Long-Acting Ocular Injectables: Are We Looking In The Right Direction?

The complex anatomy and physiological barriers of the eye make delivering ocular therapeutics challenging. Generally, effective drug delivery to the eye is hindered by rapid clearance and limited drug bioavailability. Biomaterial-based approaches have emerged to enhance drug delivery to ocular tissues and overcome existing limitations. In this review, some of the most promising long-acting injectables (LAIs) in ocular drug delivery are explored, focusing on novel design strategies to improve therapeutic outcomes. LAIs are designed to enable sustained therapeutic effects, thereby extending local drug residence time and facilitating controlled and targeted drug delivery. Moreover, LAIs can be engineered to enhance drug targeting and penetration across ocular physiological barriers.

Comparative study of spectral sensitivity, irradiance sensitivity, spatial resolution and temporal resolution in the visual systems of Ocypode quadrata and Aratus pisonii.

Early pioneering studies by Autrum on terrestrial arthropods first revealed that the visual systems of arthropods reflected their lifestyles and habitats. Subsequent studies have examined and confirmed Autrum's hypothesis that visual adaptions are driven by predator-prey interactions and activity cycles, with rapidly moving predatory diurnal species generally possessing better temporal resolution than slower moving nocturnal species. However, few studies have compared the vision between diurnal herbivores and nocturnal predators. In this study, the visual physiology of a nocturnal fast-moving predatory crab, the Atlantic ghost crab (Ocypode quadrata) and a diurnal herbivorous crab, the mangrove tree crab (Aratus pisonii), was examined. Spectral sensitivity, irradiance sensitivity and temporal resolution of the crabs were quantified using the electroretinogram (ERG), while the spatial resolution was calculated utilizing morphological methods. Both O. quadrata and A. pisonii had a single dark-adapted spectral sensitivity peak (494 and 499 nm, respectively) and chromatic adaptation had no effect on their spectral sensitivity, indicating that both species have monochromatic visual systems. The temporal resolution of O. quadrata was not significantly different from that of A. pisonii, but O. quadrata did possess a significantly greater spatial resolution and irradiance sensitivity. Both species possess an acute zone in the anterior region of their eyes. The data presented in this study will aid in the current understanding of the correlation between visual physiology and the life history of the animal.

Parametric information about eye movements is sent to the ears.

Eye movements alter the relationship between the visual and auditory spatial scenes. Signals related to eye movements affect neural pathways from the ear through auditory cortex and beyond, but how these signals contribute to computing the locations of sounds with respect to the visual scene is poorly understood. Here, we evaluated the information contained in eye movement-related eardrum oscillations (EMREOs), pressure changes recorded in the ear canal that occur in conjunction with simultaneous eye movements. We show that EMREOs contain parametric information about horizontal and vertical eye displacement as well as initial/final eye position with respect to the head. The parametric information in the horizontal and vertical directions can be modeled as combining linearly, allowing accurate prediction of the EMREOs associated with oblique (diagonal) eye movements. Target location can also be inferred from the EMREO signals recorded during eye movements to those targets. We hypothesize that the (currently unknown) mechanism underlying EMREOs could impose a two-dimensional eye-movement-related transfer function on any incoming sound, permitting subsequent processing stages to compute the positions of sounds in relation to the visual scene.

Aquaporin 5 in the eye: Expression, function, and roles in ocular diseases.

As a water channel protein, aquaporin 5 (AQP5) is essential for the maintenance of the normal physiological functions of ocular tissues. This review provides an overview of the expression and function of AQP5 in the eye and discusses their role in related eye diseases. Although AQP5 plays a vital role in ocular functions, such as maintaining corneal and lens transparency, regulating water movement, and maintaining homeostasis, some of its functions in ocular tissues are still unclear. Based on the key role of AQP5 in eye function, this review suggests that in the future, eye diseases may be treated by regulating the expression of aquaporin.

Tear film breakup time and Schirmer tear test in normal dogs: Effects of age, sex, reproductive status, skull type, and nasolacrimal duct patency.

