Teleophthalmology and Inequities in Diabetic Eye Disease at Safety Net Hospitals.

Introduction: Teleophthalmology has emerged as a convenient and cost-effective intervention to increase access to screening for diabetic retinopathy (DR), a disease that disproportionately affects socially disadvantaged communities. However, a few studies have directly compared the detection of eye disease by teleophthalmology between socially and geographically diverse communities. This study compared the rates and severity of diabetic eye disease, as detected by teleophthalmology, between safety net and non-Safety Net Hospitals (non-SNHs). Methods: Retrospective chart review of patients screened for DR at county Safety Net Hospitals (SNHs) and non-SNHs in 150 cities and 30 states. The rates of DR, macular edema, suspected cataract, suspected glaucoma, and suspected age-related macular degeneration were compared. Relative risk and severity of disease in the county SNH population were calculated. Images were graded by the same group of IRIS readers, who used at least one image per eye with a 45° field centered between the optic disc and the macula. Participants with ungradable screening images were excluded. Results: Ninety-four thousand three hundred twenty-nine participants were screened for eye disease from September 1, 2016 to August 31, 2017. Among the screened participants (54% female; mean [SD] age, 58.7 [12.9] years), overall disease detection was 31% in the county SNH population and 23.6% in the non-SNH population. Compared with the non-SNH population, the county SNH population was twice as likely to screen positive for three or more concurrent eye conditions (1.2% vs. 0.7%) and had increased prevalence of DR (20.2% vs. 16.2%), macular edema (4.9% vs. 3.4%), suspected glaucoma (9.1% vs. 4.3%), suspected cataract (9.6% vs. 4.8%), and proliferative DR (2.1% vs. 1.0%). Conclusions: Increased diabetic eye disease prevalence and severity among people seen at SNHs highlights the need for continued resources to screen, treat, and manage disease. Teleophthalmology continues to be an important tool in efforts to mitigate health inequities and address barriers faced by underserved communities.

Distribution of particles, small molecules and polymeric formulation excipients in the suprachoroidal space after microneedle injection.

The purpose of this work was to determine the effect of injection volume, formulation composition, and time on circumferential spread of particles, small molecules, and polymeric formulation excipients in the suprachoroidal space (SCS) after microneedle injection into New Zealand White rabbit eyes ex vivo and in vivo. Microneedle injections of 25-150 µL Hank's Balanced Salt Solution (HBSS) containing 0.2 µm red-fluorescent particles and a model small molecule (fluorescein) were performed in rabbit eyes ex vivo, and visualized via flat mount. Particles with diameters of 0.02-2 µm were co-injected into SCS in vivo with fluorescein or a polymeric formulation excipient: fluorescein isothiocyanate (FITC)-labeled Discovisc or FITC-labeled carboxymethyl cellulose (CMC). Fluorescent fundus images were acquired over time to determine area of particle, fluorescein, and polymeric formulation excipient spread, as well as their co-localization. We found that fluorescein covered a significantly larger area than co-injected particles when suspended in HBSS, and that this difference was present from 3 min post-injection onwards. We further showed that there was no difference in initial area covered by FITC-Discovisc and particles; the transport time (i.e., the time until the FITC-Discovisc and particle area began dissociating) was 2 d. There was also no difference in initial area covered by FITC-CMC and particles; the transport time in FITC-CMC was 4 d. We also found that particle size (20 nm-2 µm) had no effect on spreading area when delivered in HBSS or Discovisc. We conclude that (i) the area of particle spread in SCS during injection generally increased with increasing injection volume, was unaffected by particle size, and was significantly less than the area of fluorescein spread, (ii) particles suspended in low-viscosity HBSS formulation were entrapped in the SCS after injection, whereas fluorescein was not and (iii) particles co-injected with viscous polymeric formulation excipients co-localized near the site of injection in the SCS, continued to co-localize while spreading over larger areas for 2-4 days, and then no longer co-localized as the polymeric formulation excipients were cleared within 1-3 weeks and the particles remained largely in place. These data suggest that particles encounter greater barriers to flow in SCS compared to molecules and that co-localization of particles and polymeric formulation excipients allows spreading over larger areas of the SCS until the particles and excipients dissociate.

Circumferential flow of particles in the suprachoroidal space is impeded by the posterior ciliary arteries.

