Computational Study of Hydrogel Ring Device for Ocular Drug Delivery

Researchers have developed many different kinds of ocular drug delivery devices. However, most address anterior eye disorders—very few are designed specifically for the treatment of posterior eye diseases. A recently-developed hydrogel ring device is capable of delivering therapeutic quantities of the drug Ofloxacin to treat ocular infections at the back of the eye—a region typically difficult to access via systemic (e.g. ingestion of pills) and topical (e.g. eye drops) methods. Despite promising preliminary in vivo test results, much remains unknown about the precise drug transport pathway from the hydrogel ring to the posterior segment of the eye, as well as how design parameters may be altered to increase drug delivery efficiency. The aim of this work is to fully characterize the drug release and transport characteristics from the hydrogel, to ocular tissues (anterior and posterior), as well as provide a quantitative method for the optimization of various hydrogel ring design parameters. To achieve the abovementioned goals, we built a computational model using COMSOL Multiphysics to simulate the release of Ofloxacin from the hydrogel ring and to obtain the resulting drug distribution in ocular tissues at various time points. Using the model, we monitored the transient Ofloxacin concentration profile over the entire eye, for a treatment period of ten hours. Our results showed that while Ofloxacin diffuses to the anterior region much more quickly than to posterior tissues, Ofloxacin concentrations do successfully accumulate to therapeutic levels in the posterior tissues during the simulated ten-hour treatment period. This finding supports the therapeutic potential of the hydrogel ring for the treatment of posterior eye diseases. We also performed optimization analyses to determine the ideal set of hydrogel ring design parameters for the treatment of infections caused by three bacterial species commonly associated with ocular disorders: Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae. Preliminary findings suggest that the combination of an initial mass of 3 mg/m3 of Ofloxacin in the hydrogel and an Ofloxacin diffusivity of 3.11X10−9 m2/s in the hydrogel provide the best possible therapeutic outcome (from the range of values tested) for the treatment of E. coli and S. aureus infections. To our best knowledge, there is no existing computational model that simulates drug transport through the entire human eye from an ocular drug delivery device. We believe that our computational model will be highly useful for quantitative device characterization of the hydrogel ring, as well as in the optimization of the hydrogel ring design for the treatment of posterior eye disorders. This work may also serve as a model and reference for future computational work on ocular pharmacokinetics and/or ocular drug delivery devices

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

Investigation of dosing interval differences for nepafenac ophthalmic suspensions: A suspension-specific PBPK model with improved in vitro dissolution data

Nepafenac is a nonsteroidal anti-inflammatory drug (NSAID) for the treatment of inflammation associated with cataract surgery. It is marketed as two ophthalmic suspensions—NEVANAC® (0.1% administered three times a day) and ILEVRO® (0.3% administered once a day). The primary mediator of pain relief is amfenac, which is a metabolite of nepafenac. The primary goal of this project was to explain how was the dosing interval affected by changes in formulation properties. The approach incorporated three novel elements. 1) A physiologically based pharmacokinetic (PBPK) model that is specific to this application for nepafenac and amfenac was constructed, which allowed tracking the specific pharmacokinetics while minimizing the use of unnecessary compartments and variables. 2) A precorneal model was constructed to allow the modeling of interactions between formulations and the tear layer and other components on the ocular surface, which allowed assessing differences in formulation properties on the resulting pharmacokinetics. 3) A novel dissolution test (IVDT) was performed on NEVANAC® and ILEVRO® separately to determine the specific drug dissolution and distribution in each formulation and allow improved modeling of the in vivo nepafenac drug delivery. The model was written in the programming language “R” and was used for in silico simulations to assess the reasons for the dosing interval change in terms of formulation properties. This approach aligned with current FDA initiatives in quantitative modeling methods (QMM). This work facilitated explaining the dosing interval question, created increased knowledge of how to construct and evaluate ocular PBPK models, and contributed to advancing the art of ocular PBPK modeling

Delivery Systems in Ocular Retinopathies: The Promising Future of Intravitreal Hydrogels as Sustained-Release Scaffolds

