Feasibility of 2nd generation STS retinal prosthesis in dogs.

We developed a 2(nd) generation suprachoroidal transretinal stimulation (STS) system with a 49 channel electrode array and implanted in 2 dogs. One month after surgery, all electrodes were functioning and the ocular fundus was normal in both dogs. The results indicate the 2(nd) generation STS retinal prosthesis is feasible and can be considered for clinical use.

Optical imaging of retina in response to grating stimuli in cats.

We examined the intrinsic signals in response to grating stimuli in order to determine whether the light-evoked intrinsic signals of the retina are due to changes in the photoreceptor activities induced by the image projected on to the retina or are due to neural activities of the inner retina. The retinas of the left eye of 12 cats under general anesthesia were examined by a functional imaging fundus camera. Near infrared light was used to monitor the reflectance changes (RCs) of the retina. Vertical grating were used to stimulate the retina at 4 Hz. The spatial frequencies of the gratings were 0.05, 0.11, 0.22, 0.43, 0.86, 1.73, and 3.46 cycles/degree (cpd). Ten images were averaged and used to analyze the RCs to obtain the peak value (PV) of a two dimensional fast Fourier transfer of the RCs. The wavefront aberrations (WA) were measured with a compact wavefront aberrometer and the spatial modulation transfer function (MTF) of the eye was calculated. The retinal reflectance image had a grating pattern. The PV of the spatial sensitivity curve was highest at low spatial frequencies (0.05 and 0.11 cpd), and the sensitivity decreased steeply with an increase in the spatial frequency. RCs were not detectable at 3.46 cpd. The MTF decreased gradually with increases in the spatial frequencies and was 0.68 at 3.46 cpd. The reflectance pattern of the retinal intrinsic signal elicited by grating stimuli of different spatial frequencies was different from that of the MTF. This suggests that the intrinsic signal represents not only the response of the photoreceptors but also other neuronal or vascular changes in the retina.

CMOS-based smart-electrode-type retinal stimulator with bullet-shaped bulk Pt electrodes.

A CMOS-based flexible retinal stimulator equipped with bullet-shaped bulk Pt electrodes was fabricated and demonstrated. We designed a new CMOS unit chip with an on-chip stimulator, single- and multi-site stimulation modes, and monitoring functions. We have developed a new structure and packaging process of flexible retinal stimulator with bullet-type bulk Pt electrode. We have confirmed the retinal stimulation functionality in an in vivo stimulation trial on rabbit's retina.

A CMOS-based multichip flexible retinal stimulator for simultaneous multi-site stimulation.

We developed a novel CMOS-based multichip flexible neural stimulator with on-chip stimulation generator. It enables simultaneous multi-site stimulation. We also propose a new type of multi-chip retinal stimulator with single electrode / unit chip configuration. We successfully performed simultaneous multi-site stimulation in an in vivo retinal stimulation experiment using a rabbit.

Development and in vivo Demonstration of CMOS-Based Multichip Retinal Stimulator With Simultaneous Multisite Stimulation Capability.

A complementary metal-oxide semiconductor (CMOS)-based multichip flexible neural stimulator for retinal prostheses was developed. The multichip retinal stimulator is capable of simultaneous multisite stimulation. An on-chip stimulation generator was implemented on the "unit chip," which is the core device of the multichip retinal stimulator. The performance of the CMOS circuitry was characterized. A new device structure and packaging process was developed. The in vivo retinal stimulation on a rabbit's retina was successfully performed and the multisite stimulation functionality was confirmed.

Light-controlled retinal stimulation on rabbit using CMOS-based flexible multi-chip stimulator.

We implemented a light-sensing function on CMOS-based multi-chip stimulator for retinal prosthesis. Using the light-sensing circuitry attached to each stimulation electrode, the flexible multi-chip stimulator is capable of image-based patterned stimulation. We verified the function of the light-controlled decision based on the light intensity measured just beside the stimulation site. We also experimentally demonstrated in vivo retinal stimulation on rabbit's retina with light-controlled decision. The result of the present work is a simplified demonstration for the concept of retinal prosthesis with on-site imaging.

Comprehensive gene-expression profile in murine oxygen-induced retinopathy.

