Modelling the Flow of Aqueous Humor in Schlemm’s Canal in the Eye

A simple mathematical model for the transient flow of aqueous humor in the canal of Schlemm is developed to investigate the acceleration effects of a sudden elevation in the intraocular pressure on the flow characteristics of the aqueous humor in the canal. The model treats a canal segment as a tube of elliptic cross-section. Exact analytical solution to the model is obtained using separation of variables method. The effects of some important model parameters on the maximum and minimum shear stresses exerted on the Schlemm’s canal epithelial cells (wall) by flowing aqueous humor are investigated for the steady-state flow

Computational Modelling of Aqueous Humor Dynamics And Drug Delivery For Intraocular Pressure Control In Glaucoma

We present a computational model of sustained delivery of ocular pressure-lowering drugs (Timolol Maleate) to the anterior segment of the eye using drug infused contact lens. Ocular structures, aqueous humor flow and their interaction were modeled as linearly elastic solids, viscous fluid flow and fluid-structure interaction (FSI) respectively in COMSOL 5.3 as axisymmetric models. Timolol distribution from contact lens was modeled as transport of diluted species coupled with the flow dynamics (FSI velocity coupled). Aqueous humor production in the ciliary body was simulated as an inlet with a mass flow rate of 5e-8 kg/s. Over a 10-hour duration, drug transport was simulated using the diffusion-FSI coupled model and a model without FSI coupling. The coupled model provided a more accurate characterization of the drug transport and distribution. The model may be useful to study ocular drugs and their delivery to the anterior and posterior segment of the eye more accurately

Aqueous outflow imaging techniques and what they tell us about intraocular pressure regulation.

Recent advances in the medical and surgical management of open-angle glaucoma have increased the number of treatment options available. Several new intraocular pressure (IOP)-lowering treatments target the conventional aqueous outflow (AO) system. However, success rates are variable and outcomes in individual patients are often difficult to predict. Variable treatment responses remain unexplained and highlight deficiencies in our current understanding of AO regulation and IOP homeostasis. Imaging is often relied upon to confirm diagnoses and monitor treatment responses in other ocular and systemic pathologies. As yet no suitable AO imaging tool has been developed to fulfil this role in glaucoma. A variety of imaging techniques have been used to study the AO tracts of humans and animals in ex vivo and in vivo eyes. In this review, results from novel imaging techniques that assess aqueous drainage through the episcleral venous system are considered and we argue these provide new insights into AO regulation. We suggest that the ability to objectively measure AO responses to interventions would be a significant clinical advance, and we have demonstrated that this can be achieved with direct visualisation of aqueous drainage. We predict that the evolution of AO imaging technology will continue to reveal critical components of AO and IOP regulation, and that personalised IOP-lowering treatment in glaucoma care may well become a reality in the near future.1. A core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute 2. Haemoglobin Video Imaging facilities funded by Sydney Eye Hospital Foundation, Carl Zeiss Meditec, and Glaukos Corporatio

Preclinical challenges for developing long acting intravitreal medicines

The majority of blinding conditions arise due to chronic pathologies in the retina. During the last two decades, antibody-based medicines administered by intravitreal injection directly into the back of the eye have revolutionised the treatment of chronic retinal diseases characterised by uncontrolled blood vessel growth, e.g. wet age-related macular degeneration (wAMD), diabetic retinopathy (DR) and choroidal neovascularisation. Although intravitreal injections have become a commonly performed ophthalmic procedure that provides a reproducible dose to maximise drug exposure in the back of the eye, there is a need to minimise the frequency and cumulative number of intravitreal injections. Developing longer-acting intraocular therapies is one key strategy that is being pursued. Pharmaceutical preclinical development of intraocular medicines is heavily reliant on the use of animal models to determine ocular tolerability, pharmacokinetics, biodistribution and drug stability. Animal eyes are different from human eyes, such as the anatomy, organisation of vitreous macromolecular structure, aqueous outflow and immune response; all which impacts the ability to translate preclinical data into a clinical product. The development of longer acting protein formulations using animals is also limited because animals reject human proteins. Preclinical strategies also do not account for differences in the vitreous due to ageing and whether a vitrectomy has been performed. Intraocular formulations must reside and clear from the vitreous body, so there is a need for the formulation scientist to have knowledge about vitreous structure and physiology to facilitate preclinical development strategies. Preclinical pharmaceutical development paradigms used to create therapies for other routes of administration (e.g. oral and intravenous) are grounded on the use of preclinical in vitro models. Analogous pharmaceutical strategies with appropriately designed in vitro models that can account for intraocular mass transfer to estimate pharmacokinetic profiles can be used to develop in vitro-in vivo correlations (IVIVCs) to accelerate the preclinical optimisation of long acting intraocular formulations. Data can then inform preclinical in vivo and clinical studies. With the now widespread use of intravitreal injections, it has also important early in preclinical studies to ensure there is a viable regulatory pathway for new therapies. Knowledge of these factors will help in the development of long acting intravitreal medicines, which is rapidly evolving into a distinct pharmaceutical discipline

Cost-Effectiveness of Selective Laser Trabeculoplasty (SLT) versus Argon Laser Trabeculoplasty (ALT) in Uncontrolled Open Angle Glaucoma Patients having at least One Full Previous SLT: An Economic Evaluation Alongside an Ongoing Randomized Controlled Clinical Trial

