Clinical Instructor, Ophthalmology
Fellowship, Stanford University, Glaucoma (2024)
Residency: Stanford University Ophthalmology Residency (2022) CA
Internship: Alameda County Highland Hospital Internal Medicine Residency (2019) CA
Medical Education: Emory University Medical School (2018) GA
BS, The Johns Hopkins University, Biomedical Engineering (2008)
MSE, The Johns Hopkins University, Biomedical Engineering (2009)
PhD, Georgia Institute of Technology, Biomedical Engineering (2016)
MD, Emory University School of Medicine (2018)
Endoscopic enucleation and clinicopathologic correlation of a small choroidal melanoma hiding massive extrascleral extension.
American journal of ophthalmology case reports
2023; 29: 101797
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.
View details for DOI 10.1016/j.ajoc.2023.101797
View details for PubMedID 36703903
Factors affecting eye preference in a prospective randomized controlled fellow eye study comparing WFG-LASIK and WFO-LASIK treatment
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022
View details for Web of Science ID 000844437006126
A protocol to inject ocular drug implants into mouse eyes.
2022; 3 (1): 101143
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 etal. (2021).
View details for DOI 10.1016/j.xpro.2022.101143
View details for PubMedID 35141566
Teleophthalmology and Inequities in Diabetic Eye Disease at Safety Net Hospitals.
Telemedicine journal and e-health : the official journal of the American Telemedicine Association
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.
View details for DOI 10.1089/tmj.2021.0329
View details for PubMedID 34978959
An intravitreal implant injection method for sustained drug delivery into mouse eyes.
Cell reports methods
2021; 1 (8)
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.
View details for DOI 10.1016/j.crmeth.2021.100125
View details for PubMedID 35128514
Prospective, Randomized, Contralateral Eye Comparison of Wavefront-Guided Laser in Situ Keratomileusis (WFG-LASIK) and Small Incision Lenticule Extraction (SMILE) refractive surgeries.
American journal of ophthalmology
PURPOSE: Wave-front 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 are 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 UDVA, wavefront aberrometry, and a slit lamp examination. On subsequent postoperative visits at 1-mo, 3-mo, 6-mo, and 12-mo, 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 uncorrected distance visual acuity at twelve months RESULTS: Eighty-eight (88) eyes of 44 patients with myopia were enrolled in the study. Seventy-four eyes of 37 patients had successful treatments and ccompleted 12 months of follow-up. At postoperative month 12, there was significantly higher proportion of WFG-LASIK eyes who had >= 20/20 uncorrected distance visual acuity compared with SMILE eyes (94% vs 83%, p<0.05). There was no difference between spherical equivalent between WFG-LASIK eyes and SMILE eyes (-0.17±0.25 vs -0.29±0.38, p>0.05); there was no difference in higher order aberrations, including coma, trefoil, and spherical aberrations (p>0.05); and there was significantly higher proportion of WFG-LASIK eyes who had improved 5% and 25% low contrast visual acuity compared with SMILE eyes (p<0.05) CONCLUSIONS: WFG-LASIK and SMILE both offered significant 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.
View details for DOI 10.1016/j.ajo.2021.11.013
View details for PubMedID 34788593
Contamination of multiuse eyedrop bottles by exhaled air from patients wearing face masks during the COVID-19 pandemic: Schlieren imaging analysis.
Journal of cataract and refractive surgery
2021; 47 (9): 1167-1174
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.
View details for DOI 10.1097/j.jcrs.0000000000000590
View details for PubMedID 34468454
Enhancing Risk Assessment in Patients with Diabetic Retinopathy by Combining Measures of Retinal Function and Structure.
Translational vision science & technology
2020; 9 (9): 40
To determine whether combining measures of retinal structure and function predicts need for intervention for diabetic retinopathy (DR) better than either modality alone.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+).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.Prediction of subsequent intervention was best when combining structural and functional information.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.
View details for DOI 10.1167/tvst.9.9.40
View details for PubMedID 32908803
View details for PubMedCentralID PMC7453041
Ocular drug delivery targeted by iontophoresis in the suprachoroidal space using a microneedle
JOURNAL OF CONTROLLED RELEASE
2018; 277: 14-22
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.
View details for DOI 10.1016/j.jconrel.2018.03.001
View details for Web of Science ID 000430385200002
View details for PubMedID 29505807
View details for PubMedCentralID PMC5911252
The suprachoroidal space as a route of administration to the posterior segment of the eye
ADVANCED DRUG DELIVERY REVIEWS
2018; 126: 58-66
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.
