The Optejet Technology Minimizes Preservative-Mediated Cytotoxicity of Conjunctival Epithelial Cells Treated with Latanoprost In Vitro.

Purpose: Benzalkonium chloride (BAK) is a commonly used preservative to maintain sterility for multiuse eye drops such as latanoprost. One option to minimize the deleterious effects of BAK in eye drops may be to reduce the volume administered. The aim of this study was to assess the response of cells from the ocular surface to latanoprost+BAK administered by the Optejet technology, which dispenses a microdose (∼8 µL) ophthalmical spray. Methods: Cultured human conjunctival epithelial cells were exposed to the following treatments: (1) no treatment, (2) drop form of latanoprost without BAK (∼35 µL), (3) drop form of latanoprost with 0.01% BAK (∼35 µL), (4) ophthalmical spray form of latanoprost with 0.01% BAK delivered by the Optejet technology (∼8 µL). After 5 h, cells were assessed for changes in cytotoxicity, morphology, and inflammatory marker expression. Results: Latanoprost+BAK delivered by a drop induced cytotoxicity, cytoplasmic shrinkage, and loss of cell-cell contact, and expression of chemokine (C-C motif) ligand 2 and interleukin-6. In contrast, latanoprost+BAK delivered by the Optejet technology was both well tolerated and similar to no treatment controls and BAK-free latanoprost treatment. Conclusions: A microdose of latanoprost+BAK ophthalmical spray administered with the Optejet technology prevented the cytotoxicity associated with larger volumes found in eye drops. Precision dosing by the Optejet technology has the potential to decrease ocular surface disorder typically associated with eye drops containing preservatives.

Pupil dilation evaluation of two mydriatic dosing profiles delivered by the Optejet®.

Aim: To compare pupil dilation achieved by a single microdose versus two microdoses of tropicamide-phenylephrine fixed combination (TR-PH FC) delivered by the Optejet®. Patients & methods: In this assessor-masked, crossover, noninferiority study, 60 volunteers underwent two treatment visits and received either one (∼8 µl) or two sprays (∼16 µl) of TR-PH FC to both eyes in randomly assigned order. Results: At 35 min postdose, mean change in pupil diameter was 4.6 mm and 4.9 mm following one or two sprays, respectively. The estimated treatment group difference was -0.249 mm (standard error: 0.036; 95% CI: -0.320, -0.177). No adverse events were reported. Conclusion: A single microdose was noninferior to two microdoses of TR-PH FC and achieved clinically significant mydriasis in a timely manner. Clinical Trial Registration: NCT04907474 (ClinicalTrials.gov).

Pupil dilation efficacy and efficiency were evaluated using microdosing via the Optejet^®. The Optejet^® is a new ophthalmologic drug device that utilizes piezoelectric technology to deliver a fine, controlled, horizontal microdroplet spray with precise volume (∼8 µl), spray pattern and velocity. A single spray versus two sprays of tropicamide-phenylephrine fixed combination (TR-PH FC) were administered to both eyes anesthetic free. Efficacy and safety were evaluated at specific time intervals. The primary end point was the mean change in pupil diameter at 35 min compared with baseline. At 35 min, clinically relevant dilation was observed, with a mean change of 4.55 mm ± 0.68 for one spray and 4.88 ± 0.60 for two sprays. The treatment group difference of one spray of TR-PH FC was noninferior to two sprays (p < 0.001). Rapid dilation was observed at 15 min, and the proportions of eyes that achieved a pupil diameter of ≥6.0 mm were 74% and 83% of patients at 15 min with one spray and two sprays, respectively. The mydriatic agent was well tolerated with the delivery system even in the absence of topical anesthetic, with no ocular or system adverse events reported. Mydriasis is a vital component of routine eye healthcare, and the current standard-of-care mydriatic eye drops potentially have limitations, including contamination, spillage and burning/stinging. Delivery of a mydriatic with the Optejet^® may improve patient care flow in the clinical office setting.

The posterior location of the dilator muscle induces anterior iris bowing during dilation, even in the absence of pupillary block.

