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OBJECTIVE: The ocular vascular system plays an important role in preserving the visual function. Alterations in either anatomy or hemodynamics of the eye may have adverse effects on vision. Thus, an imaging approach that can monitor alterations of ocular blood flow of the deep eye vasculature ranging from capillary-level vessels to large supporting vessels would be advantageous for detection of early stage retinal and optic nerve diseases. METHODS: We propose a super-resolution ultrasound localization microscopy (ULM) technique that can assess both the microvessel and flow velocity of the deep eye with high resolution. Ultrafast plane wave imaging was acquired using an L22–14v linear array on a high frequency Verasonics Vantage system. A robust microbubble localization and tracking technique was applied to reconstruct ULM images. The experiment was first performed on pre-designed flow phantoms in vitro and then tested on a New Zealand white rabbit eye in vivo calibrated to various intraocular pressures (IOP) – 10 mmHg, 30 mmHg and 50 mmHg. RESULTS: We demonstrated that retinal/choroidal vessels, central retinal artery, posterior ciliary artery, and vortex vein were all visible at high resolution. In addition, reduction of vascular density and flow velocity were observed with elevated IOPs. CONCLUSION: These results indicate that super-resolution ULM is able to image the deep ocular tissue while maintaining high resolution that is comparable with optical coherence tomography angiography. SIGNIFICANCE: Capability to detect subtle changes of blood flow may be clinically important in detecting and monitoring eye diseases such as glaucoma.

Purpose Bioelectronic retinal prostheses that stimulate the remaining inner retinal neurons, bypassing degenerated photoreceptors, have been demonstrated to restore some vision in patients blinded by retinitis pigmentosa (RP). These implants encode luminance of the visual scene into electrical stimulation, however, leaving out chromatic information. Yet color plays an important role in visual processing when it comes to recognizing objects and orienting to the environment, especially at low spatial resolution as generated by current retinal prostheses. In this study, we tested the feasibility of partially restoring color perception in blind RP patients, with the aim to provide chromatic information as an extra visual cue. Design Case series. Participants Seven subjects blinded by advanced RP and monocularly fitted with an epiretinal prosthesis. Methods Frequency-modulated electrical stimulation of retina was tested. Phosphene brightness was controlled by amplitude tuning, and color perception was acquired using the Red, Yellow, Green, and Blue (RYGB) hue and saturation scaling model. Main Outcome Measures Brightness and color of the electrically elicited visual perception reported by the subjects. Results Within the tested parameter space, 5 of 7 subjects perceived chromatic colors along or nearby the blue-yellow axis in color space. Aggregate data obtained from 20 electrodes of the 5 subjects show that an increase of the stimulation frequency from 6 to 120 Hz shifted color perception toward blue/purple despite a significant inter-subject variation in the transition frequency. The correlation between frequency and blue-yellow perception exhibited a good level of consistency over time and spatially matched multi-color perception was possible with simultaneous stimulation of paired electrodes. No obvious correlation was found between blue sensations and array placement or status of visual impairment. Conclusions These findings present a strategy for the generation and control of color perception along the blue-yellow axis in blind patients with RP by electrically stimulating the retina. It could transform the current prosthetic vision landscape by leading in a new direction beyond the efforts to improve the visual acuity. This study also offers new insights into the response of our visual system to electrical stimuli in the photoreceptor-less retina that warrant further mechanistic investigation.

Purpose: To report the anatomical and functional outcomes of Argus II retinal prosthesis implantation in Korean patients. Methods: We included 5 consecutive patients with end-stage retinitis pigmentosa (RP) who underwent Argus II retinal prosthesis implantation and were followed for at least 12 months. The transcorneal electrical evoked response was utilized for patient selection. We used intraoperative optical coherence tomography (OCT) for optimal placement of the array and provided specialized vision rehabilitation training. A morphological evaluation using SD-OCT and a functional evaluation using computer-based visual function tests, a letter-reading ability test, and the Functional Low-Vision Observer Rated Assessment (FLORA) were conducted. Results: Postoperatively, the array was completely apposed to the retinal surface in all eyes, except for one eye which had a preexisting macular concavity. Fibrosis-like tissues of ≥50-μm thickness developed at the interface in 2 eyes. All of the patients showed improvement in computer-based visual function tests and could read ETDRS letters at a distance of 50 cm. Three patients could read Korean words. FLORA was improved in all patients, mainly in tasks of visual mobility, daily activities, and social interactions. Conclusions: Along with good anatomical outcomes and specialized rehabilitation practices, recipients of the Argus II implant showed profound improvements in functional vision and mobility.

Retinal prostheses aim at restoring partial sight to patients that are blind due to retinal degenerative diseases by electrically stimulating the surviving healthy retinal neurons. Ideally, the electrical stimulation of the retina is intended to induce localized, focused, percepts only; however, some epiretinal implant subjects have reported seeing elongated phosphenes in a single electrode stimulation due to the axonal activation of retinal ganglion cells (RGCs). This issue can be addressed by properly devising stimulation waveforms so that the possibility of inducing axonal activation of RGCs is minimized. While strategies to devise electrical stimulation waveforms to achieve a focal RGCs response have been reported in literature, the underlying mechanisms are not well understood. This article intends to address this gap; we developed morphologically and biophysically realistic computational models of two classified RGCs: D1-bistratified and A2-monostratified. Computational results suggest that the sodium channel band (SOCB) is less sensitive to modulations in stimulation parameters than the distal axon (DA), and DA stimulus threshold is less sensitive to physiological differences among RGCs. Therefore, over a range of RGCs distal axon diameters, short-pulse symmetric biphasic waveforms can enhance the stimulation threshold difference between the SOCB and the DA. Appropriately designed waveforms can avoid axonal activation of RGCs, implying a consequential reduction of undesired strikes in the visual field.

Traction exerted on the vitreous base during vitrectomy poses a risk for retinal tears. We aimed to quantify core vitreous traction during vitrectomy using spring return and pneumatic cutters. Juvenile porcine vitreous was vacuum held in a vitreous bath while traction was measured using precision force gauge during vitrectomy. The parameters included were aspiration rate, cut-rate, cutter size, and machine types. An empirical probabilistic model was developed. The traction was proportional to the aspiration rate but insignificantly dependent on the cut-rate. The traction probability was inversely proportional to the exponential function of the traction (p

The hydraulic conductivity of the vitreous humor has been measured for the bovine eye. The experiment was carried out by placing it within upright cylindrical chamber, open at both ends, and letting its liquid content drain out of the bottom opening by gravity, through a 20μm nylon mesh filter. Additional negative pressure was provided at the exit by a hanging drainage tube. The diminishing vitreous volume was measured in terms of the height in the chamber and recorded as a function of time. The reduction in the vitreous liquid content also caused the hydraulic conductivity to reduce and this parameter was quantified on the basis of previously-developed theories of fibrous porous media that have been very well established. A theoretical model with a fully analytical expression for the vitreous volume undergoing drainage was developed and used as a least-squares best fit to deliver the initial hydraulic conductivity value of K(0)/μ=(7.8 ± 3.1) × 10(−12) m(2) (Pa-s). The measurements were made with the hyaloid membrane intact and therefore represents an effective conductivity for the entire system, including possible variations within the vitreous.

