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Currently, blindness cannot be cured and patients’ living quality can be compromised severely. Ultrasonic (US) neuromodulation is a promising technology for the development of noninvasive cortical visual prosthesis. We investigated the feasibility of transcranial focused ultrasound (tFUS) for noninvasive stimulation of the visual cortex (VC) to develop improved visual prosthesis. tFUS was used to successfully evoke neural activities in the VC of both normal and retinal degenerate (RD) blind rats. Our results showed that blind rats showed more robust responses to ultrasound stimulation when compared with normal rats. ( ${p} , two-sample t-test). Three different types of ultrasound waveforms were used in the three experimental groups. Different types of cortical activities were observed when different US waveforms were used. In all rats, when stimulated with continuous ultrasound waves, only short-duration responses were observed at “US on and off” time points. In comparison, pulsed waves (PWs) evoked longer low-frequency responses. Testing different parameters of PWs showed that a pulse repetition frequency higher than 100 Hz is required to obtain the low-frequency responses. Based on the observed cortical activities, we inferred that acoustic radiation force (ARF) is the predominant physical mechanism of ultrasound neuromodulation.

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

Current treatments for meibomian gland dysfunction have several limitations, creating a necessity for other advanced treatment options. The purpose of this study is to determine the effectiveness of focused ultrasound stimulation for the treatment of dry eye disease caused by meibomian gland dysfunction. An in vivo study of nine Dutch Belted rabbits was conducted with focused ultrasound stimulation of the meibomian glands. A customized line-focused ultrasonic transducer was designed for treatment. Fluorescein imaging, Schirmer’s test, and Lipiview II ocular interferometer were used to quantify outcomes from three aspects: safety, tear production, and lipid layer thickness. Both tear secretion and lipid layer thickness improved following ultrasound treatment. Five to 10 min after the ultrasound treatment, the mean values of lipid layer thickness increased from 55.33 ± 11.15 nm to 95.67 ± 22.77 nm ( p

Retinal pigment epithelium (RPE) replacement therapy is evolving as a feasible approach to treat age-related macular degeneration (AMD). In many preclinical studies, RPE cells are transplanted as a cell suspension into immunosuppressed animal eyes and transplant effects have been monitored only short-term. We investigated the long-term effects of human Induced pluripotent stem-cell-derived RPE (iPSC-RPE) transplants in an immunodeficient Royal College of Surgeons (RCS) rat model, in which RPE dysfunction led to photoreceptor degeneration. iPSC-RPE cultured as a polarized monolayer on a nanoengineered ultrathin parylene C scaffold was transplanted into the subretinal space of 28-day-old immunodeficient RCS rat pups and evaluated after 1, 4, and 11 months. Assessment at early time points showed good iPSC-RPE survival. The transplants remained as a monolayer, expressed RPE-specific markers, performed phagocytic function, and contributed to vision preservation. At 11-months post-implantation, RPE survival was observed in only 50% of the eyes that were concomitant with vision preservation. Loss of RPE monolayer characteristics at the 11-month time point was associated with peri-membrane fibrosis, immune reaction through the activation of macrophages (CD 68 expression), and the transition of cell fate (expression of mesenchymal markers). The overall study outcome supports the therapeutic potential of RPE grafts despite the loss of some transplant benefits during long-term observations.

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.

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.

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.

Background Quantitatively investigating the biomechanics of retina with a retinal prosthetic electrode, we explored the effects of the prosthetic electrode on the retina, and further supplemented data for a potential clinical trial. Methods Biomechanical properties were assessed with a high resolution optical coherence tomography (OCT) based elastography (OCE) system. A shaker was used to initiate elastic waves and an OCT system was used to track axial displacement along with wave propagation. Rabbits received surgery to implant the retinal prosthetic electrode, and elastic wave speed was measured before and after implantation; anatomical B-mode images were also acquired. Results Spatial-temporal maps of each layer in retina with and without prosthetic electrodes were acquired. Elastic wave speed of nerve fiber to inner plexiform layer, inner nuclear to outer nuclear layer, retinal pigmented epithelium layer and choroid to sclera layer without prosthetic electrode were found to be 3.66±0.36, 5.33±0.07, 6.85±0.37, and 9.69±0.24 m/s, respectively. With prosthetic electrode, the elastic wave speed was found to be 4.09±0.26, 5.14±0.11, 6.88±0.70, and 9.99±0.73 m/s, respectively in each layer. Conclusions Our results show that the elastic wave speed in each layer of retina is slightly faster with the retinal electrode, and further demonstrate that the retinal prosthetic electrode does not affect biomechanical properties significantly. In the future, we expect OCE technology to be used by clinicians where it could become part of routine testing and evaluation of the biomechanical properties of the retina in response to long term use of prosthetic electrodes in patients.

