Impact of Retinal Degeneration on Response of ON and OFF Cone Bipolar Cells to Electrical Stimulation.

In retinal degenerative diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), the photoreceptors become stressed and start to degenerate in the early stages of the disease. Retinal prosthetic devices have been developed to restore vision in patients by applying electrical stimulation to the surviving retinal cells. However, these devices provide limited visual perception as the therapeutic interventions are generally considered in the later stages of the disease when only inner retinal layer cells are left. A potential treatment option for retinal degenerative diseases in the early stages can be stimulating bipolar cells, which receive presynaptic signals from photoreceptors. In this work, we constructed computational models of healthy and degenerated (both ON and OFF-type) cone bipolar cells (CBCs) with realistic morphologies extracted from connectomes of the healthy and early-stage degenerated rabbit retina. We examined these cells' membrane potential and axon terminal calcium current differences when subjected to electrical stimulation. In addition, we investigated how differently healthy and degenerated cells behave with respect to various stimulation parameters, including pulse duration and cells' distance from the stimulating electrode. The results suggested that regardless of the position of the OFF CBCs in the retina model, there is not a significant difference between the membrane potential of healthy and degenerate cells when electrically stimulated. However, the healthy ON CBC axon terminal membrane potential rising time-constant is shorter (0.29 ± 0.03 ms) than the degenerated cells (0.8 ± 0.07 ms). Moreover, the ionic calcium channels at the axon terminals of the cells have a higher concentration and higher current in degenerated cells (32.24 ± 6.12 pA) than the healthy cells (13.64 ± 2.88 pA) independently of the cell's position.

Brain BOLD and NIRS response to hyperoxic challenge in sickle cell disease and chronic anemias.

PURPOSE: Congenital anemias, including sickle cell anemia and thalassemia, are associated with cerebral tissue hypoxia and heightened stroke risks. Recent works in sickle cell disease mouse models have suggested that hyperoxia respiratory challenges can identify regions of the brain having chronic tissue hypoxia. Therefore, this work investigated differences in hyperoxic response and regional cerebral oxygenation between anemic and healthy subjects. METHODS: A cohort of 38 sickle cell disease subjects (age 22 ± 8 years, female 39%), 25 non-sickle anemic subjects (age 25 ± 11 years, female 52%), and 31 healthy controls (age 25 ± 10 years, female 68%) were examined. A hyperoxic gas challenge was performed with concurrent acquisition of blood oxygen level-dependent (BOLD) MRI and near-infrared spectroscopy (NIRS). In addition to hyperoxia-induced changes in BOLD and NIRS, global measurements of cerebral blood flow, oxygen delivery, and cerebral metabolic rate of oxygen were obtained and compared between the three groups. RESULTS: Regional BOLD changes were not able to identify brain regions of flow limitation in chronically anemic patients. Higher blood oxygen content and tissue oxygenation were observed during hyperoxia gas challenge. Both control and anemic groups demonstrated lower blood flow, oxygen delivery, and metabolic rate compared to baseline, but the oxygen metabolism in anemic subjects were abnormally low during hyperoxic exposure. CONCLUSION: These results indicated that hyperoxic respiratory challenge could not be used to identify chronically ischemic brain. Furthermore, the low hyperoxia-induced metabolic rate suggested potential negative effects of prolonged oxygen therapy and required further studies to evaluate the risk for hyperoxia-induced oxygen toxicity and cerebral dysfunction.

Modeling ON Cone Bipolar Cells for Electrical Stimulation.

Retinal prosthetic systems have been developed to help blind patients suffering from retinal degenerative diseases gain some useful form of vision. Various experimental and computational studies have been performed to test electrical stimulation strategies that can improve the performance of these devices. Detailed computational models of retinal neurons, such as retinal ganglion cells (RGCs) and bipolar cells (BCs), allow us to explore the mechanisms underlying the response of cells to electrical stimulation. While electrophysiological studies have shown the presence of voltage-gated ionic channels in different regions of BCs, many of the existing cone BCs models are assumed to be passive or only contain calcium channels at the synaptic terminals. We have utilized our Admittance Method (AM)-NEURON computational platform to implement a more realistic model of ON-BCs. Our model closely replicates the recent patch-clamp experiments directly measuring the response of ON-BCs to epiretinal electrical stimulation and thereby predicts the regional distributions of the ionic channels. Our computational results further indicate that outward potassium current strongly contributes to the depolarizing voltage transient of ON-BCs in response to electrical stimulation.

