Development of self-healing hydrogels to support choroidal endothelial cell transplantation for the treatment of early age related macular degeneration

Abstract

In retinal diseases such as age-related macular degeneration (AMD) and choroideremia, a key pathophysiologic step is loss of endothelial cells of the choriocapillaris, the dense vascular bed required for maintaining health and function of the retina. As such, repopulation of choroidal vasculature early in the disease process may halt disease progression. Prior studies have shown that injection of donor cells in suspension results in significant cellular efflux and poor cell survival. As such, the goal of this study was to develop a hydrogel system designed to support CEC transplantation. A library of hydrogels was synthesized using laminin (i.e., LN111, LN121, and LN421), carboxy methyl chitosan, and oxidized dextran via reversible Schiff base chemistry. Each of the developed hydrogels was readily injectable into the suprachoroidal space, with excellent gelation, mechanical, and degradation properties. Laminin-based hydrogels were compatible with immortalized CEC survival in vitro, and suprachoroidal injection of LN111 and LN121 containing gels were well-tolerated in an in vivo rat model, whereas LN421 containing gels caused significant chorioretinal inflammation. Hydrogels were detected in the suprachoroidal space of immunosuppressed rats at 1-week post-injection and were completely resorbed by 1-month post-injection. There were significantly more CECs retained in immunosuppressed rats that received cell laden hydrogels than those that received unsupported cell suspensions (i.e., CECs only). These findings pave the way for future CEC replacement studies in animal models of choroidal cell loss toward the development of future therapies. Statement of significanceAge related macular degeneration (AMD) is a leading cause of untreatable blindness in the industrial world. A key pathologic step in AMD is loss of the choriocapillaris endothelial cells, which provide vascular support to the overlying retina, including the light-sensing photoreceptors. We believe that choroidal cell replacement early in disease may prevent retinal cell death and subsequent vision loss. In this study, we present a strategy for repopulating the choriocapillaris using choroidal endothelial cell laden hydrogels. Specifically, we demonstrate the synthesis and characterization of 3 different laminin-based hydrogel systems. LN111 and LN121 hydrogels were found to increase retention of choroidal endothelial cells following suprachoroidal transplantation. These findings pave the way for future cell replacement studies in animal models of choroidal cell dropout.