Purpose: To report on the safety and efficacy of the 256-channel Intelligent Micro Implant Eye epiretinal prosthesis system (IMIE 256). Methods: The IMIE 256 implants were implanted in the right eyes of five subjects with end-stage retinitis pigmentosa. Following implantation, the subjects underwent visual rehabilitation training for 90 days, and their visual performance was evaluated using the grating visual acuity test, Tumbling E visual acuity test, direction of motion, square localization, and orientation and mobility test. To evaluate the safety of the IMIE 256, all adverse events were recorded. Results: Subjects performed significantly better on all evaluations with the IMIE 256 system on as compared with the performance at baseline or with the system off. There was a steady improvement in performance at each observation interval, indicating that the training and/or practice helped the subjects use the IMIE 256. There were two serious adverse events—electrode array movement and low intraocular pressure in one subject, which resolved with surgery. There were no other adverse events observed except those expected in the course of postoperative healing. Conclusions: These results show an improved safety and efficacy profile compared with that of the Argus II implant. Further clinical trials are needed to confirm these results in a larger number of subjects and over longer durations. Translational Relevance: To our knowledge, this study reports the first in-human data from a high-density (256 electrodes) epiretinal implant to restore sight to a subset of blind patients.

Purpose: To investigate how modulating ocular sympathetic activity affects progression of choroidal neovascularization (CNV), a hallmark feature of wet age-related macular degeneration (AMD).Methods: In the first of two studies, Brown Norway rats underwent laser-induced CNV and were assigned to one of the following groups: daily eye drops of artificial tears (n = 10; control group); daily eye drops of the β-adrenoreceptor agonist isoproterenol (n = 10); daily eye drops of the β-adrenoreceptor antagonist propranolol (n = 10); sympathetic internal carotid nerve (ICN) transection 6 weeks prior to laser-induced CNV (n = 10). In the second study, rats underwent laser-induced CNV followed by ICN transection at different time points: immediately after the laser injury (n = 6), 7 days after the laser injury (n = 6), and sham surgery 7 days after the laser injury (n = 6; control group). All animals were euthanized 14 days after laser application. CNV development was quantified with fluorescein angiography and optical coherence tomography (in vivo), as well as lesion volume analysis using 3D confocal reconstruction (postmortem). Angiogenic growth factor protein levels in the choroid were measured with ELISA.Results: In the first study, blocking ocular sympathetic activity through pharmacological or surgical manipulation led to a 75% or 70% reduction in CNV lesion volume versus the control group, respectively (P < 0.001). Stimulating ocular sympathetic activity with isoproterenol also led to a reduction in lesion volume, but only by 27% versus controls (P < 0.05). VEGF protein levels in the choroid were elevated in the three treatment groups (P < 0.01). In the second study, fluorescein angiography and CNV lesion volume analysis indicated that surgically removing the ocular sympathetic supply inhibited progression of laser-induced CNV, regardless of whether ICN transection was performed on the same day or 7 days after the laser injury.Conclusion: Surgical and pharmacological block of ocular sympathetic activity can inhibit progression of CNV in a rat model. Therefore, electrical block of ICN activity could be a potential bioelectronic medicine strategy for treating wet AMD.

End-stage age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are two major retinal degenerative (RD) conditions that result in irreversible vision loss. Permanent eye damage can also occur in battlefields or due to accidents. This suggests there is an unmet need for developing effective strategies for treating permanent retinal damages. In previous studies, co-grafted sheets of fetal retina with its retinal pigment epithelium (RPE) have demonstrated vision improvement in rat retinal disease models and in patients, but this has not yet been attempted with stem-cell derived tissue. Here we demonstrate a cellular therapy for irreversible retinal eye injuries using a “total retina patch” consisting of retinal photoreceptor progenitor sheets and healthy RPE cells on an artificial Bruch’s membrane (BM). For this, retina organoids (ROs) (cultured in suspension) and polarized RPE sheets (cultured on an ultrathin parylene substrate) were made into a co-graft using bio-adhesives [gelatin, growth factor-reduced matrigel, and medium viscosity (MVG) alginate]. In vivo transplantation experiments were conducted in immunodeficient Royal College of Surgeons (RCS) rats at advanced stages of retinal degeneration. Structural reconstruction of the severely damaged retina was observed based on histological assessments and optical coherence tomography (OCT) imaging. Visual functional assessments were conducted by optokinetic behavioral testing and superior colliculus electrophysiology. Long-term survival of the co-graft in the rat subretinal space and improvement in visual function were observed. Immunohistochemistry showed that co-grafts grew, generated new photoreceptors and developed neuronal processes that were integrated into the host retina. This novel approach can be considered as a new therapy for complete replacement of a degenerated retina.

Purpose To report the ocular and adnexal injuries sustained by patients with Thomas A. Swift’s electric rifles (TASER; TASER International, Scottsdale, AZ), review the literature, and discuss the management of this complex trauma. Design Multicenter, retrospective case series and literature review. Participants Seventeen eyes of 16 patients (5 eyes of 5 patients treated at 3 institutions, and 12 eyes of 11 previously reported cases). Methods The clinical data of 17 eyes were pooled. Spearman’s correlation coefficient was used to assess the association between the extent of TASER injury and patient outcomes. Main Outcome Measures Extent of TASER injury (zone of injury, penetrating vs. perforating) and association with patient outcomes (visual acuity [VA] and retinal detachment [RD]). Results In our cohort, 4 patients were transported by law enforcement and 1 was transferred from a community hospital. Four patients were taken to the operating room for TASER removal and globe repair; 1 patient underwent removal in the emergency room. Of 17 pooled cases, 12 (71%) involved open-globe injury. Of these, there was a high rate of zone 3 injuries (100%; n = 12) and a high incidence of RD (73%; 8 of 11, eviscerated eye excluded). Among patients with closed-globe injury (n = 5), 1 patient demonstrated exudative RD and 1 patient demonstrated retinal dialysis with RD. Of 10 patients with RD, 1 (10%) achieved resolution with monitoring (exudative RD); 1 (10%) underwent cryopexy and pneumatic retinopexy; 3 (30%) underwent vitrectomy, and 5 (50%) with poor prognosis did not undergo vitreoretinal surgery. In the 3 patients who underwent vitrectomy, all 3 (100%) demonstrated redetachment resulting from proliferative vitreoretinopathy and required additional surgery. Visual acuity on presentation was significantly correlated with final VA (ρ = 0.783; P = 0.02). Men (94%) were more likely than women (6%) to sustain TASER trauma. Median age was 26 years. There was a 50% rate of loss to follow-up. Conclusions Thomas A. Swift’s electric rifle injuries to the eyes or ocular adnexa represent complex trauma. Zone 3 injuries are common. The visual prognosis is guarded, and eyes may require multiple surgeries to preserve vision. Patients are at high risk for loss to follow-up by way of incarceration.