The retina is a complex and fragile photosensitive part of the central nervous system which is prone to degenerative diseases leading to permanent vision loss. No proven treatment strategies exist to treat or reverse the degenerative conditions. Recent investigations demonstrate that cell transplantation therapies to replace the dysfunctional retinal pigment epithelial (RPE) cells and or the degenerating photoreceptors (PRs) are viable options to restore vision. Pluripotent stem cells, retinal progenitor cells, and somatic stem cells are the main cell sources used for cell transplantation therapies. The success of retinal transplantation based on cell suspension injection is hindered by limited cell survival and lack of cellular integration. Recent advances in material science helped to develop strategies to grow cells as intact monolayers or as sheets on biomaterial scaffolds for transplantation into the eyes. Such implants are found to be more promising than the bolus injection approach. Tissue engineering techniques are specifically designed to construct biodegradable or non-degradable polymer scaffolds to grow cells as a monolayer and construct implantable grafts. The engineered cell construct along with the extracellular matrix formed, can hold the cells in place to enable easy survival, better integration, and improved visual function. This article reviews the advances in the use of scaffolds for transplantation studies in animal models and their application in current clinical trials.

Age-related macular degeneration (AMD) is the primary cause of blindness in adults over 60 years of age, and clinical trials are currently assessing the therapeutic potential of retinal pigmented epithelial (RPE) cell monolayers on implantable scaffolds to treat this disease. However, challenges related to the culture, long-term storage, and long-distance transport of such implants currently limit the widespread use of adherent RPE cells as therapeutics. Here we report a xeno-free protocol to cryopreserve a confluent monolayer of clinical-grade, human embryonic stem cell-derived RPE cells on a parylene scaffold (REPS) that yields viable, polarized, and functional RPE cells post-thaw. Thawed cells exhibit ≥ 95% viability, have morphology, pigmentation, and gene expression characteristic of mature RPE cells, and secrete the neuroprotective protein, pigment epithelium-derived factor (PEDF). Stability under liquid nitrogen (LN2) storage has been confirmed through one year. REPS were administered immediately post-thaw into the subretinal space of a mammalian model, the Royal College of Surgeons (RCS)/nude rat. Implanted REPS were assessed at 30, 60, and 90 days post-implantation, and thawed cells demonstrate survival as an intact monolayer on the parylene scaffold. Furthermore, immunoreactivity for the maturation marker, RPE65, significantly increased over the post-implantation period in vivo, and cells demonstrated functional attributes similar to non-cryopreserved controls. The capacity to cryopreserve adherent cellular therapeutics permits extended storage and stable transport to surgical sites, enabling broad distribution for the treatment of prevalent diseases such as AMD.

Currently, blindness cannot be cured and patients' living quality can be compromised severely. Ultrasonic neuromodulation is a promising technology for the development of non-invasive cortical visual prosthesis. We investigated the feasibility of transcranial focused ultrasound (tFUS) for noninvasive stimulation of the visual cortex to develop improved visual prosthesis. tFUS was used to successfully evoke neural activities in the visual cortex (VC) of both normal and retinal degenerate (RD) blind rats. Our results showed that blind rats showed more robust responses to ultrasound stimulation compared to normal rats. (p

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.

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.

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.