OBJECTIVE: The present study aimed to determine the effects of age, sex, reproductive status, skull type, and nasolacrimal duct (NLD) patency on tear production and tear film breakup time (TBUT) in normal dogs. ANIMALS STUDIED: The ophthalmic data of 82 healthy adult dogs were evaluated in this study. PROCEDURES: Age, sex, breed, and reproductive status were recorded. Schirmer tear test (STT) and TBUT were assessed in all dogs, and interferometry was available for the selected dogs. The Jones test was used to evaluate NLD patency. The cephalic index (CI) was calculated for each dog (skull width/skull length ×100). RESULTS: Mean (SD) values for the STT results for the right (OD) and left (OS) eyes were 20.6 (2.7) and 20.2 (2.7) mm/min, respectively. Mean (SD) TBUT values for OD and OS were 6.5 (2.5) and 6.1 (2.3) mm/min in all dogs, respectively. Sex and reproductive status had no significant effect on STT and TBUT (P[OU] > 0.05). Skull type significantly affected TBUT in both eyes (P(OD)  = 0.01, P(OS)  = 0.003), but had no effect on STT (P[OU] > 0.3). Age had no correlation with STT and TBUT in either eye (P[OU] > 0.05). STT and TBUT had no correlation in either eye (P[OU] > 0.2). NLD patency had no significant effect on STT or TBUT (P[OU] > 0.1). CONCLUSIONS: The results of this study showed lower TBUT values in brachycephalic breeds than in non-brachycephalic breeds. A compensatory increase in STT values was observed in dogs with low TBUT values.

Host-trailing satellite flight behaviour is associated with greater investment in peripheral visual sensory system in miltogrammine flies.

Insect sensory systems are the subjects of different selective pressures that shape their morphology. In many species of the flesh fly subfamily Miltogramminae (Diptera: Sarcophagidae) that are kleptoparasitic on bees and wasps, females perch on objects close to the host nests and, once a returning host is detected, they follow it in flight at a fixed distance behind until reaching the nest. We hypothesized that such satellite (SAT) flight behaviour, which implies a finely coordinated trailing flight, is associated with an improved visual system, compared to species adopting other, non-satellite (NON-SAT) strategies. After looking at body size and common ancestry, we found that SAT species have a greater number of ommatidia and a greater eye surface area when compared to NON-SAT species. Ommatidium area is only affected by body size, suggesting that selection changes disproportionately (relative to body size variation) the number of ommatidia and as a consequence the eye area, instead of ommatidium size. SAT species also tend to have larger ocelli, but their role in host-finding was less clear. This suggests that SAT species may have a higher visual acuity by increasing ommatidia number, as well as better stability during flight and motion perception through larger ocelli. Interestingly, antennal length was significantly reduced in SAT species, and ommatidia number negatively correlated with antennal length. While this finding does not imply a selection pressure of improved antennal sensory system in species adopting NON-SAT strategies, it suggests an inverse resource (i.e. a single imaginal disc) allocation between eyes and antennae in this fly subfamily.

Chronic Systemic Dexamethasone Regulates the Mineralocorticoid/Glucocorticoid Pathways Balance in Rat Ocular Tissues.