BACKGROUND AND OBJECTIVE: The authors describe a modified surgical technique for Argus II retinal prosthesis implantation. PATIENTS AND METHODS: The modified surgical technique was performed in a 43-year-old male with retinitis pigmentosa (RP) who underwent strabismus surgery in that eye at age 8. RESULTS: During Argus II implantation, the lateral rectus (LR) was noted to be 10 mm posterior to its original insertion due to prior strabismus surgery. The authors placed three 5-0 nylon mattress sutures at the expected location of the LR to support the external portion of the prosthesis, specifically the coil. The band was then passed through the mattress sutures, underneath the inferior, and medial recti with temporal placement of the coil. CONCLUSION: Placement of three mattress sutures allowed proper positioning of the device and enabled fixation of the suture tabs, thus minimizing the risk of postoperative conjunctival erosion and device exposure. [ Ophthalmic Surg Lasers Imaging Retina . 2019;50:116–119.]

Background: To date there are yet no available approved therapies for Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD). Methods: Single site, non-randomized safety and efficacy study presenting the preliminary results in a cohort of five late stage AMD (GA) patients successfully implanted with the Argus II Retinal Prosthesis System (Second Sight Medical Products Inc., Sylmar, CA, USA). Extensive fundus imaging including retinal photographs from which the GA area was measured. A combination of custom and traditional tests designed for very low vision subjects assessed visual function in study subjects. A Functional Low-Vision Observer Rated Assessment was carried out to evaluate the impact of the system on the subject’s daily life. In addition, a study to evaluate structural characteristics of the visual cortex of the brain was performed in one subject using magnetic resonance imaging. Results: Seven device-related adverse events were reported, four of which were classed as serious adverse events. Retinal detachment was reported in three patients and was successfully treated within 12 months of onset. Testing showed an improvement in visual function in three of five patients with the system turned on. Magnetic resonance imaging assessed in one patient after implantation indicates a selective increase in cortical myelin and thickness in visual brain regions 1 year post implantation. Conclusions: Epiretinal prostheses can successfully be implanted in those affected by GA secondary to late-stage AMD and can elicit visual percepts by electrical stimulation of residual neuroretinal elements and improve basic visual function in those affected.

Epiretinal prostheses aim at electrically stimulating the inner most surviving retinal cells—retinal ganglion cells (RGCs)—to restore partial sight to the blind. Recent tests in patients with epiretinal implants have revealed that electrical stimulation of the retina results in the percept of color of the elicited phosphenes, which depends on the frequency of stimulation. This paper presents computational results that are predictive of this finding and further support our understanding of the mechanisms of color encoding in electrical stimulation of retina, which could prove pivotal for the design of advanced retinal prosthetics that elicit both percept and color. This provides, for the first time, a directly applicable “amplitude-frequency” stimulation strategy to “encode color” in future retinal prosthetics through a predictive computational tool to selectively target small bistratified cells, which have been shown to contribute to “blue-yellow” color opponency in the retinal circuitry. The presented results are validated with experimental data reported in the literature and correlated with findings in blind patients with a retinal prosthetic implant collected by our group.

In order to measure the effective diffusion coefficient D of Bevacizumab (Avastin, Genentech) in the vitreous humor, a new technique is developed based on the “contour method” and in vivo optical coherence tomography measurements. After injection of Bevacizumab-fluorescein conjugated compound solution into the rabbit eye, the contours of drug concentration distribution at the subsurface of injection were tracked over time. The 2D contours were extrapolated to 3D contours using reasonable assumptions and a numerically integrated analytical model was developed for the theoretical contours for the irregularly shaped drug distribution in the experimental result. By floating the diffusion coefficient, different theoretical contours were constructed and the least-squares best fit to the experimental contours was performed at each time point to get the best fit solution. The approach generated consistent diffusion coefficient values based on the experiments on four rabbit eyes over a period of 3 h each, which gave D=1.2±0.6×10−6 cm2/s, and the corresponding theoretical contours matched well with the experimental contours. The quantitative measurement of concentration using optical coherence tomography and fluorescein labeling gives a new approach for the “noncontact” in vivo drug distribution measurement within vitreous.

Electrical stimulation of surviving retinal neurons has proven effective in restoring sight to totally blind patients affected by retinal degenerative diseases. Morphological and biophysical differences among retinal ganglion cells (RGCs) are important factors affecting their response to epiretinal electrical stimulation. Although detailed models of ON and OFF RGCs have already been investigated, here we developed morphologically and biophysically realistic computational models of two classified RGCs, D1-bistratified and A2-monostratified, and analyzed their response to alternations in stimulation frequency (up to 200 Hz). Results show that the D1-bistratified cell is more responsive to high frequency stimulation compared to the A2-monostratified cell. This differential RGCs response suggests a potential avenue for selective activation, and in turn different encoded percept of RGCs.

Purpose To quantitatively investigate both optic nerve head (ONH) and peripapillary sclera (PPS) biomechanical properties of porcine eyes through an ultrasonic elastography imaging system in response to both increasing and decreasing intraocular pressure (IOP). Methods The Young’s modulus of the ONH and PPS were assessed using our high resolution ultrasonic imaging system which utilized a mechanical shaker to induce shear waves and an off-axis aligned 40 MHz needle transducer to track micron-level displacement along the direction of wave propagation. In this study, imaging on a total of 8 ex vivo porcine eyes preloaded with IOPs from 6 mmHg to 30 mmHg was performed. To have a better understanding of the effect of varying IOP on biomechanics, both increasing and decreasing IOPs were investigated. Results The increase of the Young’s modulus of ONH (92.4 ± 13.9 kPa at 6 mmHg to 224.7 ± 71.1 kPa at 30 mmHg) and PPS (176.8 ± 14.3 kPa at 6 mmHg to 573.5 ± 64.4 kPa at 30 mmHg) following IOP elevation could be observed in the reconstructed Young’s modulus of the shear wave elasticity (SWE) imaging while the B-mode structural images remained almost unchanged. In addition, for the same IOP level, both ONH and PPS have a tendency to be stiffer with decreasing IOP as compared to increasing IOP. Conclusions Our results demonstrate the feasibility of using our ultrasonic elastography system to investigate the stiffness mapping of posterior eye with high resolution in both increasing and decreasing IOPs, making this technique potentially useful for glaucoma.

Objective The Argus I implant is a first-generation epiretinal prosthesis approved for an investigational clinical trial in the U.S. Its successor, the Argus II implant, has a higher electrode density for increased spatial resolution and covers a larger retinal area to accommodate a wider visual angle. Both generations of Argus restored some vision to end-stage RP patients, but it remains unclear how the increased electrode count affected the visual percepts. Here we report a study of the first person on earth with two 'bionic eyes', with an Argus I implanted in one eye and Argus II in the other, to compare the retina-electrode interface and the visual outcome of the two devices. Approach The retina-electrode interface was examined by electrode impedance, perceptual threshold, and ophthalmic images such as ocular coherence tomography data and fundus imaging. The subject's visual outcomes were evaluated by computer-based visual function tests and subjective feedback. Main results The electrode impedance of both Argus I and II slowly decreased overtime after implantation, accompanied by a gradual increase in the perceptual threshold. A quantitative analysis of the impedance and retina-electrode distance revealed somewhat different causes of impedance change in Argus I vs. II. Evaluation of the visual functions restored and feedback from the subject suggest that the Argus II device enables improved spatial visual ability over Argus I, but adaptation to prosthetic vision did not lead to a measurable performance improvement in the standard visual function tests. Significance This study of Argus I and II in the same subject directly compares for the first time the interface properties and prosthetic vision in two eyes that share the same disease mechanism and converged visual pathway in higher visual centers, offering exciting new insights into the influence of the electrode parameters and layout to prosthetic vision. Trial registration Data collected within clinical trials registered at NIH (NCT00279500 & NCT01860092).