Newborn microglia rapidly replenish the whole brain after selective elimination of most microglia (>99%) in adult mice. Previous studies reported that repopulated microglia were largely derived from microglial progenitor cells expressing nestin in the brain. However, the origin of these repopulated microglia has been hotly debated. In this study, we investigated the origin of repopulated microglia by a series of fate-mapping approaches. We first excluded the blood origin of repopulated microglia via parabiosis. With different transgenic mouse lines, we then demonstrated that all repopulated microglia were derived from the proliferation of the few surviving microglia (

Objective. Retinal implants have been developed to electrically stimulate healthy retinal neurons in the progressively degenerated retina. Several stimulation approaches have been proposed to improve the visual percept induced in patients with retinal prostheses. We introduce a computational model capable of simulating the effects of electrical stimulation on retinal neurons. Leveraging this computational platform, we delve into the underlying mechanisms influencing the sensitivity of retinal neurons’ response to various stimulus waveforms. Approach. We implemented a model of spiking bipolar cells (BCs) in the magnocellular pathway of the primate retina, diffuse BC subtypes (DB4), and utilized our multiscale admittance method (AM)-NEURON computational platform to characterize the response of BCs to epiretinal electrical stimulation with monophasic, symmetric, and asymmetric biphasic pulses. Main results. Our investigations yielded four notable results: (a) the latency of BCs increases as stimulation pulse duration lengthens; conversely, this latency decreases as the current amplitude increases. (b) Stimulation with a long anodic-first symmetric biphasic pulse (duration > 8 ms) results in a significant decrease in spiking threshold compared to stimulation with similar cathodic-first pulses (from 98.2 to 57.5 µA). (c) The hyperpolarization-activated cyclic nucleotide-gated channel was a prominent contributor to the reduced threshold of BCs in response to long anodic-first stimulus pulses. (d) Finally, extending the study to asymmetric waveforms, our results predict a lower BCs threshold using asymmetric long anodic-first pulses compared to that of asymmetric short cathodic-first stimulation. Significance. This study predicts the effects of several stimulation parameters on spiking BCs response to electrical stimulation. Of importance, our findings shed light on mechanisms underlying the experimental observations from the literature, thus highlighting the capability of the methodology to predict and guide the development of electrical stimulation protocols to generate a desired biological response, thereby constituting an ideal testbed for the development of electroceutical devices.

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.

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.

Purpose To report the intraoperative methods and anatomic results for subretinal implantation of an investigational human embryonic stem cell–derived retinal pigment epithelium (RPE) monolayer seeded on a synthetic substrate (California Project to Cure Blindness Retinal Pigment Epithelium 1 [CPCB-RPE1]) in geographic atrophy (GA). Design Single-arm, open label, prospective, nonrandomized, Phase 1/2a study. Participants Advanced non-neovascular age-related macular degeneration (NNAMD). Methods The worse-seeing eye (≤20/200) of each subject underwent subretinal implantation of a single 3.5×6.25 mm CPCB-RPE1 implant with a preplanned primary end point of safety and efficacy at 365 days. Commercially available 23-gauge vitrectomy equipment, custom surgical forceps, and operating microscope with or without intraoperative OCT (iOCT) were used. Exact Wilcoxon rank-sum tests and Spearman rank correlation coefficients were used to assess the association of the percentage of the GA area covered by the implant with patient and surgery characteristics. The partial Spearman correlation coefficient was calculated for the correlation between duration of surgery and baseline GA size after adjustment for surgeon experience. Main Outcome Measures Intraoperative exploratory measures are reported, including area of GA covered by implant, subretinal position of implant, duration of surgery, and incidence of adverse events. Operative recordings and reports were used to determine exploratory outcome measures. Results Sixteen subjects were enrolled with a median age of 78 years (range, 69–85 years). Median duration of the surgery for all subjects was 160 minutes (range, 121–466 minutes). Intraoperative OCT was used to guide subretinal placement in 9 cases. Intraoperative OCT was potentially useful in identifying pathology not evident with standard intraoperative visualization. Median GA area at baseline was 13.8 mm2 (range, 6.0–46.4 mm2), and median GA area left uncovered by the implant was 1.7 mm2 (range, 0–20.4 mm2). On average, 86.9% of the baseline GA area was covered by the implant. In 5 subjects, >90% of the GA area was covered. Baseline GA size was inversely correlated with percentage of GA area covered by the implant (rs=−0.72; P = 0.002). No unanticipated serious adverse events related to the implant or surgery were reported. Conclusions Surgical implantation of CPCB-RPE1 targeted to the area of GA in subjects with advanced NNAMD is feasible in an outpatient setting. Intraoperative OCT is not necessary but potentially useful in identifying subretinal pathology and confirming implant location.