PURPOSE: To examine the effect of the posterior location of the dilator on iris anterior curvature during dilation. METHODS: An in vivo human study, an ex vivo porcine experiment, and an in silico computational model were performed in parallel. Iris anterior curvature was measured in vivo before and after dilation by time-domain slit lamp optical coherence tomography (SL-OCT). All patients (n = 7) had undergone laser peripheral iridotomy to eliminate any pupillary block due to primary angle-closure glaucoma. In the ex vivo experiments, isolated porcine irides (n = 30) were secured at the periphery and immersed in an oxygenated Krebs-Ringer buffer. Dilation was induced pharmaceutically by the addition of 2.5% phenylephrine and 1% tropicamide. An in-house optical coherence tomography (OCT) system was used to obtain iris images before and after dilation. A finite element model was also developed based on typical geometry of the iris from the initial OCT image. The iris was modeled as a neo-Hookean solid, and the active muscle component was applied only to the region specified as the dilator. RESULTS: An increase in curvature and a decrease in chord length after dilation were observed in both experiments. In both the in vivo and ex vivo experiments, the curvature-to-chord length ratio increased significantly during dilation. Computer simulations agreed well with the experimental results only when the proper anatomic position of dilator was used. CONCLUSIONS: The posterior location of the dilator contributes to the anterior iris bowing via a nonpupillary block dependent mechanism.

Anterior-posterior asymmetry in iris mechanics measured by indentation.

Indentation and histological analysis of the porcine iris were done to assess the relative stiffness of the anterior (stroma) and posterior (dilator and sphincter) layers. The dimensions of the constituent structures were documented histologically by staining with a monoclonal anti-human α-smooth muscle actin antibody to determine the location of the stroma, sphincter, and dilator. Intact porcine irides (4-8 h post-mortem) were bisected into two equal C-shaped halves to indent both surfaces. Indentation experiments were performed using a 1 mm cylindrical indenter tip. The load-displacement curve for each experiment was used to estimate effective instantaneous and equilibrium moduli for the anterior and posterior surfaces of the tissue. A total of 18 irides (9 pairs) with 3-5 indentations per iris surface was performed. The average thickness of the samples was 550 µm; the indentation depth was limited to 60-100 µm depending on the thickness of the sample at each point. Posterior surface indentation gave larger forces than anterior, with the resulting instantaneous modulus of 6.0 ± 0.6 kPa versus 4.0 ± 0.5 kPa (mean ± 95% CI, n = 45, p < 0.001) and equilibrium modulus of 4.4 ± 0.9 versus 2.3 ± 0.3 (p = 0.007). The stress-relaxation analysis revealed that the anterior surface had a shorter relaxation time (121.31 ± 6.84 s) than the posterior surface (210.61 ± 9.41 s, p = 0.03), perhaps due to the permeability of the stroma. Recognizing that our effective modulus calculations in this study did not account for heterogeneity, viscoelasticity, or poroelasticity, we conclude that the posterior components of the iris - dilator, pigment epithelium, and sphincter - are on average stiffer than the stroma and anterior border layer.

Ex vivo porcine iris stiffening due to drug stimulation.

The purpose of this study was to quantify how the elastic modulus of the ex vivo iris changes following stimulation by pilocarpine (PILO), phenylephrine (PE), and tropicamide (TROP). Irides (n = 20) were dissected from porcine eyes within 4 h post-mortem and tested uniaxially. Either the entire iris or sector thereof was used. The samples were stretched up to 40% Green strain. The radial modulus was calculated from the linear portion of the stress-strain curve, and the azimuthal modulus was fitted to a model treating the iris as a collection of circular elastic bands. One of the three drugs (n = 6 or 7) of interest was added (80 microg/ml) to the bath surrounding the tissue, and the test was repeated. Changes in pupil diameter of free-floating samples and isometric force of mounted samples confirmed that the tissue was responsive to the drugs. The untreated iris modulus for cut sections in radial extension was 4.0 +/- 0.9 kPa (mean +/- s.d., n = 20), and treated iris modulus was 7.7 +/- 2.0 kPa (PILO, n = 7), 6.9 +/- 2.2 kPa (PE, n = 6), and 8.4 +/- 1.7 kPa (TROP, n = 7). Intact irides (n = 10) gave similar trends but values approximately 25% higher, presumably due to support from the nominally unloaded tissue. The azimuthal modulus of the untreated iris was 2.97 +/- 1.3 kPa (n = 5), and that of the treated iris (PILO) was 5.34 +/- 2.1 kPa. Although PILO, PE, and TROP work by different mechanisms, all three had similar results - an increase of modulus by a factor of two. These results suggest that in most normal situations the iris remains compliant at all pupil diameters.