Objective: The choroidal vessels, which supply oxygen and nutrient to the retina, may play a pivotal role in eye disease pathogenesis such as diabetic retinopathy and glaucoma. In addition, the retrobulbar circulation that feeds the choroid shows an important pathophysiologic role in myopia and degenerative myopia. Owing to the light-absorbing retinal pigment epithelium (RPE) and optically opaque sclera, choroidal and retrobulbar vasculature were difficult to be observed using clinically accepted optical coherence tomography angiography (OCT-A) technique. Here, we have developed super-resolution ultrasound microvessel imaging technique to visualize the deep ocular vasculature. Methods: An 18-MHz linear array transducer with compounding plane wave imaging technique and contrast agent – microbubble was implemented in this study. The centroid intensity of each microbubble was detected using image deconvolution algorithm with spatially variant point spread function, and then accumulated in successive frames in order to reconstruct microvasculature. The image deconvolution technique was first evaluated in a simulation study and experimental flow phantoms. The performance was then validated on normal rabbit eyes in vivo . Results: The image deconvolution based super-resolution ultrasound microvessel imaging technique shows good performance on either simulation study or flow phantoms. In vivo rabbit eye study indicated that the micron-level choroidal and retrobulbar vessels around the optic nerve head were successfully reconstructed in multiple 2D views and 3D volume imaging. Conclusions: Our results demonstrate the capability of using super-resolution ultrasound microvessel imaging technique to image the microvasculature of the posterior pole of the eye. This efficient approach can potentially lead to a routinely performed diagnostic procedure in the field of ophthalmology.

Age-related macular degeneration (AMD) is a progressive retinal disease and becomes the leading cause of blindness. It is well established that early detection is the key to preservation of functional vision. However, it is very difficult to diagnose AMD in very early stages, before structural changes are evident. Consequently, investigating the biomechanical properties of the retina maybe essential for understanding its physiological function. In this study, we present a shear wave-based quantitative method for estimating the elasticity of the posterior eye using shaker-based optical coherence elastography. This technique has been developed and validated on both a homogeneous phantom and a healthy rabbit in vivo. The shear wave speed from the ganglion side to the photoreceptor side of the rabbit eye is 4.1 m/s, 4.9 m/s, and 6.7 m/s, respectively. In addition, the most stiff sclera region has an average shear wave speed of 9.1 m/s. The results demonstrate the feasibility of using this technique to quantify biomechanical properties of the posterior eye and its potential translation to the clinical study. Impact statement Herein, we propose a potentially clinical applicable shaker-based optical coherence elastography (OCE) technique to characterize the biomechanical properties of the posterior eye, including different layers of the retina. Compared with either acoustic radiation force OCE or air-puff OCE, the newly developed method can induce sufficient shear wave propagation at the posterior eye with high resolution and large field of view.

Over the past 15 years, extraordinary strides have demonstrated that stem cell-based therapy is a promising treatment for retinal diseases. Retinal degenerative diseases that cause irreversible dysfunction and death of retinal pigment epithelium (RPE) and photoreceptor cells may lead to blindness. The retina, which is derived from the neuroectoderm, has little regenerative potential. Stem cell-based therapies that introduce healthy tissue into the eye have been shown to restore or rescue the degenerated retina and improve vision in animal models.

The Argus II Retinal Prosthesis is the first, and to date only, artificial visual implant commercially approved by the U.S. Food and Drug Administration (FDA). It is indicated for patients with end-stage retinitis pigmentosa (RP) in both eyes.

PURPOSE To evaluate visual and anatomical outcomes of diabetic tractional retinal detachment repaired with pars plana vitrectomy. METHODS Operative records were used to retrospectively identify all patients with tractional retinal detachments secondary to proliferative diabetic retinopathy surgically repaired with pars plana vitrectomy between November 1, 2009, and January 1, 2015 at the LAC + USC (Los Angeles County + University of Southern California) Medical Center. RESULTS A total of 403 eyes with diabetic tractional retinal detachment in 359 patients were included. Successful reattachment of the retina was achieved in 87.6% of eyes after one surgery and 92.6% of eyes at the final follow-up. Best-corrected visual acuity at the final follow-up improved two or more lines in 56.3% of eyes, was stable in 23.8% of eyes, and decreased two or more lines in 19.9% of eyes. Eyes repaired with 23-gauge and 25-gauge vitrectomy systems had similar success rates as eyes treated with 20-gauge instrumentation (P = 0.73). Eyes receiving silicone oil tamponade had lower single-surgery reattachment rates (77.6% vs. 87.6%; P = 0.013), lower reattachment rates at the final follow-up (85.7% vs. 92.6%; P = 0.048), and higher rates of vision loss (34.7% vs. 19.9%; P < 0.0001) but were more likely to have concurrent rhegmatogenous detachment (47.0% vs. 21.3%; P < 0.0001) and macula involving detachment (74.5% vs. 60.0%; P < 0.0001). CONCLUSION In this large, single-center retrospective study of patients with advanced diabetic tractional retinal detachment, vitrectomy achieved excellent anatomical outcome and improved or stabilized vision in 80.1% of eyes. Smaller gauge vitrectomy systems were found to have similar outcomes to 20-gauge instrumentation.

Purpose To report 1-year follow-up of a phase 1/2a clinical trial testing a composite subretinal implant having polarized human embryonic stem cell (hESC)-derived retinal pigment epithelium (RPE) cells on an ultrathin parylene substrate in subjects with advanced non-neovascular age-related macular degeneration (NNAMD). Methods The phase 1/2a clinical trial included 16 subjects in two cohorts. The main endpoint was safety assessed at 365 days using ophthalmic and systemic exams. Pseudophakic subjects with geographic atrophy (GA) and severe vision loss were eligible. Low-dose tacrolimus immunosuppression was utilized for 68 days in the peri-implantation period. The implant was delivered to the worst seeing eye with a custom subretinal insertion device in an outpatient setting. A data safety monitoring committee reviewed all results. Results The treated eyes of all subjects were legally blind with a baseline best-corrected visual acuity (BCVA) of ≤ 20/200. There were no unexpected serious adverse events. Four subjects in cohort 1 had serious ocular adverse events, including retinal hemorrhage, edema, focal retinal detachment, or RPE detachment, which was mitigated in cohort 2 using improved hemostasis during surgery. Although this study was not powered to assess efficacy, treated eyes from four subjects showed an increased BCVA of >5 letters (6-13 letters). A larger proportion of treated eyes experienced a >5-letter gain when compared with the untreated eye (27% vs. 7%; P = not significant) and a larger proportion of nonimplanted eyes demonstrated a >5-letter loss (47% vs. 33%; P = not significant). Conclusions Outpatient delivery of the implant can be performed routinely. At 1 year, the implant is safe and well tolerated in subjects with advanced dry AMD. Translational relevance This work describes the first clinical trial, to our knowledge, of a novel implant for advanced dry AMD.