Microneedle injection into the suprachoroidal space (SCS) enables targeted drug delivery for treatment of posterior segment diseases. This study sought to identify and characterize anatomical barriers to circumferential spread of particles in the SCS of rabbit and human cadaver eyes. These barriers could make targeting specific regions within the SCS challenging. A hollow microneedle (33-gauge, 750 µm long) was used to inject fluorescent particles into albino New Zealand White rabbit eyes ex vivo at six different positions around the limbus and a limited number of conditions in vivo. SCS injections were also performed in human cadaver eyes 8 mm and 2 mm from the optic nerve (ON). Eyes were dissected and particle distribution was quantified. In rabbit eyes, injections made in the superior or inferior hemispheres (even when injected temporally immediately adjacent to the long posterior ciliary artery (LPCA)) did not significantly cross into the other hemisphere, apparently due to a barrier formed by the LPCA. The vortex veins had a minor effect on particle deposition, limited to only around the vortex vein root. In human eyes, the short posterior ciliary arteries (SPCAs) prevented circumferential spread towards the macula and ON. In conclusion, the rabbit LPCA and the human SPCA were anatomical barriers to particle spread within the SCS. Therefore, design of drug delivery protocols targeting the SCS need to account for barriers formed by anatomical structures in order for injected drug to reach target tissues.

Over-expression of catalase in myeloid cells confers acute protection following myocardial infarction.

Cardiovascular disease is the leading cause of death in the United States and new treatment options are greatly needed. Oxidative stress is increased following myocardial infarction and levels of antioxidants decrease, causing imbalance that leads to dysfunction. Therapy involving catalase, the endogenous scavenger of hydrogen peroxide (H2O2), has been met with mixed results. When over-expressed in cardiomyocytes from birth, catalase improves function following injury. When expressed in the same cells in an inducible manner, catalase showed a time-dependent response with no acute benefit, but a chronic benefit due to altered remodeling. In myeloid cells, catalase over-expression reduced angiogenesis during hindlimb ischemia and prevented monocyte migration. In the present study, due to the large inflammatory response following infarction, we examined myeloid-specific catalase over-expression on post-infarct healing. We found a significant increase in catalase levels following infarction that led to a decrease in H2O2 levels, leading to improved acute function. This increase in function could be attributed to reduced infarct size and improved angiogenesis. Despite these initial improvements, there was no improvement in chronic function, likely due to increased fibrosis. These data combined with what has been previously shown underscore the need for temporal, cell-specific catalase delivery as a potential therapeutic option.

Design and ex vivo development of a suprachoroidal spacer implant to treat glaucoma.

Glaucoma is a leading cause of visual impairment and blindness in the United States and worldwide. Elevated intraocular pressure (IOP) has been identified as the only modifiable risk factor in glaucoma, and there exists a need for a glaucoma procedure that is safe, efficacious, and can be performed in the outpatient clinic setting. Suprachoroidal expansion has been explored as a method to lower IOP previously. The purpose of this work was to design a monolithic hydrogel implant that would not clear or degrade to potentially achieve long term (possibly permanent) IOP reduction. Here, we developed and showed ex vivo testing of a novel photo-crosslinked polyethylene glycol (PEG) suprachoroidal spacer implant delivered via a custom-designed injector system. We optimized the composition, shape, and mechanics of the implant to be suitable for implantation with the suprachoroidal space. We developed a microneedle injector system to deliver this implant. We showed precise control over implant location and volume occupied within the suprachoroidal space. Further preclinical testing is needed to demonstrate efficacy.

Development of a novel SupraChoroidal-to-Optic-NervE (SCONE) drug delivery system.

