Investigation of functional integration of cortical organoids transplanted in vivo towards future neural prosthetics applications

Abstract

Cortical organoids are rapidly emerging as models for brain development and dysfunction because they bridge the benefits of physiological manipulability of in vitro cultures with the complexity of in vivo brains. Organoids offer a host of benefits including the ability to perform patient-specific drug screening, study brain development, and investigate disease. Another promising application of organoids is as neural prosthetics, where if a brain region is damaged or degenerated, an organoid can be grown from the patient's stem cells and be implanted to restore lost function. Here, we implant hiPSC-derived cortical organoids in the retrosplenial cortices (RSC) of mice and to see if the organoids can form functional connections to the surrounding host cortices. Using transparent graphene microelectrode arrays (MEA) for electrophysiology and two-photon imaging of organoids, we observe a response to the external light stimuli, suggesting functional synaptic connections had formed between organoids and cortex. Bursts of cell population calcium activity are observed with two-photon imaging and suggest a mature internal network. Post-mortem histology and vasculature tracing suggests morphological integration of organoid cells into mouse cortex and mouse vessels and synapses into organoid. Overall, our multimodal platform offers a way to study organoids in vivo longitudinally and investigate their development and integration with host cortex and their potential use for cell replacement therapy.