Central serous chorioretinopathy (CSCR) is a retinal disease affecting the retinal pigment epithelium (RPE) and the choroid. This is a recognized side-effect of glucocorticoids (GCs), administered through nasal, articular, oral and dermal routes. However, CSCR does not occur after intraocular GCs administration, suggesting that a hypothalamic-pituitary-adrenal axis (HPA) brake could play a role in the mechanistic link between CSCR and GS. The aim of this study was to explore this hypothesis. To induce HPA brake, Lewis rats received a systemic injection of dexamethasone daily for five days. Control rats received saline injections. Baseline levels of corticosterone were measured by Elisa at baseline and at 5 days in the serum and the ocular media and dexamethasone levels were measured at 5 days in the serum and ocular media. The expression of genes encoding glucocorticoid receptor (GR), mineralocorticoid receptors (MR), and the 11 beta hydroxysteroid dehydrogenase (HSD) enzymes 1 and 2 were quantified in the neural retina and in RPE/ choroid. The expression of MR target genes was quantified in the retina (Scnn1A (encoding ENac-α, Kir4.1 and Aqp4) and in the RPE/choroid (Shroom 2, Ngal, Mmp9 and Omg, Ptx3, Plaur and Fosl-1). Only 10% of the corticosterone serum concentration was measured in the ocular media. Corticosterone levels in the serum and in the ocular media dropped after 5 days of dexamethasone systemic treatment, reflecting HPA axis brake. Whilst both GR and MR were downregulated in the retina without MR/GR imbalance, in the RPE/choroid, both MR/GR and 11ß-hsd2/11ß-hsd1 ratio increased, indicating MR pathway activation. MR-target genes were upregulated in the RPE/ choroid but not in the retina. The psychological stress induced by the repeated injection of saline also induced HPA axis brake with a trend towards MR pathway activation in RPE/ choroid. HPA axis brake causes an imbalance of corticoid receptors expression in the RPE/choroid towards overactivation of MR pathway, which could favor the occurrence of CSCR.

Variations in intraocular pressure and visual parameters before and after using mobile virtual reality glasses and their effects on the eyes.

We examined the effects of using mobile devices with immersive virtual reality for a short period on the physiological parameters of both eyes. The average age of the 50 participants (23 men and 27 women) was 17.72 ± 1.48 years, and refractive error ranged from 0 D to - 5.00 D. All the participants wore + 3.00 D glasses and underwent a 5-min relaxation adjustment through the atomization method. The participants wore immersive virtual reality (VR) glasses to watch a movie on a roller coaster for 10 min. Their relevant physiological parameters of the eyes were measured both before and after using VR glasses. Compared with before VR use, no significant difference (P > 0.05) was observed in the near-horizontal vergence and refractive error but a significant difference (P < 0.05) was observed in the amplitude of accommodation, intraocular pressure, divergence/convergence, and stereopsis after VR use. The corneal elastic coefficient was > 0.2 MPa, and we used Friedenwald's eye rigidity relationship to obtain the K value (0.065-0.09). Approximately 10% of the participants experienced cybersickness symptoms such as nausea and dizziness. The use of VR to watch three-dimensional movies reduced intraocular pressure, which may help prevent or treat glaucoma. Moreover, the binocular convergence was higher when viewing near-field objects in VR than in the real world. Therefore, individuals with convergence excess may experience symptoms. Binocular parallax is the most likely cause of cybersickness symptoms. Thus, mobile VR devices with higher quality and comfort are necessary.

Vision, cognition, and walking stability in young adults.

Downward gazing is often observed when walking requires guidance. This gaze behavior is thought to promote walking stability through anticipatory stepping control. This study is part of an ongoing effort to investigate whether downward gazing also serves to enhance postural control, which can promote walking stability through a feedback/reactive mechanism. Since gaze behavior alone gives no indication as to what information is gathered and the functions it serves, we aimed to investigate the cognitive demands associated with downward gazing, as they are likely to differ between anticipatory and feedback use of visual input. To do so, we used a novel methodology to compromise walking stability in a manner that could not be resolved through modulation of stepping. Then, using interference methodology and neuroimaging, we tested for (1) interference related to dual tasking, and (2) changes in prefrontal activity. The novel methodology resulted in an increase in the time spent looking at the walking surface. Further, while some dual-task interference was observed, indicating that this gaze behavior is cognitively demanding, several gaze parameters pertaining to downward gazing and prefrontal activity correlated. These correlations revealed that a greater tendency to gaze onto the walking surface was associated with lower PFC activity, as is expected when sensory information is used through highly automatic, and useful, neural circuitry. These results, while not conclusive, do suggest that gazing onto the walking surface can be used for purposes other than anticipatory stepping control, bearing important motor-control and clinical implications.

Human ocular mucins: The endowed guardians of sight.