PURPOSE: Targeted drug delivery to the optic nerve head may be useful in the preclinical study and later clinical management of optic neuropathies, however, there are no FDA-approved drug delivery systems to achieve this. The purpose of this work was to develop an optic nerve head drug delivery technique. METHODS: Different strategies to approach the optic nerve head were investigated, including standard intravitreal and retroorbital injections. A novel SupraChoroidal-to-Optic-NervE (SCONE) delivery was optimized by creating a sclerotomy and introducing a catheter into the suprachoroidal space. Under direct visualization, the catheter was guided to the optic nerve head. India ink was injected. The suprachoroidal approach was performed in New Zealand White rabbit eyes in vivo (25 animals total). Parameters, including microneedle size and design, catheter design, and catheter tip angle, were optimized ex vivo and in vivo. RESULTS: Out of the candidate optic nerve head approaches, intravitreal, retroorbital, and suprachoroidal approaches were able to localize India ink to within 2 mm of the optic nerve. The suprachoroidal approach was further investigated, and after optimization, was able to deposit India ink directly within the optic nerve head in up to 80% of attempts. In eyes with successful SCONE delivery, latency and amplitude of visual evoked potentials was not different than the naïve untreated eye. CONCLUSIONS: SCONE delivery can be used for targeted drug delivery to the optic nerve head of rabbits without measurable toxicity measured anatomically or functionally. Successful development of this system may yield novel opportunities to study optic nerve head-specific drug delivery in animal models, and paradigm-shifting management strategies for treating optic neuropathies. TRANSLATIONAL RELEVANCE: Here we demonstrate data on a new method for targeted delivery to the optic nerve head, addressing a significant unmet need in therapeutics for optic neuropathies.

Comparison of Subjective Visual Experiences and Ocular Symptoms After Wavefront-Guided and Wavefront-Optimized LASIK in a Prospective Fellow Eye Study.

PURPOSE: The purpose of this study was to compare the subjective visual experience and ocular symptoms of fellow eyes treated with wavefront-optimized laser-assisted in situ keratomileusis (WFO-LASIK) and wavefront-guided laser-assisted in situ keratomileusis (WFG-LASIK). DESIGN: Prospective randomized fellow eye, controlled study. METHODS: A total of 200 eyes of 100 subjects from a single academic center were enrolled and randomly assigned to treatment with WFO-LASIK in one eye and WFG-LASIK in the fellow eye. Subjects filled out a validated 14-part questionnaire for each eye at the preoperative visit and at postoperative months 1, 3, 6, and 12. RESULTS: In comparing the number of subjects who reported symptoms in the WFG- vs WFO- LASIK eyes, there was no difference in the number reporting any visual experience (glare, halos, starbursts, hazy vision, blurred vision, distortion, double or multiple images, fluctuations in vision, focusing difficulties, and depth perception; all P > .05) or ocular symptoms (photosensitivity, dry eye, foreign body sensation, ocular pain; all P > .05). There was no preference for WFG-LASIK-treated (28%) or the WFO-LASIK-treated eye (29%), with the majority of subjects reporting no preference (43%; χ2P = .972). Of the subjects who preferred one eye or the other, the preferred eye saw statistically better than the fellow eye (0.8 ± 1.4 Snellen line, P = .0002). There was no other difference in subjective visual experience, ocular symptoms, or refractive characteristics when taking into account eye preference. CONCLUSIONS: The majority of subjects had no eye preference. For subjects who did have eye preference, the only detectable difference was better visual acuity in the preferred eye.

Endoscopic enucleation and clinicopathologic correlation of a small choroidal melanoma hiding massive extrascleral extension.

Purpose: To report the unusual case of a previously stable choroidal nevus, closely followed for over 15 years, which underwent malignant transformation into small choroidal melanoma with massive extrascleral extension. Observations: A 67-year-old Caucasian female was referred to the Stanford Ocular Oncology Service with concern for malignant transformation of a previously stable choroidal nevus in her left eye. Her funduscopic examination demonstrated a dome-shaped choroidal lesion with overlying associated lipofuscin and subretinal fluid, consistent with a diagnosis of small choroidal melanoma. By B-scan ultrasonography, the lesion measured 8.0 × 6.0 mm in base and 2.1 mm in thickness. B-scan ultrasonography also disclosed an associated retroscleral mass, which appeared contiguous with the intraocular melanoma and was confirmed on subsequent orbital magnetic resonance imaging. A decision was made to proceed with enucleation. Under direct endoscopic visualization, the globe and extrascleral mass were fully isolated, mobilized, and removed in toto. At 24 months post-enucleation, the patient remains disease-free without evidence of systemic metastasis or local recurrence. Conclusions/importance: This case describes a small choroidal melanoma hiding massive extrascleral extension, underscoring the value of B-scan ultrasonography. This case also describes the unique management of choroidal melanoma with extrascleral extension using endoscopic enucleation. Performing enucleation under direct endoscopic visualization ensures complete resection and prevents inadvertent transection of the extrascleral component.

Prospective, Randomized Contralateral Eye Comparison of Wavefront-Guided Laser In Situ Keratomileusis and Small Incision Lenticule Extraction Refractive Surgeries.

