Friday, May 3, 2024
5/3/2024
SUMMARY The inner blood-retina barrier (iBRB), formed by retinal endothelial cells (RECs) and pericytes, and supported by astrocytes, is the critical pathological location mediating the manifestation and sequelae of retinal vascular diseases. Although the vascular system in the retina is one of the most studied vascular beds, there remain significant knowledge gaps in our understanding of the processes that lead to retinal vascular dysfunction. Due to the lack of in vitro models, we propose establishing 3D human iBRB models with physiological characteristics as functioning healthy tissue. In Aim 1, we will develop a tissue-engineered post-capillary venule model of the healthy iBRB. In Aim 2, we will develop a tissue-engineered capillary model of the healthy iBRB. In Aim 3, we will increase the complexity of iBRB models’ extracellular mimicry environment. In vitro microphysiological models capable of recapitulating the healthy iBRB can be applied to examine tissue perturbations towards addressing the knowledge gaps in our understanding of the processes that lead to retinal vascular dysfunction. Challenges in developing such in vitro model include a need for necessary cellular components, physiological and pathological environment mimetics, and controlled perfusion conditions. Moreover, there are significant differences along the arterio-venous axis, from arterioles to capillaries to venules, in physical dimensions, flow rates, and supporting cell organization. Therefore, the significance of this work lies in developing mimicry iBRB models that further capture different zonations in the retina’s vascular system. No model has been developed that uses human retina vascular cells and astrocytes in a 3D setting with controllable perfusion at the post-capillary venule and capillary size scales, and no study further introduced changes in oxygen concentration and matrix mechanics that allows an understanding of the impact on the retinal barrier function, underscoring the innovation herein. We use cutting-edge tissue-engineered microvessel models, stem cells, and biomaterials to develop iBRB in vitro models. Successful completion of the Aims is ensured by the interdisciplinary environment at Duke University and Johns Hopkins University, as well as the collaborative track record among Drs. Sharon Gerecht and Peter Searson, and newly joined Drs. Jeremy Kay and Xi Chen, with relevant neuroscience and clinical research expertise. The proposed work will engineer the next generation of human iBRB microphysiological systems that will enable future mechanistic studies of tissue development, function, and aging in health and disease states.
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