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.

Neurostimulation has proved to be an effective method for the restoration of visual perception lost due to retinal diseases. However, the clinically available retinal neurostimulation method is based on invasive electrodes, making it a high-cost and high-risk procedure. Recently, ultrasound has been demonstrated to be an effective way to achieve noninvasive neurostimulation. In this work, a novel racing array transducer with a contact lens shape is proposed for ultrasonic retinal stimulation. The transducer is flexible and placed outside the eyeball, similar to the application of a contact lens. Ultrasound emitted from the transducer can reach the retina without passing through the lens, thus greatly minimizing the acoustic absorption in the lens. The discretized Rayleigh&ndash, Sommerfeld method was employed for the acoustic field simulation, and patterned stimulation was achieved. A 5 MHz racing array transducer with different element numbers was simulated to optimize the array configuration. The results show that a 512-element racing array is the most appropriate configuration considering the necessary tradeoff between the element number and the stimulation resolution. The stimulation resolution at a focus of 24 mm is about 0.6 mm. The obtained results indicate that the proposed racing array design of the ultrasound transducer can improve the feasibility of an ultrasound retinal prosthesis.

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).

The goal of this study was to quantitatively assess retinal thickness using spectral domain optical coherence tomography (SD-OCT) after subretinal implantation of human embryonic stem cell-derived retinal pigment epithelium in a porcine model. The implant is called CPCB-RPE1 for the California Project to Cure Blindness-Retinal Pigment Epithelium 1. Data were derived from previous experiments on 14 minipigs that received either subretinal implantation of CPCB-RPE1 (n = 11) or subretinal bleb formation alone (sham; n = 3) using previously described methods and procedures (Brant Fernandes et al. Ophthalmic Surg Lasers Imaging Retina 47:342–51, 2016; Martynova et al. (2016) Koss et al. Graefes Arch Clin Exp Ophthalmol 254:1553–65, 2016; Hu et al. Ophthalmic Res 48:186–91, 2016; Martynova et al. ARVO Abstract 2016. SD-OCT retinal thickness (RT) and sublayer thickness over the implant were compared with topographically similar preimplantation regions as described previously Martynova et al. ARVO Abstract 2016. Imaging results were compared to postmortem histology using hematoxylin-eosin staining. RT overlying the CPCB-RPE1 postimplantation was not significantly different from preimplantation (308 ± 72 μm vs 292 ± 41 μm; p = 0.44). RT was not significantly different before and after implantation in any retinal sublayer at 1 month. Histology demonstrated grossly normal retinal anatomy as well as photoreceptor interdigitation with RPE.

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.

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.

Ultrasound is an emerging method for non-invasive neuromodulation. Studies in the past have demonstrated that ultrasound can reversibly activate and inhibit neural activities in the brain. Recent research shows the possibility of using ultrasound ranging from 0.5 to 43 MHz in acoustic frequency to activate the retinal neurons without causing detectable damages to the cells. This review recapitulates pilot studies that explored retinal responses to the ultrasound exposure, discusses the advantages and limitations of the ultrasonic stimulation, and offers an overview of engineering perspectives in developing an acoustic retinal prosthesis. For comparison, this article also presents studies in the ultrasonic stimulation of the visual cortex. Despite that, the summarized research is still in an early stage; ultrasonic retinal stimulation appears to be a viable technology that exhibits enormous therapeutic potential for non-invasive vision restoration.

