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Title: In vitro and computational modelling of drug delivery in the eye for the treatment of retinal pathologies
Author: Davies, Alys Elisabeth
ISNI:       0000 0004 7964 2427
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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Posterior segment diseases such as proliferative vitreoretinopathy and diabetic retinopathy have the potential to cause irreversible visual impairment. Delivery of therapeutic drugs to this region of the ocular globe poses many challenges owing to different anatomical and physiological constraints. There are some conditions that require drug treatment over prolonged periods of time and there is scope for the development of an extended drug delivery device to combat the burden of current treatment methods. Models can be a fast, inexpensive method of understanding the release profiles of therapeutics from such systems in an attempt to avoid toxic/ineffective treatment. Well designed, validated models could help speed the development of novel drug delivery systems and, if standardised, allow comparison between different technologies. Here the aim was to develop models of the drug clearance mechanisms in the posterior segment of the eye and test their ability to model drug transport behaviour from one potential drug delivery system. A static in vitro model of the outer blood retinal barrier (OBRB) was developed using a human retinal pigmented epithelium cell line, ARPE-19 cells, cultured on ammonium plasma treated expanded polytetrafluoroethylene (ePTFE) transwell membranes and used to evaluate the permeability of different molecular weight dextran molecules. Using COMSOL Multiphysics computational fluid dynamics (CFD) software, computational models of the transport of dextrans across this barrier within a dynamic microfluidic environment, the Kirkstall Ltd QV600 culture chamber, were developed and corresponding in vitro experiments were carried out in order to validate the simulations. This was then repeated for the release of ibuprofen (ibu) from a silicone oil (SiO) tamponade. Two other in vitro models; a spherical eye model and an eye-on-a-chip (EOC) device were also used to investigate different drug clearance mechanisms that are present in the eye in an attempt to gain a full understanding of the release dynamics of this potential delivery system. In order to build accurately described computer models, experimental data was obtained from simple experiments in each of the different in vitro models used to determine key input parameters. Within the Kirkstall QV600, transepithelial electrical resistance (TEER) and immunocytochemistry (ICC) showed increased barrier function of the ARPE-19 cells cultured under medium flow up to a flow rate of 200μL/min. At 400μL/min, there was decreased functionality and clusters of the epithelial mesenchymal transition marker, aSMA, appeared. Utilising permeability and diffusion coefficients derived from the static in vitro experiments, transport of dextrans across unseeded ePTFE membranes were able to be simulated to within 15% error of the corresponding dynamic in vitro results. The introduction of cells increased this error to a maximum 30%. Simulating the release of ibu from SiO within the same dynamic environment produced results again, within a 15% error of the in vitro data. This was able to be repeated when investigating the other clearance mechanism in the spherical eye model. Within the EOC, the percentage release of ibu was equivalent after 7 days, however the release profile over days 1, 2 and 3 was not comparable. The predicted results from the computational models showed good agreement with the results obtained from the benchtop experiments and the computer models showed that it is possible to investigate a vast range of parameters in a more time and cost efficient manner. Using a variety of models to investigate drug release from the ibu-SiO device provided a more comprehensive understanding of how both the anterior and posterior clearance mechanisms found within the posterior segment of the eye, affect the transport of the drug. Computational modelling can be a fast and cost-effective method to assist in the development of novel drug delivery devices. This study presents the design and development of three distinct yet complementary CFD models used to investigate the release of ibuprofen from silicone oil. The accuracy of these simulations was validated using data from corresponding in vitro experiments to produce models which can be used as valuable predictive tools.
Supervisor: Kearns, Victoria ; Williams, Rachel Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral