Innervating stackable neural organoid slices with tissue-like mesh electrodes for improved neural circuit development and characterization

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Neural organoids are excellent tools to study the development of human brains, however, they do not fully represent the brain structure. It is also difficult to record neuronal activities for a long time in neural organoids. To address those challenges, in this project, a new approach will be developed to derive neural organoids that better mimic brain structures. Those improved organoids will be assembled to represent interactions between various brain regions. The second objective of this project is to incorporate tissue-like, ultra-flexible mesh electrodes into those organoids. Those mesh electrodes are known to have minimal impacts on cells and can safely monitor the electrical activities of neurons chronically. The last objective is to investigate if applying electrical stimulations to neural organoids can accelerate their maturation, which usually takes several months. Together, this project will lead to improved neural organoid models and new knowledge in human brain development. The project will also support several educational and outreach activities, including new course development, undergraduate research projects, and paid internship programs. Highly motivated regional high school, undergraduate, and graduate students from diverse backgrounds will have opportunities to engage in stem cell research, which will facilitate the recruitment and retention of students in this exciting field.Neural organoids provide a promising platform for studying brain development and diseases. However, current neural organoids are still limited by the lack of proper regionalization and electrical stimulation for functional maturation and means of chronic monitoring for developmental studies. This project aims to transcend these key limitations by developing an engineered neural organoid system that is properly regionalized and innervated with a tissue-like mesh system capable of chronic monitoring and stimulation for improved studies of circuitry development in the neocortex. The overall research goal will be accomplished through three main objectives: (1) Regionalized neural organoid that enables the thalamus-subpallium-cortex projections will be assembled by stacking - sliced thalamic organoids and sliced telencephalic organoids with dorsoventrally patterned cortex and subpallium. (2) The sliced organoids will be innervated with tissue-like, ultra-flexible mesh electrodes for forming an Engineered Assembly of Sliced Organoids (EASOs) capable of real-time feedbacking the chronic developmental state. (3) Electrical stimulators will be further integrated into the mesh system for closed-loop modulation and monitoring of the EASOs, promoting functional maturation for accelerated developmental studies. The project will deepen the fundamental understanding of neural circuitry development and facilitate organoid development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.