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. 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 choroidal endothelial cell 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 self-healing hydrogels was readily injectable into the suprachoroidal space, with ideal gelation, mechanical, and degradation properties. While all hydrogels were found to be compatible with choroidal endothelial cell survival in vitro, only LN111 and LN121 gels were well-tolerated in vivo. To determine if hydrogel mediated cell delivery enhances donor cell retention and survival in vivo, iPSC-derived choroidal endothelial cell laden hydrogels were injected into the suprachoroidal space of an immunocompromised choroidal cell injury rat model. Significantly more donor cells were retained and survived in eyes that received cell laden hydrogels versus contralateral hydrogel free controls. Furthermore, donor cells positive for human nuclear antigen were identified in the choroid of hydrogel eyes only. These findings pave the way for future cell replacement studies in large animal models of choroidal cell dropout focused on evaluating functional integration of donor cells within decellularized vascular tubes.

Statement of significance

Age 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. 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 have excellent biocompatibility both in vitro and in vivo. Hydrogel mediated delivery of iPSC-derived choroidal endothelial cells enhanced donor cell retention and survival, paving the way for functional large animal studies.