View details for DOI 10.1016/j.addr.2018.03.001
View details for Web of Science ID 000436220400005
View details for PubMedID 29545195
View details for PubMedCentralID PMC5995649
Automated head motion system improves reliability and lessens operator dependence for head impulse testing of vestibular reflexes
IEEE. 2017: 94-99
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.
View details for Web of Science ID 000463744700018
View details for PubMedID 30221255
View details for PubMedCentralID PMC6136842
Clearance Kinetics and Clearance Routes of Molecules From the Suprachoroidal Space After Microneedle Injection
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
2017; 58 (1): 545-554
To determine clearance kinetics and routes of clearance of molecules from the suprachoroidal space (SCS) of live New Zealand White rabbits.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.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.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.
View details for DOI 10.1167/iovs.16-20679
View details for Web of Science ID 000392954300060
View details for PubMedID 28125841
View details for PubMedCentralID PMC5283080
Thickness and Closure Kinetics of the Suprachoroidal Space Following Microneedle Injection of Liquid Formulations
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
2017; 58 (1): 555-564
To determine the effect of injection volume and formulation of a microneedle injection into the suprachoroidal space (SCS) on SCS thickness and closure kinetics.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.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.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.
View details for DOI 10.1167/iovs.16-20377
View details for Web of Science ID 000392954300061
View details for PubMedID 28125842
View details for PubMedCentralID PMC5283084
Distribution of particles, small molecules and polymeric formulation excipients in the suprachoroidal space after microneedle injection
EXPERIMENTAL EYE RESEARCH
2016; 153: 101-109
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.
View details for DOI 10.1016/j.exer.2016.10.011
View details for Web of Science ID 000389287700012
View details for PubMedID 27742547
View details for PubMedCentralID PMC5121071
Sustained reduction of intraocular pressure by supraciliary delivery of brimonidine-loaded poly(lactic acid) microspheres for the treatment of glaucoma
JOURNAL OF CONTROLLED RELEASE
2016; 228: 48-57
Although effective drugs that lower intraocular pressure (IOP) in the management of glaucoma exist, their efficacy is limited by poor patient adherence to the prescribed eye drop regimen. To replace the need for eye drops, in this study we tested the hypothesis that IOP can be reduced for one month after a single targeted injection using a microneedle for administration of a glaucoma medication (i.e., brimonidine) formulated for sustained release in the supraciliary space of the eye adjacent to the drug's site of action at the ciliary body. To test this hypothesis, brimonidine-loaded microspheres were formulated using poly(lactic acid) (PLA) to release brimonidine at a constant rate for 35 days and microneedles were designed to penetrate through the sclera, without penetrating into the choroid/retina, in order to target injection into the supraciliary space. A single administration of these microspheres using a hollow microneedle was performed in the eye of New Zealand White rabbits and was found to reduce IOP initially by 6 mmHg and then by progressively smaller amounts for more than one month. All administrations were well tolerated without significant adverse events, although histological examination showed a foreign-body reaction to the microspheres. This study demonstrates, for the first time, that the highly-targeted delivery of brimonidine-loaded microspheres into the supraciliary space using a microneedle is able to reduce IOP for one month as an alternative to daily eye drops.
View details for DOI 10.1016/j.jconrel.2016.02.041
View details for Web of Science ID 000373429600006
View details for PubMedID 26930266
View details for PubMedCentralID PMC4828324
Circumferential flow of particles in the suprachoroidal space is impeded by the posterior ciliary arteries
EXPERIMENTAL EYE RESEARCH
2016; 145: 424-431
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.
View details for DOI 10.1016/j.exer.2016.03.008
View details for Web of Science ID 000375372300048
View details for PubMedID 26976663
View details for PubMedCentralID PMC4842093
A CMOS Neural Interface for a Multichannel Vestibular Prosthesis
IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS
2016; 10 (2): 269-279
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.
View details for DOI 10.1109/TBCAS.2015.2409797
View details for Web of Science ID 000372424600001
View details for PubMedID 25974945
View details for PubMedCentralID PMC4641830
Ocular delivery of macromolecules
JOURNAL OF CONTROLLED RELEASE
2014; 190: 172-181
Biopharmaceuticals are making increasing impact on medicine, including treatment of indications in the eye. Macromolecular drugs are typically given by physician-administered invasive delivery methods, because non-invasive ocular delivery methods, such as eye drops, and systemic delivery, have low bioavailability and/or poor ocular targeting. There is a need to improve delivery of biopharmaceuticals to enable less-invasive delivery routes, less-frequent dosing through controlled-release drug delivery and improved drug targeting within the eye to increase efficacy and reduce side effects. This review discusses the barriers to drug delivery via various ophthalmic routes of administration in the context of macromolecule delivery and discusses efforts to develop controlled-release systems for delivery of biopharmaceuticals to the eye. The growing number of macromolecular therapies in the eye needs improved drug delivery methods that increase drug efficacy, safety and patient compliance.