PurposeTo create new immunodeficient Royal College of Surgeons (RCS) rats by introducing the defective MerTK gene into athymic nude rats.MethodsFemale homozygous RCS (RCS-p+/RCS-p+) and male nude rats (Hsd:RH-Foxn1mu, mutation in the foxn1 gene; no T cells) were crossed to produce heterozygous F1 progeny. Double homozygous F2 progeny obtained by crossing the F1 heterozygotes was identified phenotypically (hair loss) and genotypically (RCS-p+ gene determined by PCR). Retinal degenerative status was confirmed by optical coherence tomography (OCT) imaging, electroretinography (ERG), optokinetic (OKN) testing, superior colliculus (SC) electrophysiology, and by histology. The effect of xenografts was assessed by transplantation of human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE) and human-induced pluripotent stem cell-derived RPE (iPS-RPE) into the eye. Morphological analysis was conducted based on hematoxylin and eosin (H&E) and immunostaining. Age-matched pigmented athymic nude rats were used as control.ResultsApproximately 6% of the F2 pups (11/172) were homozygous for RCS-p+ gene and Foxn1mu gene. Homozygous males crossed with heterozygous females resulted in 50% homozygous progeny for experimentation. OCT imaging demonstrated significant loss of retinal thickness in homozygous rats. H&E staining showed photoreceptor thickness reduced to 1-3 layers at 12 weeks of age. Progressive loss of visual function was evidenced by OKN testing, ERG, and SC electrophysiology. Transplantation experiments demonstrated survival of human-derived cells and absence of apparent immune rejection.ConclusionsThis new rat animal model developed by crossing RCS rats and athymic nude rats is suitable for conducting retinal transplantation experiments involving xenografts.

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.

Significant progress has been made recently in treating neurological blindness using implantable visual prostheses. However, implantable medical devices are highly invasive and subject to many safety, efficacy, and cost issues. The discovery that ultrasound (US) may be useful as a noninvasive neuromodulation tool has aroused great interest in the field of acoustic retinal prostheses (ARPs). We have investigated the responsiveness of rat retinal ganglion cells (RGCs) to low-frequency focused US stimulation (LFUS) at 2.25 MHz and characterized the neurophysiological properties of US responses by performing in vitro multielectrode array recordings. The results show that LFUS can reliably activate RGCs. The US-induced responses did not correspond to the standard light responses and varied greatly among cell types. Moreover, dual-peak responses to US stimulation were observed that have not been reported previously. The temporal response properties of RGCs, including their latency, firing rate, and response type, were modulated by the acoustic intensity. These findings suggest the presence of a temporal neuromodulation effect of LFUS and potentially open a new avenue in the development of ARP.

© 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 reports on the first phototherapeutic “contact lens” to manage diabetic retinopathy by reducing retinal metabolism via suppression of rod cell dark current. The contact lens is composed of PDMS embedded with a ring of gaseous tritium light sources providing continuous illumination over the lifetime of the lens. Electroretinogram responses from rabbits demonstrate bioactivity of the lens, which is further explored in 1D simulations of retinal oxygenation. Tests in human eyes validate comfort, fit, and the Troxler neural adaptation effect. With oxygen transmissibility, DK/t, of 130 Fatt, the lens meets FDA guidelines for overnight wear and offers advantages of comfort and reliability.

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.

Background Subretinal cell transplantation is a challenging surgical maneuver. This paper describes the preliminary findings of a new tissue injector for subretinal implantation of an ultrathin non-absorbable substrate seeded with human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE). Methods Ultrathin Parylene-C substrates measuring 3.5 mm × 6.0 mm seeded with hESC-RPE (implant referred to as CPCB-RPE1) were implanted into the subretinal space of 12 Yucatan minipigs. Animals were euthanized immediately after the procedure and underwent spectral domain optical coherence tomography (SD-OCT) and histological analysis to assess the subretinal placement of the implant. Evaluation of the hESC-RPE cells seeded on the substrate was carried out before and after implantation using standard cell counting techniques. Results The tissue injector delivered the CPCB-RPE1 implant through a 1.5 mm sclerotomy and a 1.0–1.5 mm retinectomy. SD-OCT scans and histological examination revealed that substrates were precisely placed in the subretinal space, and that the hESC-RPE cell monolayer continued to cover the surface of the substrate after the surgical procedure. Conclusion This innovative tissue injector was able to efficiently deliver the implant in the subretinal space of Yucatan minipigs, preventing significant hESC-RPE cell loss, minimizing tissue trauma, surgical complications and postoperative inflammation.