BACKGROUND/AIMS: To investigate the correlation between the clinical course and gene-expression pattern in murine oxygen-induced retinopathy (OIR), a commonly used model of retinopathy of prematurity (ROP). METHODS: OIR was induced in C57BL/6N mice by placing postnatal day 7 (P7) pups in 75% oxygen for 5 days. The clinical course of the OIR was evaluated on retinal flat-mounts after fluorescein isothiocyanate-conjugated dextran perfusion from P12 to P21. The expression values of 94 genes, selected by microarray analyses, were determined daily from P12 through P21 by RT-PCR with TaqMan low-density array (TLDA) and analysed by hierarchical clustering. RESULTS: TLDA cluster analyses showed a homology of gene-expression pattern between P12 and P13 and between P16 and P17. Many genes associated with inflammation were upregulated on P12 and P13 when the degree of both central avascular area and central vasoconstriction were maximal, and the upregulation of the genes continued to P21. At P16 and P17 when extraretinal neovascularisation became most noticeable, several genes associated with angiogenesis, for example, vascular endothelial growth factor-A and angiopoietin-2, were most upregulated. CONCLUSION: The gene-expression pattern was well correlated with the clinical appearance in murine OIR. These findings should contribute to the understanding of the pathological conditions in ROP.

Efficacy of intravitreal injection of bevacizumab for severe retinopathy of prematurity: a pilot study.

AIM: The aim of the study was to evaluate the short-term efficacy of intravitreal injections of bevacizumab for severe retinopathy of prematurity (ROP). METHODS: A retrospective chart review was conducted of 23 consecutive eyes (stage 3, three eyes; 4A, 18 eyes; 4B, two eyes) of 14 patients with vascularly active ROP considered at high risk for progression or development of tractional retinal detachment despite conventional laser ablation therapy. Patients received an intravitreal injection of bevacizumab (0.5 mg), either as the initial treatment (15 eyes) or at the end of vitrectomy (eight eyes). RESULTS: After injection of bevacizumab as the initial treatment, reduced neovascular activity was seen on fluorescein angiography in 14 of 15 eyes. In three eyes, a tractional retinal detachment developed or progressed after bevacizumab injection. No other ocular or systemic adverse effects were identified. Vitrectomy was performed in 20 eyes and the retina was reattached after one surgery in 18 eyes. Multiple surgeries were necessary in two eyes, resulting in retinal reattachment. CONCLUSION: There results suggest that intravitreal injection of bevacizumab seems to be associated with reduced neovascularisation without apparent ocular or systemic adverse effects, and is thus beneficial for treating severe ROP that is refractory to conventional laser therapy.

Multi-finger structure and pulsed-powering operation scheme for CMOS LSI-based flexible stimulator for retinal prosthesis.

Multi-finger structure was proposed to improve flexibility of the CMOS LSI-based multi-chip retinal stimulator. A dual-finger retinal stimulator was fabricated and its functionality was demonstrated in retinal stimulation experiments on rabbit's retina, We also proposed an idea of pulsed-powering operation scheme for the multi-chip flexible retinal stimulator. We compared the pulsed-powering scheme with conventional one in a simulation, and show that the pulsed-powering can be an alternative operation scheme for the neural stimulator that provides an improved safety to the biological tissue.

In vivo stimulation on rabbit retina using CMOS LSI-based multi-chip flexible stimulator for retinal prosthesis.

We have performed in vivo electric stimulation experiments on rabbit retina to demonstrate feasibility of CMOS LSI-based multi-chip flexible neural stimulator for retinal prosthesis. We have developed new packaging structure with an improved flexibility and device control system which totally controls the LSI-based multi-chip stimulator, counter electrode, and stimulation generator. We have implanted the fabricated multi-chip stimulator into sclera pocket for STS (Suprachoroidal Transretinal Stimulation) configuration. We successfully obtained EEP (Electrically Evoked Potential) on visual cortex evoked by the multi-chip stimulator.

Laboratory investigation of microelectronics-based stimulators for large-scale suprachoroidal transretinal stimulation (STS).

This paper describes the technological developments underlying the realization of a reliable and reproducible microchip-based stimulator with a large number of stimulus electrodes. A microchip-based stimulator with over 500 electrodes for suprachoroidal transretinal stimulation (STS) is proposed in this paper, and an example is presented. To enhance reliability and reproducibility for such a large array, we introduce a flip-chip bonding technique and place microchips on the reverse side of a substrate. A square microchip of size 600 microm was fabricated using 0.35 microm standard CMOS process technology. Twelve microchips were flip-chip bonded on a polyimide substrate through Au bumps. To evaluate the feasibility of the proposed device, we successfully fabricated a stimulator with 12 microchips and 118 electrodes made of Pt/Au bumps, and demonstrated their operation in a saline solution for 2 weeks. Also, to evaluate the device operation in vivo, a stimulator with one active IrO(x) electrode was implanted into the scleral pocket of a rabbit and electrical evoked potential (EEP) signals with a threshold of 100 microA were obtained. We also fabricated a simulator with 64 microchips that has 576 electrodes (9 electrodes in a microchip times 64 microchips).