Development of Hormonal Intravaginal Rings: Technology and Challenges.

Intravaginal rings (IVRs) are minimally invasive polymeric devices specifically designed to be used for the sustained and prolonged release of various type of drugs such as hormones. One of the benefits of using topical drug delivery systems (e.g., IVRs) is the fact that systemic drug delivery may cause drug resistance due to elevated drug levels. Topical drug delivery also provides higher concentrations of the drug to the target site and has fewer side effects. In addition, when a drug is administered vaginally, the hepatic first-pass effect is avoided, resulting in higher absorption. Contraception and treatments for specific diseases such as endometriosis and hormone deficiencies can be improved by the administration of hormones via an IVR. This article aims to classify and compare various designs of commercially available and non-commercial hormonal IVRs and to analyze their performance. Current challenges affecting the development of IVRs are investigated, and proposed solutions are discussed. A comprehensive search of publications in MEDLINE/PubMed and of commercial product data of IVRs was performed, and the materials, designs, performance, and applications (e.g., contraception, endometriosis, estrogen deficiency and urogenital atrophy) of hormonal IVRs were thoroughly evaluated. Most hormonal IVRs administer female sex hormones, i.e., estrogen and progestogens. In terms of material, IVRs are divided into 3 main groups: silicone, polyurethane, and polyethylene-co-vinyl acetate IVRs. As regards their design, there are 4 major designs for IVRs which strongly affect their performance and the timing and rate of hormone release. Important challenges include reducing the burst release and maintaining the bioavailability of hormones at their site of action over a prolonged period of administration as well as lowering production costs. Hormonal IVRs are a promising method which could be used to facilitate combination therapies by administering multiple drugs in a single IVR while eliminating the side effects of conventional drug administration methods. IVRs could considerably improve women's quality of life all over the world within a short period of time.

Retinal Oxygen Delivery, Metabolism, and Extraction Fraction during Long-Term Bilateral Common Carotid Artery Occlusion in Rats.

Retinal functional, biochemical, and anatomical changes have been previously reported in long-term experimental permanent bilateral common carotid artery occlusion (BCCAO). The purpose of the current study was to investigate progressive reductions in retinal oxygen metabolism (MO2) due to inadequate compensation by oxygen delivery (DO2) and extraction fraction (OEF) after BCCAO. Twenty-nine rats were subjected to BCCAO and were imaged after 3 hours, 3 days, 7 days, or 14 days. Six rats underwent a sham procedure. Phosphorescence lifetime and blood flow imaging were performed in both eyes to measure retinal oxygen contents and total retinal blood flow, respectively. DO2, MO2, and OEF were calculated from these measurements. Compared to the sham group, DO2 and MO2 were reduced after all BCCAO durations. OEF was increased after 3 hours and 3 days of BCCAO, but was not different from the sham group after 7 and 14 days. Between 3 and 7 days of BCCAO, DO2 increased, OEF decreased, and there was no significant difference in MO2. These findings may be useful to understand the pathophysiology of retinal ischemia.

Relating retinal blood flow and vessel morphology in sickle cell retinopathy.

PURPOSE: The purpose of the current study was to determine associations between retinal blood flow and vessel morphology metrics in sickle cell retinopathy (SCR) and healthy normal control (NC) subjects. METHODS: Optical coherence tomography angiography (OCTA) and Doppler OCT imaging were performed in 12 SCR (15 eyes) and 19 NC (26 eyes) subjects. Vessel tortuosity was measured using a dedicated image analysis algorithm applied to OCTA images. Vessel density and spacing between vessels were determined from OCTA images by a fractal dimension analysis method. Retinal blood flow was quantified using a phase-resolved technique applied to en face Doppler OCT images. RESULTS: There was a significant association between increased retinal blood flow and increased vessel tortuosity (P = 0.03). Furthermore, increased retinal blood flow was associated with increased vessel density (P = 0.03) and decreased spacing between small vessels (P = 0.01). There was no significant association between retinal blood flow and spacing between large vessels (P = 0.11). Vessel tortuosity and blood flow were increased, whereas spacing between small vessels was decreased in SCR compared to NC group (P ≤ 0.03). There were no significant differences in vessel density or spacing between large vessels between the SCR and NC groups (P ≥ 0.31). CONCLUSIONS: Associations between retinal hemodynamics and vessel morphology were reported, providing better understanding of retinal pathophysiology and insight into potential quantitative biomarkers to evaluate SCR.