Mucins are an ancient group of glycoproteins that provide viscoelastic, lubricating and hydration properties to fluids bathing wet surfaced epithelia. They are involved in the protection of underlying tissues by forming a barrier with selective permeability properties. The expression, processing and spatial distribution of mucins are often determined by organ-specific requirements that in the eye involve protecting against environmental insult while allowing the passage of light. The human ocular surface epithelia have evolved to produce an extremely thin and watery tear film containing a distinct soluble mucin product secreted by goblet cells outside the visual axis. The adaptation to the ocular environment is notably evidenced by the significant contribution of transmembrane mucins to the tear film, where they can occupy up to one-quarter of its total thickness. This article reviews the tissue-specific properties of human ocular mucins, methods of isolation and detection, and current approaches to model mucin systems recapitulating the human ocular surface mucosa. This knowledge forms the fundamental basis to develop applications with a promising biological and clinical impact.

Long-term effect of contact lens wear: A citation network study.

BACKGROUND: Contact lenses can cause complications in 2/3 of the total population, but in most cases, they are mild and easy to manage. However, most of the studies are short-term. The aim of the study was to analyze the publications on the long-term effects of contact lens wear to understand the current research landscape through the analysis of dating networks as well as determining the different research areas and the most cited publications. METHODS: The Web of Science database was used to perform the publication search, looking for the terms "Long-term" AND "contact lens wear" within the period between 1977 and January 2021. The CitNetExplorer and CiteSpace software were then used to conduct the publication analysis. To obtain the graphics, the VOSviewer software was used. RESULTS: A total of 721 publications were found with 2999 citations generated within the network. The year 2010 was singled out as a "key year", considering the number of publications that emerged in that year and increase in adaptations of contact lens worldwide. The most widely cited publication was "Effects of long-term extended contact lens wear on the human cornea", an article by Holden et al., which was published in 1985. By using the clustering function, we were able to establish three clusters that encompassed the different research areas within this field: morphological changes, the loss of corneal sensitivity, tear film characteristics and longitudinal changes in ocular physiology. CONCLUSIONS: The main research topic in this field focuses on the morphological changes that take place in the corneal endothelial cell layer.

Modulation of magnetoencephalography alpha band activity by radiofrequency electromagnetic field depicted in sensor and source space.

Several studies reported changes in spontaneous electroencephalogram alpha band activity related to radiofrequency electromagnetic fields, but findings showed both an increase and a decrease of its spectral power or no effect. Here, we studied the alpha band modulation after 900 MHz mobile phone radiofrequency exposure and localized cortical regions involved in these changes, via a magnetoencephalography (MEG) protocol with healthy volunteers in a double-blind, randomized, counterbalanced crossover design. MEG was recorded during eyes open and eyes closed resting-state before and after radiofrequency exposure. Potential confounding factors, known to affect alpha band activity, were assessed as control parameters to limit bias. Entire alpha band, lower and upper alpha sub-bands MEG power spectral densities were estimated in sensor and source space. Biochemistry assays for salivary biomarkers of stress (cortisol, chromogranin-A, alpha amylase), heart rate variability analysis and high-performance liquid chromatography for salivary caffeine concentration were realized. Results in sensor and source space showed a significant modulation of MEG alpha band activity after the radiofrequency exposure, with different involved cortical regions in relation to the eyes condition, probably because of different attention level with open or closed eyes. None of the control parameters reported a statistically significant difference between experimental sessions.

Thermographic ocular temperature correlated with rectal temperature in cats.