Delivery systems; Hydrogels; RetinopathiesSistemes de lliurament; Hidrogels; RetinopatiesSistemas de liberación; Hidrogeles; RetinopatíasSlow-release delivery systems are needed to ensure long-term sustained treatments for retinal diseases such as age-related macular degeneration and diabetic retinopathy, which are currently treated with anti-angiogenic agents that require frequent intraocular injections. These can cause serious co-morbidities for the patients and are far from providing the adequate drug/protein release rates and required pharmacokinetics to sustain prolonged efficacy. This review focuses on the use of hydrogels, particularly on temperature-responsive hydrogels as delivery vehicles for the intravitreal injection of retinal therapies, their advantages and disadvantages for intraocular administration, and the current advances in their use to treat retinal diseases.This research was partially funded by ANID FONDECYT Regular (Chile) through project Nº 1210476 (granted to E.D.-L.). D.R. is recipient of a PTA fellowship from the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain. S.J.C. receives financial support from the Helmut Ecker Foundation

Asymmetry in Drug Permeability through the Cornea

The permeability through the cornea determines the ability of a drug or any topically applied compound to cross the tissue and reach the intraocular area. Most of the permeability values found in the literature are obtained considering topical drug formulations, and therefore, refer to the drug permeability inward the eye. However, due to the asymmetry of the corneal tissue, outward drug permeability constitutes a more meaningful parameter when dealing with intraocular drug-delivery systems (i.e., drug-loaded intraocular lenses, intraocular implants or injections). Herein, the permeability coefficients of two commonly administered anti-inflammatory drugs (i.e., bromfenac sodium and dexamethasone sodium) were determined ex vivo using Franz diffusion cells and porcine corneas in both inward and outward configurations. A significantly higher drug accumulation in the cornea was detected in the outward direction, which is consistent with the different characteristics of the corneal layers. Coherently, a higher permeability coefficient was obtained for bromfenac sodium in the outward direction, but no differences were detected for dexamethasone sodium in the two directions. Drug accumulation in the cornea can prolong the therapeutic effect of intraocular drug-release systemThis project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement N° 813440 (ORBITAL—Ocular Research by Integrated Training And Learning) and is also supported by the Fundação para a Ciência e Tecnologia (FCT) [UID/QUI/00100/2019, UIDB/00100/2020 and UID/BIM/04585/2020]S

Ocular, Neural, and Cellular Biodistribution of Multifunctional Antioxidants

Aging is a complex biological process which stems from a growing imbalance between the regenerative capacity of an organism and endogenous as well as exogenous damaging factors. This imbalance leads to the slow deterioration of individual cells, organs, and eventually the entire organism. The free radical theory of aging combines the evolutionary and mechanistic aspects of aging, postulating that the innate process is caused by deleterious, irreversible, and inevitable changes in biological systems caused by oxidative damage that accumulates over the lifespan. Evidence of this phenomenon is supported by the pathogenesis of age-related diseases, such as age-related macular degeneration and Alzheimer’s disease, which show that there is an age-related decrease of cellular antioxidant defenses. This results in the dyshomeostasis of redox-active metals, such as iron, copper, and zinc, and in turn exacerbates the oxidative stress induced by reactive oxygen species and free radicals such as superoxide, hydrogen peroxide, and the hydroxyl radical. Our laboratory has developed two series of multifunctional antioxidants (MFAOs), the JHX and HK series, which can simultaneously chelate biologically active transition metals and scavenge free radicals. These orally-active compounds have demonstrated therapeutic effects against age-related eye diseases, such as cataract and macular degeneration. Despite their efficacy, little is known about the ocular biodistribution of these orally-administered molecules. I have conducted a biodistribution study of 24 such molecules. These included the MFAOs, their monofunctional free radical scavenging (FRS) and biologically active transition metal chelating (CHL) analogs, as well as their nonfunctional (NF) analogs in Sprague Dawley rats. In Chapter Two, I demonstrate that all compounds can be detected unmetabolized in the cornea, iris with the ciliary body, lens, neural retina, retinal pigmented epithelium with the choroid, brain, sciatic nerve, kidney, and liver. In Chapter Three, I describe the predictive models of ocular, neural, and visceral tissue distribution, which I developed based on the biodistribution data from Chapter Two, using hierarchical cluster analysis (HCA) and quantitative structure activity relationship analysis (QSAR). The results indicated that both HCA and QSAR analysis yielded many predictive models which agree with other reported trends of drug delivery to ocular, neural, and visceral tissues. In Chapter Four, I present my investigation into the potential pharmacological chaperone activity of two oxysterols, lanosterol and 25-hydroxycholesterol, to three model αB-crystallin chaperone proteins in silico and compare their binding against the MFAOs. Our results confirm that the oxysterols fail to meet the predictive binding threshold, indicating weak binding affinity to the model αB-crystallin proteins. However, their predicted Kd values matched experimentally reported values. The MFAOs exceeded the threshold for predictive binding and support previous in vivo studies which suggest our molecules may have some chaperone activity. Finally, in Chapter Five, I will present several synthetic approaches for the preparation of various novel triphenylphosphonium-linked (TPP) JHXseries compounds. I will also discuss their in vitro evaluation in HEI-OC1 inner ear cells. Since mitochondrial dysfunction is linked to neurodegeneration, we hypothesized that directly linking a mitochondria-targeting moiety to our compounds would increase their potency by quenching free radicals at their main generation source. Our results indicate that the TPP compounds do not adversely affect mitochondria as shown using a viability assay and Rhodamine-123 fluorescence stain