Relationship between retinal vessel tortuosity and oxygenation in sickle cell retinopathy.

BACKGROUND: Reduced retinal vascular oxygen (O2) content causes tissue hypoxia and may lead to development of vision-threatening pathologies. Since increased vessel tortuosity is an early sign for some hypoxia-implicated retinopathies, we investigated a relationship between retinal vascular O2 content and vessel tortuosity indices. METHODS: Dual wavelength retinal oximetry using a commercially available scanning laser ophthalmoscope was performed in both eyes of 12 healthy (NC) and 12 sickle cell retinopathy (SCR) subjects. Images were analyzed to quantify retinal arterial and venous O2 content and determine vessel tortuosity index (VTI) and vessel inflection index (VII) in circumpapillary regions. Linear mixed model analysis was used to determine the effect of disease on vascular O2 content, VTI and VII, and relate vascular O2 content with VTI and VII. Models accounted for vessel type, fellow eyes, age and mean arterial pressure. RESULTS: Retinal arterial and venous O2 content were lower in SCR (O2A = 11 ± 4 mLO2/dL, O2V = 7 ± 2 mLO2/dL) compared to NC (O2A = 18 ± 3 mLO2/dL, O2V = 13 ± 3 mLO2/dL) subjects (p < 0.001). As expected, O2 content was higher in arteries (15 ± 5 mLO2/dL) than veins (10 ± 4 mLO2/dL) (p < 0.001), but not different between eyes (OD: 12 ± 5 mLO2/dL; OS:13 ± 5 mLO2/dL) (p = 0.3). VTI was not significantly different between SCR (0.18 ± 0.07) and NC (0.15 ± 0.04) subjects, or between arteries (0.18 ± 0.07) and veins (0.16 ± 0.04), or between eyes (OD: 0.18 ± 0.07, OS:0.17 ± 0.05) (p ≥ 0.06). VII was significantly higher in SCR (10 ± 2) compared to NC subjects (8 ± 1) (p = 0.003). VII was also higher in veins (9 ± 2) compared to arteries (8 ± 5) (p = 0.04), but not different between eyes (OD: 9 ± 2; OS: 9 ± 2) (p = 0.2). There was an inverse linear relationship between vascular O2 (13 ± 5 mLO2/dL) content and VII (9 ± 2) (ß = -0.5; p = 0.02). CONCLUSIONS: The findings augment knowledge of relationship between retinal vascular oxygenation and morphological changes and potentially contribute to identifying biomarkers for assessment of retinal hypoxia due to SCR and other retinopathies.

Alterations in Retinal Oxygen Delivery, Metabolism, and Extraction Fraction During Bilateral Common Carotid Artery Occlusion in Rats.

Purpose: The purpose of the current study was to investigate alterations in retinal oxygen delivery, metabolism, and extraction fraction and elucidate their relationships in an experimental model of retinal ischemia. Methods: We subjected 14 rats to permanent bilateral common carotid artery occlusion using clamp or suture ligation, or they underwent sham procedure. Within 30 minutes of the procedure, phosphorescence lifetime imaging was performed to measure retinal vascular oxygen tension and derive arterial and venous oxygen contents, and arteriovenous oxygen content difference. Fluorescent microsphere and red-free retinal imaging were performed to measure total retinal blood flow. Retinal oxygen delivery rate (DO2), oxygen metabolism rate (MO2), and oxygen extraction fraction (OEF) were calculated. Results: DO2 and MO2 were lower in ligation and clamp groups compared to the sham group, and also lower in the ligation group compared to the clamp group (P ≤ 0.05). OEF was higher in the ligation group compared to clamp and sham groups (P ≤ 0.03). The relationships of MO2 and OEF with DO2 were mathematically modeled by exponential functions. With moderate DO2 reductions, OEF increased while MO2 minimally decreased. Under severe DO2 reductions, OEF reached a maximum value and subsequently MO2 decreased with DO2. Conclusions: The findings improve knowledge of mechanisms that can maintain MO2 and may clarify the pathophysiology of retinal ischemic injury.