Body temperature reflects the animal health and/or disease conditions. During clinical examination, temperature measurement is a basic step in veterinary medicine. The conventional method used is the rectal thermometry, particularly stressful in some subjects, especially for cats. A less stressful alternative method, such as infrared thermal imaging camera, is used in various fields of medicine for diagnosis, prognosis and correct therapeutic approaches. To evaluate the usefulness of infrared thermal imaging for the assessment of ocular temperature, twenty cats of different breeds (European, Siamese and Persian, 4-6 years old, mean body weight 4.3 ± 0.30 Kg) were enrolled in the study. In order to evaluate the applicability of the ocular temperature assessment through thermal imaging as a tool for measuring the animal's body temperature, the obtained values were compared with the rectal temperature values recorded in each cat by means of a digital thermo-camera. There were no differences between left and right eye; and a difference of about 1.19 °C between the ocular and rectal temperature value was recorded (p < 0.0001). Rectal and ocular temperatures were positively correlated (p < 0.0001; r = 0.93). In conclusion, we show that ocular temperature is an alternative method for body temperature measurement that can be used in clinical evaluation of cats, especially in cases where rectal temperature recording is not possible.

PERG adaptation for detection of retinal ganglion cell dysfunction in glaucoma: a pilot diagnostic accuracy study.

It has been previously demonstrated that the adaptive phase changes of steady-state pattern electroretinogram (SS-PERG), recorded during 4-min presentation of patterned stimuli, are reduced in glaucoma suspects and patients compared to normal subjects. Our study aims at testing the hypothesis that adaptive changes of SS-PERG, recorded using the novel optimized Next Generation PERG (PERGx) protocol, differ between glaucoma patients and controls. In this pilot cross-sectional study, we included 28 glaucoma patients and 17 age-matched normal subjects. Both patients and controls underwent a full ophthalmologic examination, visual field testing, OCT and PERGx. The PERGx signal was sampled over 2 min (providing 1 noise and 9 signal packets) in response to alternating gratings generated on an OLED display. PERGx amplitude and phase were analyzed to quantify adaptive changes over recording time. Receiver operating characteristic (ROC) curves were used to study the diagnostic accuracy of PERGx parameters in distinguishing glaucoma patients from normal subjects. PERGx amplitude and phase data showed declining trends in both groups. PERGx amplitude slope and grand-average vector amplitude and phase were significantly different in patients compared to controls (p < 0.01), whereas phase angular dispersion was greater in patients but not significantly different between the two groups. The area under the ROC curves were 0.87 and 0.76 for PERGx amplitude slope and grand-average vector amplitude, and 0.62 and 0.87 for PERGx angular dispersion and grand-average vector phase, respectively. The PERGx paradigm resulted highly accurate in detecting the reduction of amplitude adaptive changes in glaucoma patients, presumably due to the loss of functional retinal ganglion cell autoregulation. Thus, PERG adaptation, recorded by this new protocol, might be helpful in the identification and diagnosis of early glaucomatous dysfunction.

Age-related changes of color visual acuity in normal eyes.

PURPOSE: To evaluate the age-related change in color visual acuity (CVA) in normal eyes. METHODS: In total, 162 normal eyes (162 subjects, women: 52, men: 110, age range: 15-68 years) with best-corrected visual acuity (BCVA) ≥20/13 were enrolled. Fifteen colors from the New Color Test (chroma 6) were applied to Landolt "C" rings, white point D65 was applied as background, and a luminance of 30 cd/m2 was set for both the rings and the background. These rings were used to measure the chromatic spatial discrimination acuity as the CVA value, while changing the stimulus size. Correlations of the CVA value of each color and age were evaluated. Mean CVA values of all 15 colors (logarithm of the minimum angle of resolution) were compared between age groups in 10-year increments. RESULTS: Nine CVA values (red, yellow-red, red-yellow, green, blue-green, green-blue, purple, red-purple, and purple-red) were negatively correlated with age (all p<0.05); the remaining six (yellow, green-yellow, yellow-green, blue, purple-blue, and blue-purple), as well as BCVA were not. The age groups with the best to worst mean CVA values of 15 colors were as follows: 20-29 (mean ± standard deviation, 0.303 ± 0.113), 30-39 (0.324 ± 0.096), 10-19 (0.333 ± 0.022), 50-59 (0.335 ± 0.078), 40-49 (0.339 ± 0.096), and 60-69 (0.379 ± 0.125) years. There were statistically significant differences between mean CVA values of the following groups: 20-29 and 40-49 years; 20-29 and 60-69 years; 30-39 and 60-69 years (all p<0.01). CONCLUSIONS: The CVA values related to the medium/long-wavelength-sensitive cones were more susceptible to aging than those related to the short-wavelength-sensitive cones. This differed from previous reports, and may be related to the difference in the range of foveal cone function evaluated with each examination.