Comparison of three techniques of foveal translocation in patients with subfoveal choroidal neovascularization resulting from age-related macular degeneration.

PURPOSE: To report the results of three methods of foveal translocation in the presence of subfoveal choroidal neovascular membrane resulting from age-related macular degeneration. METHODS: We treated 51 eyes of 51 consecutive patients with subfoveal choroidal neovascular membranes resulting from age-related macular degeneration with one of three techniques of foveal translocation surgery: foveal translocation with partial retinotomy (n = 6), limited translocation (n = 9), and translocation with 360-degree retinotomy (n = 36). All patients were followed for at least 6 months postoperatively. The size of the choroidal neovascular membrane and the amount of foveal displacement, the best-corrected visual acuity, and complications were recorded preoperatively and postoperatively. RESULTS: The mean distance of the foveal translocation was greater in the 360-degree retinotomy group (3340 microm) than in the partial retinotomy (1060 microm, P <.001) and the limited translocation groups (1120 microm, P <.001). A final visual acuity of 20/200 or better was achieved in two eyes (33%) in the partial retinotomy group, seven eyes (78%) in the limited translocation group, and 23 eyes (64%) in the 360-degree retinotomy group. The final visual acuity improved by 0.2 logarithm of minimal angle of resolution (logMAR) unit or more in one eye (17%), one eye (11%), and seven eyes (19%), respectively. The final visual acuity was maintained within 1 line in zero eyes, five eyes (56%), and 19 eyes (53%), respectively. A retinal detachment developed postoperatively in five eyes (83%), zero eyes (0%), and 15 eyes (42%), respectively. CONCLUSIONS: A significant number of patients improved or maintained best-corrected visual acuity after translocation with 360-degree retinotomy, and limited translocation, whereas translocation with 360-degree retinotomy is suitable for larger choroidal neovascular membranes because it resulted in the greatest foveal displacement among the three translocation procedures.

Evaluation of the peripheral visual field after foveal translocation.

PURPOSE: To evaluate the peripheral visual field after foveal translocation with scleral imbrication or 360-degree retinotomy. METHODS: Retrospective, single-center, nonrandomized study. We calculated the rate of preservation of the peripheral visual field using Goldmann perimetry by dividing the width of the postoperative V-4 isopter by the preoperative width and expressing the result as a percentage. RESULTS: In nine eyes that underwent scleral imbrication, the rate of preservation was 100.0% superiorly, 102.6% superotemporally, 99.9% temporally, 97.9% inferotemporally, 96.9% inferiorly, 82.3% inferonasally, 93.7% nasally, and 87.3% superonasally. In 33 eyes that underwent 360-degree retinotomy, it was 89.1%, 87.0%, 81.9%, 78.1%, 86.6%, 90.0%, 89.9%, and 86.8%, respectively. CONCLUSION: After foveal translocation with scleral imbrication, the peripheral visual field was preserved except for slight narrowing nasally; 360-degree retinotomy resulted in preservation of the visual field, except for slight narrowing in all meridians.

Topographic analysis of astigmatism induced by scleral shortening in pig eyes.

BACKGROUND: Corneal astigmatism is a severe postoperative problem in foveal translocation surgery. We evaluated the corneal astigmatism induced by scleral shortening in pig eyes in vitro. METHODS: We created three sizes of scleral shortening in pig eyes and examined the preoperative and postoperative corneal astigmatism. The three sizes of scleral shortening were; 6 mm x 12 mm, 9 mm x 12 mm, and 6 mm x 16 mm (radial x circumferential). The shortenings were created 11 mm from the limbus with 10 eyes in each group. Videokeratographic measurements were performed using the CAS System 2000, preoperatively and postoperatively, and the astigmatism caused by the scleral shortening was evaluated. RESULTS: The surgically-induced astigmatism was 2.1 +/- 1.2 diopters (D) in the 6 mm x 12 mm group, 5.2+/-1.5 D in the 9 mm x 12 mm group, and 3.7+/-1.0 D in the 6 mm x 16 mm group. Corneal astigmatism caused by scleral shortening depended on both the radial and circumferential shortening. Pre- and postoperative topographic corneal maps showed an irregular astigmatism pattern (lazy bowtie pattern). Because the central zone of the cornea showed a relatively regular astigmatism, the corneal astigmatism induced by scleral shortening did not affect the predicted corneal acuity. CONCLUSIONS: In foveal translocation surgery with scleral shortening, an excessive scleral resection in the radial direction can cause clinically intolerable regular and irregular astigmatism. Minimal scleral shortening that will satisfy the required translocated distance is recommended to reduce the risk/benefit ratio.