View details for DOI 10.1016/j.jconrel.2014.06.043
View details for Web of Science ID 000345910900005
View details for PubMedID 24998941
View details for PubMedCentralID PMC4142116
Over-Expression of Catalase in Myeloid Cells Confers Acute Protection Following Myocardial Infarction
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
2014; 15 (5): 9036-9050
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.
View details for DOI 10.3390/ijms15059036
View details for Web of Science ID 000336841800113
View details for PubMedID 24853285
View details for PubMedCentralID PMC4057773
Directional Plasticity Rapidly Improves 3D Vestibulo-Ocular Reflex Alignment in Monkeys Using a Multichannel Vestibular Prosthesis
JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY
2013; 14 (6): 863-877
Bilateral loss of vestibular sensation can be disabling. We have shown that a multichannel vestibular prosthesis (MVP) can partly restore vestibular sensation as evidenced by improvements in the 3-dimensional angular vestibulo-ocular reflex (3D VOR). However, a key challenge is to minimize misalignment between the axes of eye and head rotation, which is apparently caused by current spread beyond each electrode's targeted nerve branch. We recently reported that rodents wearing a MVP markedly improve 3D VOR alignment during the first week after MVP activation, probably through the same central nervous system adaptive mechanisms that mediate cross-axis adaptation over time in normal individuals wearing prisms that cause visual scene movement about an axis different than the axis of head rotation. We hypothesized that rhesus monkeys would exhibit similar improvements with continuous prosthetic stimulation over time. We created bilateral vestibular deficiency in four rhesus monkeys via intratympanic injection of gentamicin. A MVP was mounted to the cranium, and eye movements in response to whole-body passive rotation in darkness were measured repeatedly over 1 week of continuous head motion-modulated prosthetic electrical stimulation. 3D VOR responses to whole-body rotations about each semicircular canal axis were measured on days 1, 3, and 7 of chronic stimulation. Horizontal VOR gain during 1 Hz, 50 °/s peak whole-body rotations before the prosthesis was turned on was <0.1, which is profoundly below normal (0.94 ± 0.12). On stimulation day 1, VOR gain was 0.4-0.8, but the axis of observed eye movements aligned poorly with head rotation (misalignment range ∼30-40 °). Substantial improvement of axis misalignment was observed after 7 days of continuous motion-modulated prosthetic stimulation under normal diurnal lighting. Similar improvements were noted for all animals, all three axes of rotation tested, for all sinusoidal frequencies tested (0.05-5 Hz), and for high-acceleration transient rotations. VOR asymmetry changes did not reach statistical significance, although they did trend toward slight improvement over time. Prior studies had already shown that directional plasticity reduces misalignment when a subject with normal labyrinths views abnormal visual scene movement. Our results show that the converse is also true: individuals receiving misoriented vestibular sensation under normal viewing conditions rapidly adapt to restore a well-aligned 3D VOR. Considering the similarity of VOR physiology across primate species, similar effects are likely to occur in humans using a MVP to treat bilateral vestibular deficiency.
