Development of Early/Dry Age-related Macular Degeneration Model using 3D Printing Technology

Abstract

The human eye composed of various kinds of the cells, including endothelial, epithelial, and neuronal cells. These cells are interconnected and performed their own functions to transport the electrical signal of projected image to brain for allowing human to recognize objects. The breakdown of this system decreases the quality of human life, since various activities of life are strongly related to visual acuity. One of the severe disease is the age-related macular degeneration (AMD), which is leading cause of the global blindness, however, there is no treatment. Numerous studies have been conducted to develop retinal alternatives for retinal regeneration or in vitro retina models for evaluation by pharmaceutical industries. The traditional microfluidic based lab-on-a-chip platform has been widely used for retinal model, however, it requires time-consuming and labor-intensive process and have difficulties to mimic complex retinal extracellular matrix (ECM) and compartmentalized cellular structure. To overcome these limitations, we developed Bruch’s membrane derived bioink (BM-ECM) and retina derived bioink (RdECM) to recapitulate the retinal specific microenvironment. Furthermore, Bruch’s membrane mimetic substrate (BMMS) was developed using 3D printing system. The BMMS had similar structural and molecular composition with natural BM and facilitated rapid maturation of RPE. Finally, we developed the 3D printing based BRB model with vascular structure by printing endothelial cell and RPE cell each side of BMMS. The developed vascularized BRB model showed enhanced functionality than non-vascularized model, in aspect of barrier and clearance functions, polarized secretion of anti-angiogenic factor and secretion of enzyme to support the visual function. Then, the model was induced chemical hypoxia and treated amyloid-beta to develop the disease model and their responses against drug were analyzed. The processes developed in this dissertation, including developing tissue-specific bioinks, tissue mimetic substrate and printing compartmentalized cellular structure, could be ued in development of various types of in vitro model and contribute one step forward in tissue engineering field.