A typical retinal prosthesis is composed of multiple main functional blocks that operate as an integrated system, including an image acquisition module, an electronics module, and an electrode array. The image acquisition device is responsible for obtaining light information. The images are converted to electrical signals and processed by the electronics module into an electrical stimulation pattern that is applied to the retina through multielectrode array. These three main functional blocks are implemented in a variety of ways. Implementation depends on whether the array is passive (no implanted power source) or active (implanted power source). Another distinguishing design choice of retinal prostheses is the location of electrode array forming a functional interface with retina, which fall into three types: epiretinal (on the top surface of retina), subretinal (between retina and RPE/choroid), and suprachoroidal prostheses (between sclera and choroid). In this chapter, we will review important bioengineering considerations for retinal prostheses.

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.

Age-related macular degeneration (AMD) is an eye condition that is considered to be one of the leading causes of blindness among people over 50. Recent studies suggest that the mechanical properties in retina layers are affected during the early onset of disease. Therefore, it is necessary to identify such changes in the individual layers of the retina so as to provide useful information for disease diagnosis. In this study, we propose using an acoustic radiation force optical coherence elastography (ARF-OCE) system to dynamically excite the porcine retina and detect the vibrational displacement with phase resolved Doppler optical coherence tomography. Due to the vibrational mechanism of the tissue response, the image quality is compromised during elastogram acquisition. In order to properly analyze the images, all signals, including the trigger and control signals for excitation, as well as detection and scanning signals, are synchronized within the OCE software and are kept consistent between frames, making it possible for easy phase unwrapping and elasticity analysis. In addition, a combination of segmentation algorithms is used to accommodate the compromised image quality. An automatic 3D segmentation method has been developed to isolate and measure the relative elasticity of every individual retinal layer. Two different segmentation schemes based on random walker and dynamic programming are implemented. The algorithm has been validated using a 3D region of the porcine retina, where individual layers have been isolated and analyzed using statistical methods. The errors compared to manual segmentation will be calculated.

Evaluate parylene scaffold feasibility in cartilage lesion treatment, introducing a novel paradigm combining a reparative and superficial reconstructive procedure. Fifteen rabbits were used. All animals had both knees operated and the same osteochondral lesion model was created bilaterally. The parylene scaffold was implanted in the right knee, and the left knee of the same animal was used as control. The animals were euthanized at different time points after surgery: four animals at three weeks, three animals at six weeks, four animals at nine weeks, and four animals at 12 weeks. Specimens were analyzed by International Cartilage Repair Society (ICRS) macroscopic evaluation, modified Pineda histologic evaluation of cartilage repair, and collagen II immunostaining. Parylene knees were compared to its matched contra-lateral control knees of the same animal using the Wilcoxon matched-pairs signed rank. ICRS mean ± SD values for parylene versus control, three, six, nine and twelve weeks, respectively: 7.83 ± 1.85 versus 4.42 ± 1.08, p = 0.0005; 10.17 ± 1.17 versus 6.83 ± 1.17, p = 0.03; 10.89 ± 0.60 versus 7.33 ± 2.18, p = 0.007; 10.67 ± 0.78 versus 7.83 ± 3.40, p = 0.03. Modified Pineda mean ± SD values for parylene versus control, six, nine and twelve weeks, respectively: 3.37 ± 0.87 versus 6.94 ± 1.7, p < 0.0001; 5.73 ± 2.05 versus 6.41 ± 1.7, p = 0.007; 3.06 ± 1.61 versus 6.52 ± 1.51, p < 0.0001. No inflammation was seen. Parylene implanted knees demonstrated higher collagen II expression via immunostaining in comparison to the control knees. Parylene scaffolds are a feasible option for cartilage lesion treatment and the combination of a reparative to a superficial reconstructive procedure using parylene scaffolds led to better results than the reparative procedure alone.

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.