Divergence in photoreceptor cell death and neuroinflammation in transvitreal and transscleral subretinal delivery in mice

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Subretinal injections provide direct access to photoreceptors and RPE, which is crucial for the delivery of gene therapy and neuroprotective approaches. To access the subretinal space, transvitreal (TV) and transscleral (TS) subretinal injections have been widely used in humans and animal models. In this work, we investigated recent trends and outcomes of utilizing TV and TS subretinal models of retinal detachment (RD). A literature review revealed an increasing utilization of both models over the past two decades, with TS emerging as the predominant model since 2012. Subretinal injection in CX3CR1 + /GFP CCR2 + /RFP mice revealed early inflammatory responses, with TS injections inducing higher infiltration of CD11b + CCR2 + cells compared to TV. Further leukocyte immunophenotyping indicated divergent infiltration patterns, with the TS approach exhibiting higher proportions of neutrophils and macrophages/microglia-like cells, while the TV injections had higher CD45hi CD11b + Ly6G- Ly6C + infiltration. Notably, late-stage analysis demonstrates higher photoreceptor cell death in the TS approach, paralleled by increased subretinal infiltration of CD11b + cells. Both models showed significant reactive gliosis, suggesting comparable late-stage wound healing responses. These findings underscore the utility of these approaches for subretinal delivery, offering insights into their distinctive leukocyte infiltration and late-stage tissue responses.