Basic fibroblast growth factor inhibits choriocapillaris atrophy in rabbit.

PURPOSE: To examine the effect of basic fibroblast growth factor on induced choriocapillaris atrophy in vivo. METHODS: Choriocapillaris atrophy was surgically induced in rabbits by a hydraulic retinal detachment followed by debridement of the retinal pigment epithelium under the detached retina. Three concentrations of basic fibroblast growth factor (0.1 microg/0.1 ml, 1 microg/0.1 ml, or 5 microg/0.1 ml) were injected into the subretinal space and into the vitreous cavity 1, 3, and 5 days after the surgery. For control, only Tris buffer was injected in the same manner. The rabbits were euthanized 7 days after the surgery. Choroidal vascular casts were made and examined by scanning electron microscopy. The choriocapillaris atrophy was quantified by computer-assisted image analysis of photographs of the choriocapillaries. The area of the choriocapillaris and number of intercapillary spaces in the choriocapillaris that corresponded to the density of the capillary network were measured. RESULTS: The average area of the choriocapillaris in the eyes treated with 1 microg/0.1 ml of basic fibroblast growth factor was significantly larger at 75.1 +/- 3.0% than that in the control eyes at 67.2 +/- 5.6% (P =.021). The average area of the choriocapillaris in the 0.1 microg/0.1 ml of basic fibroblast growth factor group was not statistically different from the control. The number of intercapillary spaces of the choriocapillaris was 132 +/- 12 in the 0.1 microg/0.1 ml of basic fibroblast growth factor group, 124 +/- 46 in the 1 microg/0.1 ml of basic fibroblast growth factor group, and 75 +/- 14 in the control group. The higher number of spaces in the treated group was statistically significant (P =.026). CONCLUSIONS: Basic fibroblast growth factor decreased the atrophy of the choriocapillaris after removal of the retinal pigment epithelium in rabbit eyes. These results suggest that basic fibroblast growth factor may play a role in the survival of the choriocapillaris in vivo.

Effect of Ca(2+)-free and Mg(2+)-free BSS Plus solution on the retinal pigment epithelium and retina in rabbits.

PURPOSE: To determine whether intravitreal irrigation with Ca(2+)-free and Mg(2+)-free BSS Plus (Alcon Laboratory, Fort Worth, Texas) solution alters the adhesiveness between the retinal pigment epithelium and the retina of rabbits. METHODS: Thirty-four eyes of 34 Dutch pigmented rabbits underwent lensectomy and vitrectomy. Subsequently, the vitreous cavity of 24 eyes was irrigated with Ca(2+)-free and Mg(2+)-free BSS Plus solution for 10 or 20 minutes. The other 10 eyes were irrigated with BSS Plus solution for 20 minutes as controls. To determine the adhesiveness between the retinal pigment epithelium and retina, a retinal detachment was produced in 12 of the 34 eyes. The apical surface of the retinal pigment epithelium and the photoreceptor outer segments were examined by scanning electron microscopy. Retinal physiology was assessed by electroretinography and retinal morphology by light microscopy. RESULTS: After retinal detachment was produced, the number of cone sheaths on the apical surface of the retinal pigment epithelium after irrigation with Ca(2+)-free and Mg(2+)-free BSS Plus solution for 20 minutes (33 +/- 15, mean +/- SD) was significantly less than the number of cone sheaths on the apical surface of the retinal pigment epithelium of eyes after irrigation with BSS Plus solution for 20 minutes (120 +/- 50) or the number of cone sheaths on the apical surface of the retinal pigment epithelium of eyes after 10 minutes of irrigation with Ca(2+)-free and Mg(2+)-free BSS Plus solution (115 +/- 49; P =.02). The b-wave amplitudes in the eyes irrigated with Ca(2+)-free and Mg(2+)-free BSS Plus solution for 20 minutes were depressed compared with the b-waves in eyes irrigated with BSS Plus solution for 20 minutes on the first postoperative day (P =.03). After the third postoperative day, there was no significant difference in the b-waves (P >.06). Light microscopy demonstrated no morphologic abnormalities after the use of both solutions. CONCLUSIONS: Intravitreal irrigation with Ca(2+)-free and Mg(2+)-free BSS Plus solution for 20 minutes altered the adhesion between the retinal pigment epithelium microvilli and retinal outer segments and made the creation of retinal detachment less traumatic. These results suggest that Ca(2+)-free and Mg(2+)-free BSS Plus solution may be of clinical value for the creation of an intentional retinal detachment for foveal translocation surgery.