PURPOSE: Wavefront-guided laser in situ keratomileusis (WFG-LASIK) and small incision lenticule extraction (SMILE) are keratorefractive surgeries that can improve uncorrected visual acuity in myopic patients. Comparison of visual outcomes in myopic patients treated with LASIK and SMILE is needed. DESIGN: Prospective, randomized contralateral eye-controlled trial. METHODS: We performed a single-center prospective, randomized contralateral eye comparison of WFG-LASIK and SMILE (NCT03067077). Myopic patients with low levels of astigmatism were treated with WFG-LASIK in one eye and SMILE in the fellow eye from March 2017 to March 2021. Treatments were randomized by ocular dominance. WFG-LASIK and SMILE were performed. Postoperative evaluation at 1 day consisted of uncorrected distance visual acuity (UDVA), wavefront aberrometry, and a slit-lamp examination. On subsequent postoperative visits at 1 month, 3 months, 6 months, and 12 months, UDVA, manifest refraction, 5% and 25% low-contrast visual acuity, wavefront aberrometry, and slit-lamp examination were performed. MAIN OUTCOME MEASURE: The primary outcome measure was UDVA at 12 months. RESULTS: Eighty-eight eyes of 44 patients with myopia were enrolled in the study. Seventy-four eyes of 37 patients had successful treatments and completed 12 months of follow-up. At postoperative month 12, there were a significantly higher proportion of WFG-LASIK eyes that had ≥20/20 UDVA compared with SMILE eyes (94% vs 83%, P < .05). There was no difference between spherical equivalent between WFG-LASIK eyes and SMILE eyes (-0.17 ± 0.25 vs -0.29 ± 0.38, P > .05); there was no difference in higher order aberrations, including coma, trefoil, and spherical aberrations (P > 0.05); and there were a significantly higher proportion of WFG-LASIK eyes that had improved 5% and 25% low-contrast visual acuity compared with SMILE eyes (P < 0.05). CONCLUSIONS: WFG-LASIK and SMILE both offered marked improvements in corrected distance visual acuity and excellent predictability in both eyes. Compared with SMILE, WFG-LASIK resulted in faster visual recovery, better low-contrast visual acuity, and greater gains in uncorrected visual acuity.

A protocol to inject ocular drug implants into mouse eyes.

Ocular drug implants (ODIs) are beneficial for treating ocular diseases. However, the lack of a robust injection approach for small-eyed model organisms has been a major technical limitation in developing ODIs. Here, we present a cost-effective, minimally invasive protocol to deliver ODIs into the mouse vitreous called Mouse Implant Intravitreal Injection (MI3). MI3 provides two alternative surgical approaches (air-pressure or plunger) to deliver micro-scaled ODIs into milli-scaled eyes, and expands the preclinical platforms to determine ODIs' efficacy, toxicity, and pharmacokinetics. For complete details on the use and execution of this protocol, please refer to Sun et al. (2021).

Cross-axis adaptation improves 3D vestibulo-ocular reflex alignment during chronic stimulation via a head-mounted multichannel vestibular prosthesis.

By sensing three-dimensional (3D) head rotation and electrically stimulating the three ampullary branches of a vestibular nerve to encode head angular velocity, a multichannel vestibular prosthesis (MVP) can restore vestibular sensation to individuals disabled by loss of vestibular hair cell function. However, current spread to afferent fibers innervating non-targeted canals and otolith end organs can distort the vestibular nerve activation pattern, causing misalignment between the perceived and actual axis of head rotation. We hypothesized that over time, central neural mechanisms can adapt to correct this misalignment. To test this, we rendered five chinchillas vestibular deficient via bilateral gentamicin treatment and unilaterally implanted them with a head-mounted MVP. Comparison of 3D angular vestibulo-ocular reflex (aVOR) responses during 2 Hz, 50°/s peak horizontal sinusoidal head rotations in darkness on the first, third, and seventh days of continual MVP use revealed that eye responses about the intended axis remained stable (at about 70% of the normal gain) while misalignment improved significantly by the end of 1 week of prosthetic stimulation. A comparable time course of improvement was also observed for head rotations about the other two semicircular canal axes and at every stimulus frequency examined (0.2-5 Hz). In addition, the extent of disconjugacy between the two eyes progressively improved during the same time window. These results indicate that the central nervous system rapidly adapts to multichannel prosthetic vestibular stimulation to markedly improve 3D aVOR alignment within the first week after activation. Similar adaptive improvements are likely to occur in other species, including humans.