View details for DOI 10.1007/s10162-013-0413-0
View details for Web of Science ID 000326289200006
View details for PubMedID 24013822
View details for PubMedCentralID PMC3825024
Restoration of 3D vestibular sensation in rhesus monkeys using a multichannel vestibular prosthesis
2011; 281 (1-2): 74-83
Profound bilateral loss of vestibular hair cell function can cause chronically disabling loss of balance and inability to maintain stable vision during head and body movements. We have previously shown that chinchillas rendered bilaterally vestibular-deficient via intratympanic administration of the ototoxic antibiotic gentamicin regain a more nearly normal 3-dimensional vestibulo-ocular reflex (3D VOR) when head motion information sensed by a head-mounted multichannel vestibular prosthesis (MVP) is encoded via rate-modulated pulsatile stimulation of vestibular nerve branches. Despite significant improvement versus the unaided condition, animals still exhibited some 3D VOR misalignment (i.e., the 3D axis of eye movement responses did not precisely align with the axis of head rotation), presumably due to current spread between a given ampullary nerve's stimulating electrode(s) and afferent fibers in non-targeted branches of the vestibular nerve. Assuming that effects of current spread depend on relative orientation and separation between nerve branches, anatomic differences between chinchilla and human labyrinths may limit the extent to which results in chinchillas accurately predict MVP performance in humans. In this report, we describe the MVP-evoked 3D VOR measured in alert rhesus monkeys, which have labyrinths that are larger than chinchillas and temporal bone anatomy more similar to humans. Electrodes were implanted in five monkeys treated with intratympanic gentamicin to bilaterally ablate vestibular hair cell mechanosensitivity. Eye movements mediated by the 3D VOR were recorded during passive sinusoidal (0.2-5 Hz, peak 50°/s) and acceleration-step (1000°/s(2) to 150°/s) whole-body rotations in darkness about each semicircular canal axis. During constant 100 pulse/s stimulation (i.e., MVP powered ON but set to stimulate each ampullary nerve at a constant mean baseline rate not modulated by head motion), 3D VOR responses to head rotation exhibited profoundly low gain [(mean eye velocity amplitude)/(mean head velocity amplitude) < 0.1] and large misalignment between ideal and actual eye movements. In contrast, motion-modulated sinusoidal MVP stimuli elicited a 3D VOR with gain 0.4-0.7 and axis misalignment of 21-38°, and responses to high-acceleration transient head rotations exhibited gain and asymmetry closer to those of unilaterally gentamicin-treated animals (i.e., with one intact labyrinth) than to bilaterally gentamicin-treated animals without MVP stimulation. In comparison to responses observed under similar conditions in chinchillas, acute responses to MVP stimulation in rhesus macaque monkeys were slightly better aligned to the desired rotation axis. Responses during combined rotation and prosthetic stimulation were greater than when either stimulus was presented alone, suggesting that the central nervous system uses MVP input in the context of multisensory integration. Considering the similarity in temporal bone anatomy and VOR performance between rhesus monkeys and humans, these observations suggest that an MVP will likely restore a useful level of vestibular sensation and gaze stabilization in humans.
View details for DOI 10.1016/j.heares.2011.08.008
View details for Web of Science ID 000297430300010
View details for PubMedID 21888961
View details for PubMedCentralID PMC3254699
Design and Performance of a Multichannel Vestibular Prosthesis That Restores Semicircular Canal Sensation in Rhesus Monkey
IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING
2011; 19 (5): 588-598
In normal individuals, the vestibular labyrinths sense head movement and mediate reflexes that maintain stable gaze and posture. Bilateral loss of vestibular sensation causes chronic disequilibrium, oscillopsia, and postural instability. We describe a new multichannel vestibular prosthesis (MVP) intended to restore modulation of vestibular nerve activity with head rotation. The device comprises motion sensors to measure rotation and gravitoinertial acceleration, a microcontroller to calculate pulse timing, and stimulator units that deliver constant-current pulses to microelectrodes implanted in the labyrinth. This new MVP incorporates many improvements over previous prototypes, including a 50% decrease in implant size, a 50% decrease in power consumption, a new microelectrode array design meant to simplify implantation and reliably achieve selective nerve-electrode coupling, multiple current sources conferring ability to simultaneously stimulate on multiple electrodes, and circuitry for in vivo measurement of electrode impedances. We demonstrate the performance of this device through in vitro bench-top characterization and in vivo physiological experiments with a rhesus macaque monkey.
View details for DOI 10.1109/TNSRE.2011.2164937
View details for Web of Science ID 000295792900015
View details for PubMedID 21859631
View details for PubMedCentralID PMC3303754
Cross-axis adaptation improves 3D vestibulo-ocular reflex alignment during chronic stimulation via a head-mounted multichannel vestibular prosthesis
EXPERIMENTAL BRAIN RESEARCH
2011; 210 (3-4): 595-606
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.
View details for DOI 10.1007/s00221-011-2591-5
View details for Web of Science ID 000289484300022
View details for PubMedID 21374081
View details for PubMedCentralID PMC3270066
Effects of Biphasic Current Pulse Frequency, Amplitude, Duration, and Interphase Gap on Eye Movement Responses to Prosthetic Electrical Stimulation of the Vestibular Nerve
IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING
2011; 19 (1): 84-94
An implantable prosthesis that stimulates vestibular nerve branches to restore sensation of head rotation and vision-stabilizing reflexes could benefit individuals disabled by bilateral loss of vestibular (inner ear balance) function. We developed a prosthesis that partly restores normal function in animals by delivering pulse frequency modulated (PFM) biphasic current pulses via electrodes implanted in semicircular canals. Because the optimal stimulus encoding strategy is not yet known, we investigated effects of varying biphasic current pulse frequency, amplitude, duration, and interphase gap on vestibulo-ocular reflex (VOR) eye movements in chinchillas. Increasing pulse frequency increased response amplitude while maintaining a relatively constant axis of rotation. Increasing pulse amplitude (range 0- 325 μA) also increased response amplitude but spuriously shifted eye movement axis, probably due to current spread beyond the target nerve. Shorter pulse durations (range 28- 340 μs) required less charge to elicit a given response amplitude and caused less axis shift than longer durations. Varying interphase gap (range 25- 175 μs) had no significant effect. While specific values reported herein depend on microanatomy and electrode location in each case, we conclude that PFM with short duration biphasic pulses should form the foundation for further optimization of stimulus encoding strategies for vestibular prostheses intended to restore sensation of head rotation.