Human Stem Cells for Ophthalmology: Recent Advances in Diagnostic Image Analysis and Computational Modelling

\ua9 2023, The Author(s).Purpose of Review: To explore the advances and future research directions in image analysis and computational modelling of human stem cells (hSCs) for ophthalmological applications. Recent Findings: hSCs hold great potential in ocular regenerative medicine due to their application in cell-based therapies and in disease modelling and drug discovery using state-of-the-art 2D and 3D organoid models. However, a deeper characterisation of their complex, multi-scale properties is required to optimise their translation to clinical practice. Image analysis combined with computational modelling is a powerful tool to explore mechanisms of hSC behaviour and aid clinical diagnosis and therapy. Summary: Many computational models draw on a variety of techniques, often blending continuum and discrete approaches, and have been used to describe cell differentiation and self-organisation. Machine learning tools are having a significant impact in model development and improving image classification processes for clinical diagnosis and treatment and will be the focus of much future research

Human corneal cell culture models for drug toxicity studies

In vivo toxicity and absorption studies of topical ocular drugs are problematic, because these studies involve invasive tissue sampling and toxic effects in animal models. Therefore, different human corneal models ranging from simple monolayer cultures to three-dimensional models have been developed for toxicological prediction with in vitro models. Each system has its own set of advantages and disadvantages. Use of non-corneal cells, inadequate characterization of gene-expression profiles, and accumulation of genomic aberrations in human corneal models are typical drawbacks that decrease their reliability and predictive power. In the future, further improvements are needed for verifying comparable expression profiles and cellular properties of human corneal models with their in vivo counterparts. A rapidly expanding stem cell technology combined with tissue engineering may give future opportunities to develop new tools in drug toxicity studies. One approach may be the production of artificial miniature corneas. In addition, there is also a need to use large-scale profiling approaches such as genomics, transcriptomics, proteomics, and metabolomics for understanding of the ocular toxicity.Peer reviewe

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

Development of Imaging Paradigms for Drug Distribution and Fate in the Eye

Aging-associated vision loss is increasingly prevalent in our population and intravitreal injections are commonly used to administer ocular drugs to the posterior segment of the eye. This work aims to visualize and predict the delivery of ocular drugs by combining micro- computed tomography (micro-CT) imaging and computational fluid dynamics (CFD) modeling. Intravitreal injections were administered into ex vivo porcine eyes and imaged for an extended period of time to track the progression of the injected drug mimic. Non-invasive imaging allowed for precise determination of contrast agent concentration, flow patterns and fate. A computational model was developed that provided quantitative agreement with the concentration values found in the experimental study and allowed for easy manipulation of parameters. The ability to accurately model drug transport following an intravitreal injection provides vital information to better understand the specific concentration and time frame for the drug to reach the target sit