Contamination of multiuse eyedrop bottles by exhaled air from patients wearing face masks during the COVID-19 pandemic: Schlieren imaging analysis.

PURPOSE: To determine whether mask-induced redirected exhaled air through the superior mask gap contacts multiuse eyedrop bottles during drop administration and the efficacy of interventions to reduce such exposure. SETTING: Academic ophthalmology center. DESIGN: Interventional analysis. METHODS: Schlieren airflow imaging was taken of an examinee wearing frequently used face masks and enacting common clinical scenarios-with and without manual occlusion of the superior mask gap and/or neck extension-and maximum visible vertical breath plume height was quantified. Bottle height during eyedrop administration was measured for 4 ophthalmologists during instillation to 8 eyes of 4 subjects. RESULTS: Breath plume height (mean ± SD 275.5 ± 16.3 mm) was significantly greater than mean bottle height (13.9 ± 4.7 mm; P < .01). Plume height was reduced with manual mask occlusion vs without (P < .01) and was also lower than mean bottle height with manual mask occlusion (P < .01) but not in the absence of occlusion (P < .01). Neck extension alone did not adequately redirect liberated breath to prevent contact with a bottle. CONCLUSIONS: Exhaled air liberated from commonly worn patient face masks was able to contact multiuse eyedrop bottles during eyedrop administration. These findings have important patient safety implications during the coronavirus disease 2019 pandemic and with other respiratory pathogens because these multiuse bottles could potentially serve as vectors of disease. Occlusion of the superior mask gap significantly reduces breath contamination and should be strongly considered by eyecare providers during drop administration in eye clinics.

An intravitreal implant injection method for sustained drug delivery into mouse eyes.

Using small molecule drugs to treat eye diseases carries benefits of specificity, scalability, and transportability, but their efficacy is significantly limited by a fast intraocular clearance rate. Ocular drug implants (ODIs) present a compelling means for the slow and sustained release of small molecule drugs inside the eye. However, methods are needed to inject small molecule ODIs into animals with small eyes, such as mice, which are the primary genetic models for most human ocular diseases. Consequently, it has not been possible to fully investigate efficacy and ocular pharmacokinetics of ODIs. Here, we present a robust, cost-effective, and minimally invasive method called "mouse implant intravitreal injection" (MI3) to deliver ODIs into mouse eyes. This method will expand ODI research to cover the breadth of human eye diseases modeled in mice.

Enhancing Risk Assessment in Patients with Diabetic Retinopathy by Combining Measures of Retinal Function and Structure.

Purpose: To determine whether combining measures of retinal structure and function predicts need for intervention for diabetic retinopathy (DR) better than either modality alone. Methods: The study sample consisted of 279 diabetic patients who participated in an earlier cross-sectional study. Patients were excluded if they were previously treated for macular edema or proliferative DR or if they had other retinopathies. Medical records were reviewed for ocular interventions including vitrectomy, intravitreal injection, and laser treatment. Need for intervention was analyzed using Kaplan-Meier analyses and Cox proportional hazards. Baseline electroretinograms and fundus photographs were obtained. Two definitions of structural positive findings were as follows: 1. Early Treatment of Diabetic Retinopathy Study diabetic retinopathy severity scale (ETDRS-DR) severity ≥ level 53 (ETDRS-DR+) and 2. ETDRS-DR+ or clinically significant macular edema (VTDR+). A positive function finding corresponded to a RETeval DR Score >23.5 (RETeval+). Results: For patients with VTDR+ the incidence of intervention was 19%, 31%, and 53% after 1, 2, and 3 years of follow-up. In these patients, intervention incidence increased to 34%, 54%, and 74% the subsequent 1, 2, and 3 years if function was above criterion (RETeval+), whereas RETeval- results reduced the risk to 3%, 4%, and 29%, respectively, reducing risk to similar levels seen for patients with VTDR- results at baseline. Conclusions: Prediction of subsequent intervention was best when combining structural and functional information. Translational Relevance: This study demonstrates that clinical management of diabetic retinopathy is improved by adding electroretinography to fundus photographic information in assessing the risk of the need for intervention.

The suprachoroidal space as a route of administration to the posterior segment of the eye.

