The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjogren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.

TFOS DEWS II pathophysiology report

The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype.

TFOS DEWS II Management and Therapy Report

The importance of the cornea to the ocular structure and visual system is often overlooked because of the cornea's unassuming transparent nature. The cornea lacks the neurobiological sophistication of the retina and the dynamic movement of the lens; yet, without its clarity, the eye would not be able to perform its necessary functions. The complexity of structure and function necessary to maintain such elegant simplicity is the wonder that draws us to one of the most important components of our visual system.

Anatomy and physiology of the cornea

The major challenge faced by today's pharmacologist and formulation scientist is ocular drug delivery. Topical eye drop is the most convenient and patient compliant route of drug administration, especially for the treatment of anterior segment diseases. Delivery of drugs to the targeted ocular tissues is restricted by various precorneal, dynamic and static ocular barriers. Also, therapeutic drug levels are not maintained for longer duration in target tissues. In the past two decades, ocular drug delivery research acceleratedly advanced towards developing a novel, safe and patient compliant formulation and drug delivery devices/techniques, which may surpass these barriers and maintain drug levels in tissues. Anterior segment drug delivery advances are witnessed by modulation of conventional topical solutions with permeation and viscosity enhancers. Also, it includes development of conventional topical formulations such as suspensions, emulsions and ointments. Various nanoformulations have also been introduced for anterior segment ocular drug delivery. On the other hand, for posterior ocular delivery, research has been immensely focused towards development of drug releasing devices and nanoformulations for treating chronic vitreoretinal diseases. These novel devices and/or formulations may help to surpass ocular barriers and associated side effects with conventional topical drops. Also, these novel devices and/or formulations are easy to formulate, no/negligibly irritating, possess high precorneal residence time, sustain the drug release, and enhance ocular bioavailability of therapeutics. An update of current research advancement in ocular drug delivery necessitates and helps drug delivery scientists to modulate their think process and develop novel and safe drug delivery strategies. Current review intends to summarize the existing conventional formulations for ocular delivery and their advancements followed by current nanotechnology based formulation developments. Also, recent developments with other ocular drug delivery strategies employing in situ gels, implants, contact lens and microneedles have been discussed.

Ocular drug delivery systems: An overview

Purpose: To determine whether posterior capsule opacification (PCO) is influenced by intraocular lens (IOL) material.

Setting: A British teaching hospital eye department.

Methods: Ninety eyes were prospectively randomized to receive a poly(methyl methacrylate) (PMMA), silicone, or AcrySof® IOL. All lenses had 6,0 mm optics and PMMA haptics. A standardized surgical protocol was performed by a single surgeon using an extracapsular technique with capsulorhexis. Patients having surgical complications were excluded, and all patients had standardized medication and follow-up. Posterior capsule opacification was assessed by a digital retroillumination camera using a dedicated software program based on the analysis of texture in the image and calculated as the percentage area of opacified capsule. Data were analyzed 2 years postoperatively.

Results: There was a significant difference in percentage of PCO at 2 years among the three lens types (P < .0001). The AcrySof lenses were associated with less PCO (median 11.75%) than PMMA (43.65%) and silicone (33.50%) lenses (P < .001 and P = .025, respectively). The difference between PMMA and silicone lenses was not statistically significant.

Conclusion: Intraocular lenses made from AcrySof were associated with a significantly reduced degree of PCO.

Relationship between intraocular lens biomaterials and posterior capsule opacification.

Purpose: To assess the efficacy and safety of a soft acrylic intraocular lens (IOL) in small incision cataract surgery. Methods: Sixty-four eyes of 64 patients (mean age 71.0 ± 7.7 [SD] years) who had phacoemulsification and implantation of a soft acrylic IOL were followed for 2 years. Results: At day 1, 96.9% of patients had corrected visual acuity of 20/40 or better, and 50.0% had 20/20 or better. At 2 years postoperatively, 100% had 20/40 or better, and 86.3% had 20/20. Surgically induced keratometric cylinder remained quite stable throughout the 2 year follow-up period, with axis-based astigmatism of ±0.3 diopters. Flare intensity measured with the laser flare-cell meter was less than that with other type of IOLs measured, including poly(methyl methacrylate) and silicone. Neodymium:YAG laser capsulotomy was performed in seven cases (11.1 %) without causing damage to the optic. No other postoperative complications were encountered. Conclusion: Soft acrylic IOLs have clinically apparent advantages in small incision cataract surgery.

