Abstract
Disorders of the eye leading to visual impairment are a major issue that affects millions of people. On the other side ocular toxicities were described for e.g. molecularly targeted therapies in oncology and may hamper their development. Current ocular model systems feature a number of limitations affecting human-relevance and availability. To find new options for pharmacological treatment and assess mechanisms of toxicity, hence, novel complex model systems that are human-relevant and readily available are urgently required. Here, we report the development of a human immunocompetent Choroid-on-Chip (CoC), a human cell-based in vitro model of the choroid layer of the eye integrating melanocytes and microvascular endothelial cells, covered by a layer of retinal pigmented epithelial cells. Immunocompetence is achieved by perfusion of peripheral immune cells. We demonstrate controlled immune cell recruitment into the stromal compartments through a vascular monolayer and in vivo-like cytokine release profiles. To investigate applicability for both efficacy testing of immunosuppressive compounds as well as safety profiling of immunoactivating antibodies, we exposed the CoCs to cyclosporine and tested CD3 bispecific antibodies.
Highlights
Disorders of the eye leading to visual impairment are a major issue that affects millions of people
To address the key physiological characteristics related to choroidal drug reactions and considering immunology, we developed a human immunocompetent choroidal in vitro model that mimics the tissue vascularization, pigmentation and immune response in the presence of circulating immune cells
The epithelium consists of a monolayer of human induced pluripotent stem cell-derived retinal pigmented epithelium (RPE) in the top channel
Summary
Disorders of the eye leading to visual impairment are a major issue that affects millions of people. OoC models mimic the microphysiological environment cells experience in a tissue including the vasculature-like perfusion They are developed to potentiate several functional readouts using very low cell numbers. The rise of complex treatment modalities, increasing attrition rates and low of predictivity of current model systems created an urgent need for human-relevant and well-characterized in vitro models to support drug development (i) in efficacy testing by building in vitro disease models and (ii) in toxicity testing by providing a unique tool for mechanistic studies. To develop ophthalmic drugs and study ocular toxicity, novel human-relevant ocular tissue models are urgently needed[6]. One such ocular tissue, is the choroid of the eye which belongs to the uveal tract. Posterior uveitis involves inflammation of the retina, choroid and sometimes the optic nerve and in spite of not being the most common type of uveitis it is the most sight-threatening kind, with potential for causing severe structural damage and visual impairment[10]
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