Background and objective: ALT and SLT are both safe and effective for glaucoma treatment. We performed a cost-effectiveness analysis (CEA) of SLT versus ALT for a six-month follow-up period in uncontrolled open angle glaucoma patients having at least one full previous SLT from an ongoing RCT. Methods: Trial based treatment costing and IOP reduction at 6-month follow-up from baseline for both intervention arms were calculated. A decision tree model was developed considering possible clinical pathways of patients undergoing repeat laser trabeculoplasty. CEA among ALT and SLT was done, and ICERs were calculated from both societal and ministry perspective. One way sensitivity analysis was done for cost and effectiveness parameters. Results: From Societal perspective, expected cost/effectiveness for ALT and SLT was $458/0.143 mmHg vs$448/0.123 mmHg respectively and from ministry perspective, $467/0.154 mmHg vs$446/0.122 mmHg, respectively. To switch from SLT to ALT, it would cost $356.49 for each extra unit IOP reduction from societal perspective and from ministry perspective, the same would cost$ 649.71. This ICERs were much higher in comparison to ICERS of other IOP lowering medications in similar situations. Conclusion: Neither ALT nor SLT strategies were clearly dominated by any other. ALT is slightly more effective and slightly costly over SLT. Sensitivity analysis with effectiveness variables showed dominance of SLT over ALT for some instances. SLT has the theoretical plausibility of repeatability and is also easier to perform than ALT. All these factors should be considered when opting between ALT and SLT strategies

Numerical solution of flow resistance in outflow pathway and intravitreal drug delivery in vitrectomised eyes

In this study, numerical computations of the ocular fluid dynamics in a human eye are presented with a perspective of understanding the mechanisms of increased flow resistance. In the present study, the TM is represented as a multilayered-graded porous structure with specific pore size and void fraction. The flow patterns and pressure distribution in anterior chamber are analyzed to delineate key flow mechanism; the shear stresses on the lens, iris and IW of SC are also examined to locate the maximum values. Inside the human eye, the largest pressure drop occurs across JCT and IW of SC. The highest pressure in SC is at the midpoint between two collector channels (CC). The pressure falls near CC which implies that the IW of SC will experience more pressure difference towards CC, and the canal may show a greater tendency to collapse close to the CC exits. The maximum velocity is found in the vicinity of IW pores. It is also seen that AH velocity funneling out of the IW pores is higher in the region underlying the collector. Analysis is also carried out for glaucomatous condition where the IOP is increased to a high value of 8000 Pa. The later part of thesis is dedicated to the drug delivery to the posterior segment of the eye. The main objective of this study is to characterize the spatio-temporal evolution of drug distribution following intravitreal injection into a vitreous substitute such as silicone oil and in the case of vitreous liquefaction caused due to aging. Both direct injection of drugs and injection of time released drugs are studied. The results show that the concentration distribution is highly dependent on the vitreous substitute, diffusion coefficient of the drug and the permeability of the retinal surface. For drugs with high diffusion coefficients, convection plays a small role whereas for the drugs with low diffusion coefficients and low viscosity vitreous fluids, convection is seen to play a more important role and can lead to high drug concentrations on the retina which can be potentially toxic. Time-released drug injection is shown to avoid conditions of retinal toxicity

Decorin reduces intraocular pressure and retinal ganglion cell loss in rodents through fibrolysis of the scarred trabecular meshwork

Purpose. To investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis. Methods. Adult rats had intracameral (IC) injections of human recombinant (hr) TGF-β over 30 days (30d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21d and 30d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed. Results. Transforming growth factor–β injections caused sustained increases in ECM deposition in the TM and raised IOP by 17d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30d. Decorin treatment from 17d reduced TGF-β–induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss. Conclusions. Human recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma

Longer-term Baerveldt to Trabectome glaucoma surgery comparison using propensity score matching

Purpose: To apply propensity score matching to compare Baerveldt glaucoma drainage implant (BGI) to Trabectome-mediated ab interno trabeculectomy (AIT). Recent data suggests that AIT can produce results similar to BGI which is traditionally reserved for more severe glaucoma. Methods: BGI and AIT patients with at least 1 year of follow-up were included. The primary outcome measures were intraocular pressure (IOP), number of glaucoma medications, and a Glaucoma Index (GI) score. GI reflected glaucoma severity based on visual field, the number of preoperative medications, and preoperative IOP. Score matching used a genetic algorithm consisting of age, gender, type of glaucoma, concurrent phacoemulsification, baseline number of medications, and baseline IOP. Patients with neovascular glaucoma, with prior glaucoma surgery, or without a close match were excluded. Results: Of 353 patients, 30 AIT patients were matched to 29 BGI patients. Baseline characteristics including, IOP, the number of glaucoma medications, type of glaucoma, the degree of VF loss and GI were not significantly different between AIT and BGI. BGI had a preoperative IOP of 21.6 ± 6.3 mmHg compared to 21.5 ± 7.4 for AIT on 2.8 ± 1.1 medications and 2.5 ± 2.3 respectively. At 30 months, the mean IOP was 15.0 ± 3.9 mmHg for AIT versus 15.0 ± 5.7 mmHg for BGI (p > 0.05), while the number of drops was 1.5 ± 1.3 for AIT (change: p = 0.001) versus 2.4 ± 1.2 for BGI (change: p = 0.17; AIT vs BGI: 0.007). Success, defined as IOP  0.05) and 50% versus 52% at 2.5 years. Conclusions: A propensity score matched comparison of AIT and BGI demonstrated a similar IOP reduction through 1 year. AIT required fewer medications