Two year clinical study of a soft acrylic intraocular lens

Purpose: The cytotoxicity of a range of commercial ophthalmic solutions in the presence and absence of preservatives was assessed in human corneal endothelial cells (HCECs), corneal epithelia and conjunctival epithelia using in vitro techniques.



Methods:  Cell survival was measured using the WST-1 assay for endothelial cells and the MTT assay for epithelial cells. Commercially available timolol, carteolol, cromoglicate, diclofenac, bromfenac and hyaluronic acid ophthalmic solutions were assessed for cytotoxicity in the presence and absence of preservatives. The preservatives benzalkonium, chlorobutanol and polysorbate were also tested. The survival of cells exposed to test ophthalmic solutions was expressed as a percentage of cell survival in the control solution (distilled water added to media) after 48 h exposure.



Results:  HCEC survival was 20–30% in ophthalmic solutions diluted 10-fold. The survival of HCEC was significantly greater in all solutions in the absence of preservative than in the presence of preservative. The survival of corneal and conjunctival epithelia was consistent with that of HCECs for all test ophthalmic solutions. The preservatives polysorbate and benzalkonium were highly cytotoxic with cell survival decreasing to 20% at the concentration estimated in commercial ophthalmic solutions. By comparison, the survival of cells exposed to chlorobutanol was 80% or greater.



Conclusions:  The cytotoxicity of ophthalmic solutions to HCEC, corneal epithelia and conjunctival epithelia decreased in the absence of preservative.

Cytotoxicity of ophthalmic solutions with and without preservatives to human corneal endothelial cells, epithelial cells and conjunctival epithelial cells.

Comparative Study of Intraocular Lens Implantation Through 3.2- and 5.5-mm Incisions

Clinical and Experimental Observation of Glistening in Acrylic Intraocular Lenses

Purpose: To investigate the possible relationship between temperature and water absorption in acrylic intraocular lenses (IOLs).

Setting: Laboratory setting, Miyata Eye Clinic, Hiroshima, Japan.

Methods: The equilibrium water content (amount of water absorbed per weight of the resin × 100) in 2 hydrophobic acrylic IOLs (AcrySof® MA60BM [Alcon] and Sensar® AR40 [AMO]) was calculated at 30°C, 40°C, and 50°C. The 2 IOLs were also subjected to 3 changes in temperature: from 37°C to 35°C, 39°C to 35°C, and 41°C to 35°C. They were incubated in physiological saline at the higher temperature for 2 hours and at the lower temperature for 30 days before being examined for glistening formation.

Results: The water content was higher in the AR40 IOL than in the MA60BM IOL at all temperatures. A temperature-dependent increase in water content was seen in both IOLs, greater in the MA60BM. With a temperature change from 37°C to 35°C, glistening formation was not observed in either IOL. With a temperature change from 39°C to 35°C, glistenings were observed in the MA60BM IOL, and with a temperature change from 41°C to 35°C, they were observed in both IOLs.

Conclusion: The change in the equilibrium water content caused by temperature changes between 30°C and 40°C is an important factor in glistening formation, and thus an IOL featuring less temperature-dependent water absorption is less likely to form glistenings.

Shigeo Yaguchi

Papers

Two year clinical study of a soft acrylic intraocular lens

Cytotoxicity of ophthalmic solutions with and without preservatives to human corneal endothelial cells, epithelial cells and conjunctival epithelial cells.

Comparative Study of Intraocular Lens Implantation Through 3.2- and 5.5-mm Incisions

Clinical and Experimental Observation of Glistening in Acrylic Intraocular Lenses

Equilibrium water content and glistenings in acrylic intraocular lenses.