Artificial vision is restoring sight by electrical stimulation of the visual system at the level of retina, optic nerve, lateral geniculate body, or occipital cortex. The development of artificial vision began with occipital cortex prosthesis; however, retinal prosthesis has advanced faster in recent years. Currently, multiple efforts are focused on finding the optimal approach for restoring vision through an implantable retinal microelectrode array system. Retinal prostheses function by stimulating the inner retinal neurons that survive retinal degeneration. In these devices, the visual information, gathered by a light detector, is transformed into controlled patterns of electrical pulses, which are in turn delivered to the surviving retinal neurons by an electrode array. Retinal prostheses are classified based on where the stimulating array is implanted (ie, epiretinal, subretinal, suprachoroidal, or episcleral). Recent regulatory approval of 2 retinal prostheses has greatly escalated interest in the potential of these devices to treat blindness secondary to outer retinal degeneration. This review will focus on the technical and operational features and functional outcomes of clinically tested retinal prostheses. We will discuss the major barriers and some of the more promising solutions to improve the outcomes of restoring vision with electrical retinal stimulation.

Purpose To describe a case of small retinal vessel vasculopathy postvaccination. Methods We report the case of a 41-year-old white man who presented with a "second blind spot," describing a nasal scotoma in the right eye that started 4 days after vaccinations against Neisseria meningitidis and the yellow fever virus, and after a 2-month period of high stress and decreased sleep. Clinical examination, Humphrey visual field testing, and multimodal imaging with fundus photographs, autofluorescence, fluorescein angiography, and spectral domain optical coherence tomography and angiography were performed. Results Clinical examination revealed a well-circumscribed, triangular area of retinal graying of about 1-disk diameter in size, located at the border of the temporal macula. This corresponded to a deep scotoma similar in size to the physiologic blind spot on Humphrey visual field 24-2 testing. There was mild hypoautofluoresence of this lesion on autofluorescence, hypofluorescence on fluorescein angiography, and focal attenuation of a small artery just distal to the bifurcation of an artery supplying the involved area. Spectral domain optical coherence tomography through the lesion conveyed hyperreflectivity most prominent in the inner and outer plexiform layers, with extension of the hyperreflectivity into the ganglion cell and inner nuclear layers. Spectral domain optical coherence tomography angiography demonstrated arteriolar and capillary dropout, more pronounced in the superficial retinal layer compared to the deeper retinal layer. At 1-month follow-up, his scotoma improved with monitoring, with reduction from -32 dB to -7 dB on Humphrey visual field testing. There was clinical resolution of the area of graying and decreased hyperreflectivity on spectral domain optical coherence tomography, with atrophy of the inner retina. Spectral domain optical coherence tomography angiography showed progression of arteriolar and capillary dropout, more so in the superficial than in the deep capillary plexus. Conclusion We describe a case of small artery occlusion in a previously healthy patient, 4 days after vaccination against N. meningitidis and yellow fever. Fluorescein angiography yielded greater diagnostic value than OCTA for evaluating the occlusion, whereas spectral domain optical coherence tomography angiography enabled better visualization of capillary dropout and layer-specific assessment. Further research is required to determine whether vaccination in general, or directed specifically at N. meningitidis or yellow fever, is associated with small vessel vasculopathy and the underlying pathogenesis.

The mechanosensitivity of the optic nerve head (ONH) plays a pivotal role in the pathogenesis of glaucoma. Characterizing elasticity of the ONH over changing physiological pressure may provide a better understanding of how changes in intraocular pressure (IOP) lead to changes in the mechanical environment of the ONH. Optical coherence elastography (OCE) is an emerging technique that can detect tissue biomechanics noninvasively with both high temporal and spatial resolution compared with conventional ultrasonic elastography. We describe a confocal OCE system in measuring ONH elasticity in vitro, utilizing a pressure inflation setup in which IOP is controlled precisely. We further utilize the Lamb wave model to fit the phase dispersion curve during data postprocessing. We present a reconstruction of Young’s modulus of the ONH by combining our OCE system with a Lamb wave model for the first time. This approach enables the quantification of Young’s modulus of the ONH, which can be fit using a piecewise polynomial to the corresponding IOP.

Purpose: To investigate specific effects of denervation and stimulation of the internal carotid nerve (ICN) on the choroid and retina. Methods: Female Sprague Dawley rats underwent unilateral ICN transection (n = 20) or acute ICN electrical stimulation (n = 7). Rats in the denervation group were euthanized 6 weeks after nerve transection, and eyes were analyzed for changes in choroidal vascularity (via histomorphometry) or angiogenic growth factors and inflammatory markers (via ELISA). Rats in the stimulation group received acute ICN electrical stimulation with a bipolar cuff electrode over a range of stimulus amplitudes, frequencies, and pulse widths. Choroidal blood flow and pupil diameter were monitored before, during, and after stimulation. Results: Six weeks after unilateral ICN transection, sympathectomized choroids exhibited increased vascularity, defined as the percentage of choroidal surface area occupied by blood vessel lumina. Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein levels in denervated choroids were 61% and 124% higher than in contralateral choroids, respectively. TNF-α levels in denervated retinas increased by 3.3-fold relative to levels in contralateral retinas. In animals undergoing acute ICN electrical stimulation, mydriasis and reduced choroidal blood flow were observed in the ipsilateral eye. The magnitude of the reduction in blood flow correlated positively with stimulus frequency. Conclusions: Modulation of ICN activity reveals a potential role of the ocular sympathetic system in regulating endpoints related to neovascular diseases of the eye.

Patients diagnosed with Retinitis Pigmentosa (RP) show, in the advanced stage of the disease, severely restricted peripheral vision causing poor mobility and decline in quality of life. This vision loss causes difficulty identifying obstacles and their relative distances. Thus, RP patients use mobility aids such as canes to navigate, especially in dark environments. A number of high-tech visual aids using virtual reality (VR) and sensory substitution have been developed to support or supplant traditional visual aids. These have not achieved widespread use because they are difficult to use or block off residual vision. This paper presents a unique depth to high-contrast pseudocolor mapping overlay developed and tested on a Microsoft Hololens 1 as a low vision aid for RP patients. A single-masked and randomized trial of the AR pseudocolor low vision aid to evaluate real world mobility and near obstacle avoidance was conducted consisting of 10 RP subjects. An FDA-validated functional obstacle course and a custom-made grasping setup were used. The use of the AR visual aid reduced collisions by 50% in mobility testing (p = 0.02), and by 70% in grasp testing (p = 0.03). This paper introduces a new technique, the pseudocolor wireframe, and reports the first significant statistics showing improvements for the population of RP patients with mobility and grasp.