The combination of acute exercise and eye closure has a synergistic effect on alpha activity.

Acute aerobic exercise increases the brain cortical activity in alpha frequency. Eye closure also increases alpha activity. However, whether the two have an additive or a synergistic effect on alpha activity has never been explored. This study observed electroencephalography (EEG) from fifteen participants seated on the cycle ergometer before, during, and after a cycling exercise with the eyes open and with them closed. Exercise intensity was set to a target heart rate (120-130 bpm), corresponding to light-to-moderate intensity exercise. Each epoch was 6 min and the last 4 min (eyes closed in the first 2 min and eyes open in the second 2 min) were analyzed. The EEG power spectrum densities were calculated for alpha frequency band activity (8-13 Hz). At rest, alpha activity was significantly greater with the eyes closed than open. Exercise significantly increased alpha activity in both eye conditions. More importantly, in the occipital site, the alpha-increasing effect of their combination was significantly greater than the sum of the effect of each, showing a synergistic effect. We concluded that acute light-to-moderate intensity exercise with the eyes closed has a synergistic effect on alpha activity.

A new, fluorescence-based method for visualizing the pseudopupil and assessing optical acuity in the dark compound eyes of honeybees and other insects.

Recent interest in applying novel imaging techniques to infer optical resolution in compound eyes underscores the difficulty of obtaining direct measures of acuity. A widely used technique exploits the principal pseudopupil, a dark spot on the eye surface representing the ommatidial gaze direction and the number of detector units (ommatidia) viewing that gaze direction. However, dark-pigmented eyes, like those of honeybees, lack a visible pseudopupil. Attempts over almost a century to estimate optical acuity in this species are still debated. Here, we developed a method to visualize a stable, reliable pseudopupil by staining the photoreceptors with fluorescent dyes. We validated this method in several species and found it to outperform the dark pseudopupil for this purpose, even in pale eyes, allowing more precise location of the gaze centre. We then applied this method to estimate the sampling resolution in the frontal part of the eye of the honeybee forager. We found a broad frontal acute zone with interommatidial angles below 2° and a minimum interommatidial angle of 1.3°, a broader, sharper frontal acute zone than previously reported. Our study provides a new method to directly measure the sampling resolution in most compound eyes of living animals.

Agreement of rebound and applanation tonometry intraocular pressure measurements during atmospheric pressure change.

This study investigated the agreement of intraocular pressure measurements using rebound tonometry and applanation tonometry in response to atmospheric changes in a hyperbaric chamber. Twelve eyes of 12 healthy subjects were included in this prospective, comparative, single-masked study. Intraocular pressure measurements were performed by rebound tonometry followed by applanation tonometry in a multiplace hyperbaric chamber at 1 Bar, followed by 2, 3 and 4 Bar during compression and again at 3 and 2 Bar during decompression. Mean differences between rebound and applanation intraocular pressure measurements were 1.6, 1.7, and 2.1 mmHg at 2, 3, and 4 Bar respectively during compression and 2.6 and 2.2 mmHg at 3 and 2 Bar during decompression. Lower limits of agreement ranged from -3.7 to -5.9 mmHg and upper limits ranged from -0.3 to 1.9 mmHg. Multivariate analysis showed that the differences between rebound and applanation intraocular pressure measurements were independent of atmospheric pressure changes (p = 0.79). Intraocular pressure measured by rebound tonometry shows a systematic difference compared to intraocular measured by applanation tonometry, but this difference is not influenced by changes of atmospheric pressure up to 4 Bar in a hyperbaric chamber. Agreement in magnitude of change between devices suggests rebound tonometry is viable for assessing intraocular pressure during atmospheric changes. Future studies should be designed in consideration of expected differences in IOP values provided by the two devices.