Effect of a nitric oxide synthase inhibitor on lens-induced myopia.

PURPOSE: It has still not been determined whether the retinal mechanism causing form-deprivation myopia (FDM) is different from that causing lens-induced myopia (LIM). We previously reported that FDM was blocked by an intravitreal injection of the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). In this study, we investigated the effect of L-NAME on LIM in chicks. METHOD: The left eyes of 6-day-old chicks were injected with 30 microl of nontoxic concentrations of L-NAME (< or = 360 mM) or saline. The right eyes were injected with 30 microl of saline. A -16 dpt lens was placed in front of the left eye for 6 days. Another group of 6 chicks were injected with 180 mM L-NAME (left eye) and with saline (right eye) before placing -16 dpt lenses in front of both eyes. After removing the lens, the refraction and the axial length were measured. The effect of L-NAME (180 mM) on the retina of a separate group of chicks was examined by electroretinography 60 min after an intravitreal injection in non-LIM-treated eyes. RESULTS: The eyes of chicks that were injected with 180 or 360 mM L-NAME were less myopic and had significantly shorter axial lengths than control eyes. A significant decrease of the On response and an increase of the Off response were observed. CONCLUSION: The injection of L-NAME into developing chick eyes that were then covered with a -16 dpt lens resulted in a modifications of retinal function and an inhibition of the development of myopia. These results, combined with the earlier findings, suggest that NO modulates a common retinal pathway that leads to both LIM and FDM.

Visual function after foveal translocation with 360-degree retinotomy and simultaneous torsional muscle surgery in patients with myopic neovascular maculopathy.

PURPOSE: To assess functional and anatomical outcomes after foveal translocation with 360-degree retinotomy and simultaneous torsional muscle surgery in patients with myopic neovascular maculopathy. METHODS: Foveal translocation with 360-degree retinotomy was performed in 11 eyes of 11 patients with myopic neovascular maculopathy. Ten eyes had simultaneous torsional muscle surgery with recession of the superior oblique muscle and tucking of the inferior oblique muscle. Silicone oil removal with or without intraocular lens implantation was performed 2 to 8 weeks after the primary procedure. Visual acuity, binocular function, and degree of cyclotorsion were assessed preoperatively and postoperatively. Angles of retinal and globe rotation, distance of foveal shift, and surgical complications were also investigated. RESULTS: With a mean postoperative follow-up of 6.2 months (range, 3 to 13 months), vision improved (greater than 0.2 logarithm of minimal angle of resolution [logMAR] units) in eight eyes, was unchanged in two eyes, and worsened (greater than 0.2 logMAR units) in 1 eye. Seven of 11 eyes (64%) had a final visual acuity of 20/50 or better. Five patients developed or maintained binocular fusion, four patients continued to have suppression, and two patients developed diplopia that was managed by spectacles with Fresnel prisms. Subjective cyclotorsion was less than 8 degrees in 10 eyes. Mean retinal and globe rotations were 23.4 degrees and 19.8 degrees, respectively. Average size of the choroidal neovascular membrane was 0.8 disk diameter, whereas the average distance of foveal shift was 1.5 disk diameter. After the primary procedure, three eyes developed retinal detachment, one eye macular hole, and one eye proliferative vitreoretinopathy. These complications were successfully managed by additional surgery. CONCLUSION: Foveal translocation with 360-degree retinotomy is effective in restoring vision in some patients with myopic neovascular maculopathy. Although the development of torsional diplopia is generally obviated by simultaneous extraocular muscle surgery, a relatively high incidence of surgical complications should be taken into account with this procedure.