The suprachoroidal space (SCS) is a potential space between the sclera and choroid that traverses the circumference of the posterior segment of the eye. The SCS is an attractive site for drug delivery because it targets the choroid, retinal pigment epithelium, and retina with high bioavailability, while maintaining low levels elsewhere in the eye. Indeed, phase III clinical trials are investigating the safety and efficacy of SCS drug delivery. Here, we review the anatomy and physiology of the SCS; methods to access the SCS; kinetics of SCS drug delivery; strategies to target within the SCS; current and potential clinical indications; and the safety and efficacy of this approach in preclinical animal studies and clinical trials.

Ocular drug delivery targeted by iontophoresis in the suprachoroidal space using a microneedle.

Treatment of many posterior-segment ocular indications would benefit from improved targeting of drug delivery to the back of the eye. Here, we propose the use of iontophoresis to direct delivery of negatively charged nanoparticles through the suprachoroidal space (SCS) toward the posterior pole of the eye. Injection of nanoparticles into the SCS of the rabbit eye ex vivo without iontophoresis led to a nanoparticle distribution mostly localized at the site of injection near the limbus and <15% of nanoparticles delivered to the most posterior region of SCS (>9 mm from the limbus). Iontophoresis using a novel microneedle-based device increased posterior targeting with >30% of nanoparticles in the most posterior region of SCS. Posterior targeting increased with increasing iontophoresis current and increasing application time up to 3 min, but further increasing to 5 min was not better, probably due to the observed collapse of the SCS within 5 min after injection ex vivo. Reversing the direction of iontophoretic flow inhibited posterior targeting, with just ~5% of nanoparticles reaching the most posterior region of SCS. In the rabbit eye in vivo, iontophoresis at 0.14 mA for 3 min after injection of a 100 µL suspension of nanoparticles resulted in ~30% of nanoparticles delivered to the most posterior region of the SCS, which was consistent with ex vivo findings. The procedure was well tolerated, with only mild, transient tissue effects at the site of injection. We conclude that iontophoresis in the SCS using a microneedle has promise as a method to target ocular drug delivery within the eye, especially toward the posterior pole.

Clearance Kinetics and Clearance Routes of Molecules From the Suprachoroidal Space After Microneedle Injection.

Purpose: To determine clearance kinetics and routes of clearance of molecules from the suprachoroidal space (SCS) of live New Zealand White rabbits. Methods: Suprachoroidal space collapse rate and pressure changes after microneedle injection into SCS were determined. Fluorescent fundus images were acquired to determine clearance rates of molecules ranging in size from 332 Da to 2 MDa. Microneedle injections of fluorescein were performed, and samples were taken from various sites over time to determine amount of fluorescein exiting the eye. Clearance transport was modeled theoretically and compared with experimental data. Results: After injection, pressures in SCS and vitreous humor spiked and returned to baseline within 20 minutes; there was no difference between these two pressures. Suprachoroidal space collapse occurred within 40 minutes. One hour after fluorescein injection, 46% of fluorescein was still present in the eye, 15% had transported across sclera, 6% had been cleared by choroidal vasculature, and 4% had exited via leakage pathways. Characteristic clearance time increased in proportion with molecular radius, but total clearance of 2 MDa FITC-dextran was significantly slower (21 days) than smaller molecules. These data generally agreed with predictions from a theoretical model of molecular transport. Conclusions: Guided by experimental data in the context of model predictions, molecular clearance from SCS occurred in three regimes: (1) on a time scale of approximately 10 minutes, fluid and molecules exited SCS by diffusion into sclera and choroid, and by pressure-driven reflux via transscleral leakage sites; (2) in approximately 1 hour, molecules cleared from choroid by blood flow; and (3) in 1 to 10 hours, molecules cleared from sclera by diffusion and convection.

Thickness and Closure Kinetics of the Suprachoroidal Space Following Microneedle Injection of Liquid Formulations.