Purpose To characterize histologic changes in the optic nerve and the retina of an end-stage retinitis pigmentosa (RP) patient after long-term implantation with the Argus II retinal prosthesis system. Methods Serial cross sections from the patient's both eyes were collected postmortem 6 years after implantation. Optic nerve from both eyes were morphometrically analyzed and compared. Retina underneath and outside the array was analyzed and compared with corresponding regions in the fellow eye. Results Although the optic nerve of the implant eye demonstrated significantly more overall atrophy than the fellow eye (P < 0.01), the temporal quadrant that retinotopically corresponded to the location of the array did not show additional damage. The total neuron count of the macular area was not significantly different between the two eyes, but the tack locations and their adjacent areas showed significantly fewer neurons than other perimacular areas. There was an increased expression of glial fibrillary acidic protein (GFAP) throughout the retina in the implant eye versus the fellow eye, but there was no significant difference in the cellular retinaldehyde-binding protein (CRALBP) expression. Except for the revision tack site, no significant increase of inflammatory reaction was detected in the implant eye. Conclusion Long-term implantation and electrical stimulation with an Argus II retinal prosthesis system did not result in significant tissue damage that could be detected by a morphometric analysis. Translational Relevance This study supports the long-term safety of the Argus II device and encourages further development of bioelectronics devices at the retina-machine interface.

The Argus II retinal prosthesis (Second Sight Medical Products, Sylmar, CA, USA) is an electronic epiretinal implant designed for use in patients with end-stage retinitis pigmentosa, as well as for other outer retinal degenerative conditions, such as choroideremia, Leber’s congenital amaurosis, Bardet-Biedl syndrome, Usher syndrome and rod–cone disease.1 This device was tested in a clinical trial of 30 subjects in the USA and in Europe to measure the rate of serious adverse events (SAEs) and to assess its effects on functional vision and visual acuity.2–4 Subjects performed better on visual tasks with the device turned on and retained these improvements at 5 years postsurgery.4 Additionally, an acceptable safety profile enabled approval of the device for consumer use by the European regulatory authorities in 2011 (Conformite Europeenne (CE) mark) and by the US Food and Drug Administration (FDA) in 2013 (FDA approval). The implant is composed of an extraocular component, namely, an electronics case and implant coil, as well as an intraocular component involving a 60-electrode array that is tacked over the macula (figure 1). The extraocular and intraocular components are connected by a trans-scleral silicone-coated polyamide electrode cable, and the implantation procedure involves a 5.2 mm pars plana sclerotomy incision to insert the electrode array and the electrode cable into the eye. The sclerotomy is then sutured around the cable and covered by an allograft or autograft material.5 Figure 1 The Argus II retinal prosthesis. Labelled image of the Argus II implant (adapted from Humayun et al 2). As with any system having both intraocular and extraocular components, the trans-scleral electrode cable that traverses the sclerotomy permanently is a high-risk feature of the device, as leakage through the pars plana incision can result in chronic hypotony. The percentages of clinical trial subjects who experienced hypotony were 10.0% at …

Retinal degenerative diseases, which include age-related macular degeneration and inherited disorders like retinitis pigmentosa, all have some degree of dysfunction and loss of retinal pigmented epithelium (RPE) cells and photoreceptors. Cell therapy has been proposed as a promising approach to treat this group of diseases. For example, RPE can be differentiated in vitro from stem cells and then transplanted into patients with advanced dry age-related macular degeneration with geographic atrophy of RPE (GA).

Retinal prostheses aim to restore vision to blind individuals suffering from retinal diseases such as retinitis pigmentosa and age-related macular degeneration. These devices function by electrically stimulating surviving retinal neurons, whose activation is interpreted by the brain as a visual percept. Many prostheses are currently under development. They are categorized as epiretinal, subretinal, and suprachoroidal prostheses on the basis of the placement of the stimulating microelectrode array. Each can activate ganglion cells through direct or indirect stimulation. The response of retinal neurons to these modes of stimulation are discussed in detail and are placed in context of the visual percept they are likely to evoke. This article further reviews challenges faced by retinal prosthesis and discusses potential solutions to address them.

This article describes the history of visual prostheses, with emphasis on the development of the Argus II retinal prosthesis system (Second Sight Medical Products, Inc., Sylmar, CA). A brief overview of cortical electrical stimulation in the blind is provided, followed by an account of the design and development of retinal stimulation equipment at the Duke Eye Center in the late 1980s; the first human intraoperative tests there and the subsequent 8 years of tests at the Wilmer Eye Institute; the transfer of the project to the Doheny Eye Institute at the University of Southern California and the founding of Second Sight Medical Products; and the development and clinical trials of the Argus I and Argus II systems. In a series of vignettes, we pay tribute to the many colleagues and patient volunteers without whose help the work would not have been possible.

PURPOSE To evaluate intraocular pressure (IOP) changes during experimental vitrectomy and the efficacy of Constellation Vision System's IOP control (IOPc) feature in reestablishing baseline pressure. METHODS Using a pressure transducer in freshly enucleated porcine eyes, a broad range of parameters (baseline pressures, aspiration levels, and cut rates) were tested with 23- and 25-gauge probes and IOPc turned ON versus OFF. RESULTS IOPc turned ON was significantly more effective than IOPc turned OFF in controlling IOP drop and stabilizing pressure during vitrectomy using a wide range of baseline pressures (20-70 mmHg). The 23-gauge system consistently presented a reduced drop from baseline compared with the 25-gauge system. The overall average drop for the 23- and 25-gauge systems was 12.79 mmHg and 21.17 mmHg, respectively. Both gauge sizes reestablished baseline pressure approximately 1.6 seconds after the initial pressure drop generated at the beginning of aspiration. A peak of IOP (overshooting) was observed when the pressure was returning to baseline using both 23- and 25-gauge systems. CONCLUSION Using IOPc feature turned ON, 23- and 25-gauge probes were effective in reestablishing and sustaining baseline infusion pressures, although 23-gauge probes showed less IOP fluctuation than did 25-gauge probes.

Objective: Presbyopia is a common age-related condition that prevents people from focusing on near objects. The etiology of presbyopia continues to be debated, but the end effect of all postulated mechanisms is the lack of deformation of the human lens. Using our understanding of the biomechanical properties of the natural human lens, we created a unique accommodating intraocular lens. Although this lens can be used for lenticular disease such as myopia and hyperoperopia, this study addresses the needs of cataract patients with presbyopia. Methods: The lens was implanted into presbyopic human cadaver eyes. Focal length of the lens was measured with simulated muscle contraction. Lens dimensions were measured using artificial tissue and a finite-element analysis (FEA) to simulate accommodation. Lens power was measured at various fill volumes. Accelerated soak testing for an equivalent of 7.4 years was performed and lens weight and optical transmittance were measured. Results: Previously presbyopic human eyes were able to accommodate between 2.0 and 7.4 diopters after lens implantation. FEA and lens measurements demonstrated a change in curvature of the anterior and posterior portions of the lens during accommodation. After accelerated aging, lens weight remained unchanged and optical transmission was 96%. Lens power increased with fill volume. Conclusion: A deformable liquid lens reversed presbyopia, can be individualized by optically adjusting for each patient, is stable for long periods of time, and is compatible with minimally invasive surgical techniques. Significance: A deformable liquid-filled lens can significantly improve accommodation over the presbyopic natural lens.

