In Vitro Cornea Models in Contact Lens Based Ocular Drug Delivery
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The development of suitable in vitro release and diffusion models for contact lens-based drug delivery may lead to the establishment of in vitro/in vivo correlations. It is evident that an in vitro model that can reproduce the in vivo results would prevent the disqualification of an otherwise effective drug delivery material or method due to poor release results obtained using unsuitable release models. Conversely, it would also aid in discarding materials with poor properties more efficiently. An overwhelming amount of research has shown that both drug-soaked silicone hydrogel and conventional hydrogel materials are unable to continuously release medication at therapeutic levels. For example, studies have shown that commercially available contact lenses can reach extended drug release for up to 24 hours in vivo while significantly shorter release of the same drug from similar contact lens materials have been observed when tested using current in vitro release models. The lack of appropriate in vitro release and diffusion models that are more representative of the physiological conditions in the eye has provided the impetus for this thesis. The guiding objective of this thesis was to investigate the several well-recognized passive/static in vitro ocular drug release models and to introduce novel dynamic in vitro drug release and diffusion experimental models which may help in explaining the discrepancies between in vitro and in vivo results. To effectively recreate the human eye environment in drug delivery studies, the model needs to consider the limited volume and replenishment of the tear as well as the incorporation of corneal cells. By comparing three in vitro models (i.e., fixed volume, dynamic, and cell), the results presented in this thesis aim to offer a robust, reliable and cost effective testing platform more suitable for assessing the drug releasing capabilities of hydrogel contact lenses. The release results prove the importance of a dynamic release platform for testing contact lens materials by identifying interactions between the drug and lens material that would otherwise be disregarded in the fixed volume model. While interactions between lens and material are important to consider during developement and testing in the experimental model, another important parameter to consider is drug interactions with cells. Prodrugs such as prostaglandins belong to a large group of ophthalmic drugs. These compounds are precursors to ophthalmic drugs that are specifically designed to improve the drug residence time in tear film and enhance the drug uptake by the cell membrane. Within corneal cells, these prodrugs can be metabolized through different pathways into the active form of the drug, before reaching the targeted tissue. By using an in vitro cornea model, it was demonstrated that the 24-hour release of prostaglandin prodrug from a pre-soaked silicone hydrogel was comparable to the daily dose of that ophthalmic drug delivered as an eye-drop. These results emphasized the importance of the presence of cells when characterizing the release of drug-delivery materials, and demonstrated how experimental in vitro models have a significant impact on the outcomes of testing ophthalmic drug delivery materials. It was also further hypothesized in this thesis that a cell-based in vitro cornea model combined with a tear replenishment method to study drug release from a contact lens is better suited for release studies from ophthalmic materials. Through modeling the microfluidics of in vivo tear replenishment and using a curved surface to grow cells, a tear replenishment cell culture system was developed as an in vitro testing platform for ocular drug delivery. Via continuous replenishment of a tear solution analogue over the surface of the cell culture model, results from this work demonstrated yet another important role that a dynamic release model will have in predicting the amount of drug loss from a contact lens into the tear film/lacrimal system. Recreating the geometry of the ocular surface as well as the microfluidics of tear replenishment combined with the incorporation of human corneal epithelial cells in this research proved the potential of drug eluting contact lenses when tested under more realistic conditions. The results and the new models developed in this research project may also help to explain or provide means to investigate the discrepancies between in vitro and in vivo studies.