Purpose: To determine the effect of injection volume and formulation of a microneedle injection into the suprachoroidal space (SCS) on SCS thickness and closure kinetics. Methods: Microneedle injections containing 25 to 150 µL Hanks' balanced salt solution (HBSS) were performed in the rabbit SCS ex vivo. Distribution of SCS thickness was measured by ultrasonography and three-dimensional (3D) cryo-reconstruction. Microneedle injections were performed in the rabbit SCS in vivo using HBSS, Discovisc, and 1% to 5% carboxymethyl cellulose (CMC) in HBSS. Ultrasonography was used to track SCS thickness over time. Results: Increasing HBSS injection volume increased the area of expanded SCS, but did not increase SCS thickness ex vivo. With SCS injections in vivo, the SCS initially expanded to thicknesses of 0.43 ± 0.06 mm with HBSS, 1.5 ± 0.4 mm with Discovisc, and 0.69 to 2.1 mm with 1% to 5% CMC. After injection with HBSS, Discovisc, and 1% CMC solution, the SCS collapsed to baseline with time constants of 19 minutes, 6 hours, and 2.4 days, respectively. In contrast, injections with 3% to 5% CMC solution resulted in SCS expansion to 2.3 to 2.8 mm over the course of 2.8 to 9.1 hours, after which the SCS collapsed to baseline with time constants of 4.5 to 9.2 days. Conclusions: With low-viscosity formulations, SCS expands to a thickness that remains roughly constant, independent of the volume of fluid injected. Increasing injection fluid viscosity significantly increased SCS thickness. Expansion of the SCS is hypothesized to be controlled by a balance between the viscous forces of the liquid formulation and the resistive biomechanical forces of the tissue.

Automated head motion system improves reliability and lessens operator dependence for head impulse testing of vestibular reflexes.

Deficiency of the eye-stabilizing vestibulo-ocular reflex (VOR) is a defining feature in multiple diseases of the vestibular labyrinth, which comprises the inner ear's sensors of head rotation, translation and orientation. Diagnosis of these disorders is facilitated by observation and measurement of eye movements during and after head motion. The video head impulse test has recently garnered interest as a clinical diagnostic assessment of vestibular dysfunction. In typical practice, it involves use of video-oculography goggles to measure eye movements while a clinician examiner grasps the subject's head and manually rotates it left or right at sufficient acceleration to cover ~20 deg over ~150 mS, reaching a peak velocity of >120 deg/S midway through the movement. Manual delivery of head impulses incurs significant trial-by-trial, inter-session and inter-operator variability, which lessens the test's reliability, efficiency, safety and standardization across testing facilities. We describe application of a novel, compact and portable automated head impulse test (aHIT™) device that delivers highly repeatable head motion stimuli about axes parallel to those of the vestibular labyrinth's six semicircular canals, with programmable Gaussian and sinusoidal motion profiles at amplitudes, velocities and accelerations sufficient to test VOR function over the spectral range for which the VOR dominates other vision-stabilizing reflexes. We tested the aHIT™ on human subjects and demonstrated its high reproducibility compared to manually delivered head impulses. This device has the potential to be a valuable clinical and research tool for diagnostic evaluation and investigation of the vestibular system.

A CMOS Neural Interface for a Multichannel Vestibular Prosthesis.

We present a high-voltage CMOS neural-interface chip for a multichannel vestibular prosthesis (MVP) that measures head motion and modulates vestibular nerve activity to restore vision- and posture-stabilizing reflexes. This application specific integrated circuit neural interface (ASIC-NI) chip was designed to work with a commercially available microcontroller, which controls the ASIC-NI via a fast parallel interface to deliver biphasic stimulation pulses with 9-bit programmable current amplitude via 16 stimulation channels. The chip was fabricated in the ONSemi C5 0.5 micron, high-voltage CMOS process and can accommodate compliance voltages up to 12 V, stimulating vestibular nerve branches using biphasic current pulses up to 1.45±0.06 mA with durations as short as 10 µs/phase. The ASIC-NI includes a dedicated digital-to-analog converter for each channel, enabling it to perform complex multipolar stimulation. The ASIC-NI replaces discrete components that cover nearly half of the 2nd generation MVP (MVP2) printed circuit board, reducing the MVP system size by 48% and power consumption by 17%. Physiological tests of the ASIC-based MVP system (MVP2A) in a rhesus monkey produced reflexive eye movement responses to prosthetic stimulation similar to those observed when using the MVP2. Sinusoidal modulation of stimulus pulse rate from 68-130 pulses per second at frequencies from 0.1 to 5 Hz elicited appropriately-directed slow phase eye velocities ranging in amplitude from 1.9-16.7 °/s for the MVP2 and 2.0-14.2 °/s for the MVP2A. The eye velocities evoked by MVP2 and MVP2A showed no significant difference ( t-test, p=0.34), suggesting that the MVP2A achieves performance at least as good as the larger MVP2.