Purpose To explore the utility of using ultra-widefield imaging to visualize the Argus II implant in the eyes of three patients with retinitis pigmentosa. Methods Case series of three patients with retinitis pigmentosa who were implanted with the Argus II Retinal Prosthesis System; two of whom were enrolled in the Argus II clinical trial and one received the implant after the commercial release of the device. Optomap widefield fundus autofluorescence and color images of both eyes were taken in all three patients by an experienced technician using the Optos 200Tx imaging system. Analysis focused on fundus autofluorescence images of the implanted eyes and consisted of assessing the location and configuration of the Argus II electrode array and cable, and also the condition of the surrounding retina. Analysis was led by an experienced vitreoretinal surgeon. Results Optos fundus autofluorescence images of the implanted eyes in all 3 patients gave a wide-angle view of the retina, with the electrode array and cable clearly visible. The status of the array and cable was able to be determined without difficulty. All 3 cases showed an appropriate mild-to-moderate bowing of the cable, and also the electrode array being positioned on or near the macula with a superotemporal tilt. Other features, such as "bone spicules," were also clearly seen. Optos color images were not as useful in the analysis because of an exaggerated green light artifact seen in the implanted versus the nonimplanted eyes. Conclusion Optomap fundus autofluorescence widefield images are useful in determining the configuration of the Argus II cable and the position of the electrode array on the retina and therefore are a useful component of the postoperative surveillance of patients implanted with the device. Using autofluorescence avoids the generation of a light reflection artifact often seen with Optos color imaging.

Objective: To both qualitatively and quantitatively investigate corneal biomechanical properties through an ultrasonic microelastography imaging system, which is potentially useful in the diagnosis of diseases, such as keratoconus, postrefractive keratectasia, and tracking treatment such as cross-linking surgery. Methods: Our imaging system has a dual-frequency configuration, including a 4.5 MHz ring transducer to push the tissue and a confocally aligned 40 MHz needle transducer to track micron-level displacement. Two-dimensional/three-dimensional acoustic radiation force impulse (ARFI) imaging and Young's modulus in the region of interest were performed on ex vivo porcine corneas that were either cross-linked using formalin solution or preloaded with intraocular pressure (IOPs) from 5 to 30 mmHg. Results: The increase of corneal stiffness and the change in cross-linked volume following formalin crosslinking could be precisely observed in the ARFI images and reflected by the reconstructed Young's modulus while the B-mode structural images remained almost unchanged. In addition, the relationship between the stiffness of the cornea and IOPs was investigated among 12 porcine corneas. The corneal stiffness is significantly different at various IOPs and has a tendency to become stiffer with increasing IOP. Conclusion: Our results demonstrate the principle of using ultrasonic microelastography techniques to image the biomechanical properties of the cornea. Integrating high-resolution ARFI imaging labeled with reconstructed Young's modulus and structural imaging of the cornea can potentially lead to a routinely performed imaging modality in the field of ophthalmology.

© 2018 Optical Society of America. Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly (over the age of 60 years) in western countries. In the early stages of the disease, structural changes may be subtle and cannot be detected. Recently it has been postulated that the mechanical properties of the retina may change with the onset of AMD. In this manuscript, we present a novel, non-invasive means that utilizes synchronized acoustic radiation force optical coherence elastography (ARF-OCE) to measure and estimate the elasticity of cadaver porcine retina. Both regions near the optic nerve and in the peripheral retina were studied. An acoustic force is exerted on the tissue for excitation and the resulting tissue vibrations, often in the nanometer scale, are detected with high-resolution optical methods. Segmentation has been performed to isolate individual layers and the Young’s modulus has been estimated for each. The results have been successfully compared and mapped to corresponding histological results using H&E staining. Finally, 64 elastograms of the retina were analyzed, as well as the elastic properties, with stiffness ranging from 1.3 to 25.9 kPa in the ganglion to the photoreceptor sides respectively. ARF-OCE allows for the elasticity mapping of anatomical retinal layers. This imaging approach needs further evaluation but has the potential to allow physicians to gain a better understanding of the elasticity of retinal layers in retinal diseases such as AMD.

Retinal pigment epithelium (RPE) dysfunction and loss are a hallmark of non-neovascular age-related macular degeneration (NNAMD). Without the RPE, a majority of overlying photoreceptors ultimately degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement strategies may delay disease progression or restore vision. A prospective, interventional, U.S. Food and Drug Administration-cleared, phase 1/2a study is being conducted to assess the safety and efficacy of a composite subretinal implant in subjects with advanced NNAMD. The composite implant, termed the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1), consists of a polarized monolayer of human embryonic stem cell-derived RPE (hESC-RPE) on an ultrathin, synthetic parylene substrate designed to mimic Bruch's membrane. We report an interim analysis of the phase 1 cohort consisting of five subjects. Four of five subjects enrolled in the study successfully received the composite implant. In all implanted subjects, optical coherence tomography imaging showed changes consistent with hESC-RPE and host photoreceptor integration. None of the implanted eyes showed progression of vision loss, one eye improved by 17 letters and two eyes demonstrated improved fixation. The concurrent structural and functional findings suggest that CPCB-RPE1 may improve visual function, at least in the short term, in some patients with severe vision loss from advanced NNAMD.

This paper presents a wireless, implantable continuous intraocular pressure (IOP) monitoring system that features a parylene-on-oil sensor encapsulation method for achieving long-term low-drift in vivo. The system is implanted in the superotemporal quadrant of the eye between the sclera and conjunctiva. It consists of a commercial pressure sensor (STMicroelectronics LPS25H) with digital readout, a 65nm CMOS chip that supports wireless power/data telemetry and the I2C serial communication interface with the pressure sensor. The chip and pressure sensor are assembled on a flexible polyimide PCB, and then the sensor is submerged in biocompatible silicone oil and coated with parylene in situ. The implant uses an on-chip integrated RF coil to receive power from near-field RF coupling at 915 MHz and transmit measurement bits via RF-backscattering to an external reader. A 2 mm × 1.2 mm chip is fabricated in TSMC 65nm CMOS process. The IOP implant achieves a pressure sensitivity of 0.17 mmHg with a total power consumption of 9.7μW. We demonstrate pressure offset drift of less than 0.5 mmHg for more than 4 months over a temperature range of 27–38 °C. The implant successfully tracks induced IOP variations in a porcine eye ex vivo, validating the system functionality and surgical implantation.

Aged related macular degeneration (AMD) and retinitis pigmentosa (RP) are two degenerative diseases that affect mainly the photoreceptors layer, rendering the retina unable to translate light into biological signals and causing blindness in patients. In these conditions, inner retinal neurons (bipolar cells and ganglion cells) are less affected by disease, allowing the retina to be electrically stimulated to restore a sense of vision. Visual prostheses have been studied as a method to restore vision for decades, starting in 1929 when Foerster, a German neurosurgeon, exposed the occipital pole of one cerebral hemisphere and electrically stimulated the visual cortex in a sighted patient, reporting that his patient saw a small spot of light. In the years since Foerster's experiments, various attempts were made to develop visual cortex prostheses. Although stimulating the visual cortex showed promise, its organization is very complex and the surgical access is difficult, which why different locations for a visual prosthesis started to be explored. As retinal surgery begun to develop in the 1970s, it followed that retinal prostheses were investigated as an alternative to visual cortex prostheses. Other implant areas along the visual pathway that have been studied include the optic nerve and lateral geniculate nucleus, but this chapter will focus on retinal implants.