View details for DOI 10.1109/TNSRE.2010.2065241
View details for Web of Science ID 000287096900011
View details for PubMedID 20813652
View details for PubMedCentralID PMC3110786
Chronic Stimulation of the Semicircular Canals Using a Multichannel Vestibular Prosthesis: Effects on Locomotion and Angular Vestibulo-Ocular Reflex in Chinchillas
IEEE. 2011: 3519-3523
Bilateral loss of vestibular sensation causes difficulty maintaining stable vision, posture and gait. An implantable prosthesis that partly restores vestibular sensation could significantly improve quality of life for individuals disabled by this disorder. We have developed a head-mounted multichannel vestibular prosthesis (MVP) that restores sufficient semicircular canal function to recreate a 3D angular vestibulo-ocular reflex (aVOR). In this study, we evaluated effects of chronic MVP stimulation on locomotion in chinchillas. Two of three animals examined exhibited significant improvements in both locomotion and aVOR.
View details for Web of Science ID 000298810002310
View details for PubMedID 22255099
View details for PubMedCentralID PMC3307049
Restoring the 3D Vestibulo-Ocular Reflex via Electrical Stimulation: The Johns Hopkins Multichannel Vestibular Prosthesis Project
IEEE. 2011: 3142-3145
Bilateral loss of vestibular sensation causes difficulty maintaining stable vision, posture and gait. An implantable prosthesis that partly restores normal activity on branches of the vestibular nerve should improve quality of life for individuals disabled by this disorder. We have developed a head-mounted multichannel vestibular prosthesis that restores sufficient semicircular canal function to partially recreate a normal 3-dimensional angular vestibulo-ocular reflex in animals. Here we describe several parallel lines of investigation directed toward refinement of this approach toward eventual clinical application.
View details for Web of Science ID 000298810002217
View details for PubMedID 22255006
View details for PubMedCentralID PMC3270063
Current and future management of bilateral loss of vestibular sensation - an update on the Johns Hopkins Multichannel Vestibular Prosthesis Project.
Cochlear implants international
2010; 11 Suppl 2: 2-11
Bilateral loss of vestibular sensation can disable individuals whose vestibular hair cells are injured by ototoxic medications, infection, Meniere's disease or other insults to the labyrinth including surgical trauma during cochlear implantation. Without input to vestibulo-ocular and vestibulo-spinal reflexes that normally stabilize the eyes and body, affected patients suffer blurred vision during head movement, postural instability, and chronic disequilibrium. While individuals with some residual sensation often compensate for their loss through rehabilitation exercises, those who fail to do so are left with no adequate treatment options. An implantable neuroelectronic vestibular prosthesis that emulates the normal labyrinth by sensing head movement and modulating activity on appropriate branches of the vestibular nerve could significantly improve quality of life for these otherwise chronically dizzy patients. This brief review describes the impact and current management of bilateral loss of vestibular sensation, animal studies supporting the feasibility of prosthetic vestibular stimulation, and a vestibular prosthesis designed to restore sensation of head rotation in all directions. Similar to a cochlear implant in concept and size, the Johns Hopkins Multichannel Vestibular Prosthesis (MVP) includes miniature gyroscopes to sense head rotation, a microcontroller to process inputs and control stimulus timing, and current sources switched between pairs of electrodes implanted within the vestibular labyrinth. In rodents and rhesus monkeys rendered bilaterally vestibulardeficient via treatment with gentamicin and/or plugging of semicircular canals, the MVP partially restores the vestibulo-ocular reflex for head rotations about any axis of rotation in 3-dimensional space. Our efforts now focus on addressing issues prerequisite to human implantation, including refinement of electrode designs and surgical technique to enhance stimulus selectivity and preserve cochlear function, optimization of stimulus protocols, and reduction of device size and power consumption.
View details for DOI 10.1179/146701010X12726366068454
View details for PubMedID 21756683