Age-related macular degeneration: interventional tissue engineering and predictive modeling of disease progression

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people over the age of 50. As many as 50 million people are affected by AMD worldwide and prevalence is expected to continue to rise due to an aging population. There are two forms of the disease, dry (geographic atrophy) and wet (choroidal neovascularization), both of which result in retinal degeneration and central vision loss. Although anti-vascular endothelial growth factor therapies are moderately successful at treating the wet form, there are no treatments currently available for the more common dry form. Pharmacological therapies have been extensively explored for the treatment of dry AMD, but have achieved little success because the pathogenesis underlying AMD is unknown and likely varies among patients . Recently, tissue engineering has emerged as a promising approach to restore function by replacing diseased retinal tissue with healthy retinal pigment epithelium (RPE). While AMD-associated vision loss occurs when photoreceptors degenerate, this process arises as a consequence of earlier RPE dysfunction. In the healthy retina, the RPE acts as a critical regulator of the microenvironment for both photoreceptors and the nearby vasculature. However in AMD, the RPE no longer performs these essential homeostatic functions leading to photoreceptor apoptosis and vision loss. This dissertation describes the development and in vitro characterization of a tissue engineering scaffold for RPE delivery as potential treatment for dry AMD. First, a novel microfabrication-based method termed "pore casting" was developed to produce thin scaffolds with highly controlled pore size, shape, and spacing. Next, human RPE were cultured on pore-cast poly(c-caprolactone) (PCL) scaffolds and compared to cells on track-etched polyester, the standard RPE culture substrate. RPE on porous PCL demonstrated enhanced maturation and function compared to track-etched polyester including improved pigmentation, barrier formation, gene expression, growth factor secretion, and phagocytic degradation. Lastly, this study established a patient-specific method for predicting AMD progression using retinal oxygen concentration. This approach differs from current diagnosis techniques because it uses physiologically-relevant mechanisms rather than generalized clinical associations which have little, if any, prognostic value.