can be seen (D). Drawing of stimulus pattern (E) and waveforms of artifacts derived from nine electrodes with different electric current intensity (electrodes 1 [1 mA], 2 [0.9 mA], 3 [0.8 mA], 9 [0.2 mA]). Amplitudes of artifacts increase with increasing current intensity (F).
Figure 6.
 
Light microscopic photographs of the retina and sclera of the implanted eyes. (A, C) Photographs of the retina and sclera around the electrode array of dog 1. There is no obvious change in the structure of the retina and the choroid around the array. Magnifications: (A) ×40; (C) ×400. (B, D) Photographs of the retina and sclera around the array of dog 2. Local damage to the retina and choroid at the site of the implanted electrode array can be seen (arrowheads); however, other areas of the retina on the array are intact (arrows). Magnifications: (B) ×40; (D) ×400. Scale bars: (A, B) ×500 μm; (C, D) 100 μm. (asterisk) Edge of the array distal to the cable.
Figure 6.
 
Light microscopic photographs of the retina and sclera of the implanted eyes. (A, C) Photographs of the retina and sclera around the electrode array of dog 1. There is no obvious change in the structure of the retina and the choroid around the array. Magnifications: (A) ×40; (C) ×400. (B, D) Photographs of the retina and sclera around the array of dog 2. Local damage to the retina and choroid at the site of the implanted electrode array can be seen (arrowheads); however, other areas of the retina on the array are intact (arrows). Magnifications: (B) ×40; (D) ×400. Scale bars: (A, B) ×500 μm; (C, D) 100 μm. (asterisk) Edge of the array distal to the cable.
Table 1.
 
Amplitudes and Latencies of Electroretinograms of 3 Dogs
Table 1.
 
Amplitudes and Latencies of Electroretinograms of 3 Dogs
Dog Left Eye (operated) Right Eye (unoperated)
a-Wave b-Wave a-Wave b-Wave
Amp (μV) Latency (ms) Amp (μV) Latency (ms) Amp (μV) Latency (ms) Amp (μV) Latency (ms)
1 170 44.7 264 56.7 144 45.0 225 57.6
2 233 45.0 383 69.3 270 46.5 484 70.5
3 118 45.0 244 73.8 82.7 45.3 215 71.1
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