UCSF

Ocular disease treatment with pharmaceutical agents poses a unique set of challenges that can be attributed to the distinctive anatomy of the eye. Novel methods to overcome the barriers of the eye to deliver therapeutics are an area of focus for both academic and industrial researchers. In this dissertation, an in vitro model of the posterior ocular epithelial barrier was leveraged to characterize drug transport using microfabricated polymer devices. The influence of planar microdevice geometry on macromolecule permeability was investigated. Planar microdevices enhanced the transport of large molecular weight dextrans in a size dependent fashion. This phenomena was initiated by a non-toxic interaction between the microdevices and retinal tight junction proteins, suggesting that increased transport occurs via a paracellular pathway. Chitosan surface modified planar devices did not demonstrate a comparable permeability enhancing effect.

A comparison between supermicro, micro- and nanofiber films was conducted to elucidate the impact device size has on macromolecule drug transport. Our results demonstrated increased permeability, through a paracellular initiated mechanism, in the presence of micro- and nanofiber films but not supermicro fiber films. Further, drug properties such as molecule shape, charge and size demonstrated that they could enhance or diminish transport irrespective of device size. Which provided valuable insight into drug classes that would be best served by this delivery modality. Finally, co-delivery of a therapeutic and verapamil, an efflux pump inhibitor, was investigated as a strategy for enhancing permeability of small molecules. Our results displayed a drug permeability reduction in the presence of verapamil; suggesting that transporter protein localization as well as inhibitor specificity are important variables for the success of a small molecule co-delivery approach. The aforementioned experiments demonstrate distinct techniques for modulating drug transport across the ocular barrier using microfabricated polymer devices. Further, the observed trends can be used to design enhanced delivery systems for the administration of ocular therapeutics.