Age-related macular degeneration (AMD) is a progressive disease of photoreceptors and retinal pigment epithelium (RPE). Geographic atrophy (GA) is initiated by dysfunction and loss of RPE cells followed by photoreceptor loss. Thus, replacing lost and sick RPE with healthy cells may restore vision in GA. Human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) are two main sources for this replacement. There are currently two major approaches to RPE stem cell integration with the human retina. The first employs bolus injections of RPE cell suspension under the retina and the second relies on prefabricated RPE stem cell sheets implanted in the subretinal space. Due to immune considerations, current hESC-RPE trials use immunosuppressant medications for a limited period up to, during, and after implantation. RPE stem cell grafts show great promise in restoring vision in patients with geographic atrophy due to AMD, as limited clinical trials in humans have already shown positive results, and more results are forthcoming.

Retinal prostheses deliver controlled electrical impulses to retina which elicit light perception in patients with damaged/degenerated photoreceptors. It has been shown that retinal prostheses are able to restore simple but useful vision to those who have been otherwise blind for decades. The idea of using electricity to stimulate the visual system is as old as two centuries, but the development of the retinal prostheses only took off in the most recent two decades. During this period, a variety of devices have been developed and investigated, among which two have received regulatory approvals for clinical use, Argus II and Alpha-IMS. Meanwhile new technologies and stimulation strategies are being pursued to improve the visual experience of the blind. Given the momentum of the field, it is anticipated that the next generation prostheses will enable the blind patients to perform more complex visual tasks such as reading. This chapter will overview the historical aspects of the representative retinal prostheses, briefly accounting the background and the current status.

Investigating biomechanical properties of the cornea can have many clinical applications, including the diagnosis of keratoconus and post-refractive keratectasia. However, ascertaining the biomechanical properties of cornea remains a challenge because of the low resolution of currently available modalities cannot provide a point-to-point stiffness mapping of cornea. In this study, we reported a high-resolution ultrasonic micro-elastograhy technique for non-invasive mapping of corneal biomechanical properties relative to its morphological structure.

More and more researches are exploring the neurostimulation effect of ultrasound (US) on the central nervous system (e.g. brain and retina) and the peripheral nervous system (such as skin). US stimulation has been regarded as a new noninvasive neurostimulation approach by many researchers. Our previous studies had shown that the temporal response patterns of RGCs could be stimulated by US in vitro. In this article, we apply low-frequency (2.25 MHz) focused US stimulation to the rat retina in vivo to investigate the effect on the primary visual cortex.

This paper reports on the first implantable phototherapy device to treat diabetic retinopathy by modulating rod cell metabolism through reduction of dark current. Utilizing a tritium-based radioluminescent light source capable of emitting around 505nm, the device achieves phototherapeutic activity for up to a 12-year service lifetime and

Purpose Epiretinal and subretinal prosthesis have been shown to be a valid way to provide some vision to patients with advanced outer retinal degeneration and profound vision loss. However, the field of vision for these patients is markedly limited by the area occupied by the electrode array. In this study, we aimed to evaluate the feasibility of implantation of multiple suprachoroidal electrode arrays in a single eye in order to increase the field of vision in patients implanted with retinal prosthesis. Methods The right eye of seventeen Dutch rabbits (age range, 5–6 months) was used for the study. Multiple inactive custom-made electrode arrays were inserted into the suprachoroidal space (SCS) and animals were followed up for up to 6 months using fundus photography, optical coherence tomography (OCT), and fluorescein angiography (FA). Results It was possible to surgically implant up to 8 electrode arrays in a single eye. None of the rabbits showed any major complications. The electrodes were well tolerated and remained in position in all rabbits. There was no evidence of retinal damage on follow-up exams and FA throughout the study. Conclusion Multiple suprachoroidal electrode array implantation is feasible and may provide a novel approach to increase the field of vision in subjects implanted with retinal prosthesis.

Age-related macular degeneration and keratoconus are two ocular diseases occurring in the posterior and anterior eye, respectively. In both conditions, the mechanical elasticity of the respective tissues changes during the early onset of disease. It is necessary to detect these differences and treat the diseases in their early stages to provide proper treatment. Acoustic radiation force optical coherence elastography is a method of elasticity mapping using confocal ultrasound waves for excitation and Doppler optical coherence tomography for detection. We report on an ARF-OCE system that uses modulated compression wave based excitation signals, and detects the spatial and frequency responses of the tissue. First, all components of the system is synchronized and triggered such that the signal is consistent between frames. Next, phantom studies are performed to validate and calibrate the relationship between the resonance frequency and the Young’s modulus. Then the frequency responses of the anterior and posterior eye are detected for porcine and rabbit eyes, and the results correlated to the elasticity. Finally, spatial elastograms are obtained for a porcine retina. Layer segmentation and analysis is performed and correlated to the histology of the retina, where five distinct layers are recognized. The elasticities of the tissue layers will be quantified according to the mean thickness and displacement response for the locations on the retina. This study is a stepping stone to future in-vivo animal studies, where the elastic modulus of the ocular tissue can be quantified and mapped out accordingly.

Open globe injuries are full-thickness injuries sustained to the eye wall (cornea or sclera), which cause immediate drops in intraocular pressure that may lead to retinal detachment and permanent vision loss if not treated rapidly after injury. The current standard of care for open globe injuries consists of suturing the margins closed, but the technique can be time-consuming, requires specialized training and equipment, and can lead to patient discomfort, abrasion, and infection from eye rubbing. We engineered an injectable, thermoresponsive sealant (TRS) and a custom tool to occlude open globe injuries. The smart hydrogel sealant consists of physically cross-linked N-isopropylacrylamide copolymerized with butylacrylate. At low temperatures, it can be injected as a liquid, and when raised to body temperature, a heat-induced gelation converts the hydrogel into a solidified occlusion. The sealant can be repositioned or removed without causing additional trauma via exposure to cold water. In vitro and ex vivo assessments of mechanical adhesion to eye tissue revealed maintenance of intraocular pressure that is five times greater than the physiological range with reversible seal strength comparable to cyanoacrylate (super glue). In vivo assessment in a rabbit model of ocular trauma demonstrated ease of use for TRS deployment, statistically significant improvement in wound sealing, and no evidence of neurotoxicity, retinal tissue degradation, or significant chronic inflammatory response after 30 days of exposure. Given the advantages of body heat-induced gelation, rapid reversible occlusion, and in vivo safety and efficacy, shape-adaptable TRSs have translational potential as smart wound sealants for temporary occlusion of surgical incisions or traumatic injuries.

Retinitis Pigmentosa (RP) is a degenerative disease of the retina that leads to vision loss. Retinal prostheses are being developed in order to restore functional vision in patients suffering from RP. We conducted in-vivo experiments in order to identify strategies to efficiently stimulate the retina. We electrically stimulated the retina and measured electrically evoked potentials (EERs) from the superior colliculus of rats. We compared the strength of EERs when voltage-controlled and current-controlled pulses of varying pulse width and charge levels were applied to the retina. In addition to comparing EER strength, we evaluated improvement in power efficiency afforded by a high surface area platinum-iridium material. Voltage-controlled pulses were more efficient than current-controlled pulses when the pulses have a short duration (< 1 ms) and current-controlled pulses were more efficient than voltage-controlled pulses when the pulse width was greater than 1 ms. The high surface area platinum-iridium stimulation electrode consumed power significantly lower than a standard platinum-iridium electrode.