Abstract The proposed work aims at the development of an enhanced organoid-based in vitro pre-clinical drug screening platform for neurological and neurodegenerative brain diseases. 2D in vitro cell cultures and non- human animals have been the mainstay of pre-clinical drug development and mechanistic studies for decades. However, 2D cell cultures and animals do not accurately recapitulate the complexity and unique features of human physiology, thus behave differently from their in vivo and human counterparts in many key characteristics of cellular behavior, limiting our ability to accurately model brain diseases. Thanks to advancements in human induced pluripotent stem cell (hiPSC) technology, complex structures resembling developing organs, named organoids, have been generated for many types of organs, including brain organoids. These human organoids replicate critical organ and tissue-specific features not observed in animal models or 2D cell cultures, thus providing a unique opportunity to model human organ structure and function under healthy and disease conditions. A major limitation for brain organoid research is the lack of adequate instrumentation to monitor spatial and temporal organization of neural networks. Specifically, organoids are spherical whereas commercial microelectrode arrays (MEAs) are flat, which reduces the accuracy to determine neural network organization because the cellular surface area for recording neural signals is limited and organoids remodel on flat surfaces. To enhance the value of brain organoids for preclinical research and disease modeling, an MEA technology is needed that enables monitoring of neural signals across as much of the surface of the physiologically intact organoid as possible. No such commercial platform currently exists. This application aims to solve this problem by utilizing BMSEED’s stretchable microelectrodes to create pockets of variable sizes to contain the organoid, retain its shape and physiological function, and envelope it with microelectrodes for recording of neural activity across its surface. This novel 3D platform, the Organoid- Based Stimulating und Recording Vacuum Equipment (OBSuRVE), integrates three modules that (i) create the pockets in the adaptable contour for organoid research Multidimensional Electrode Array (conforMEA), (ii) record neural signals, and (iii) image cells and cellular processes. Specifically, this proposal has three aims. The first specific aim is focused on building the OBSuRVE platform, and to adapt the conforMEAs to meet the need for organoids research. The second specific aim is the evaluation of the electrical and mechanical properties of the platform. The third specific aim is the validation of the OBSuRVE platform for drug screening and disease modeling using brain organoids. The focus of this proposal are human brain organoids because neurological and neurodegenerative diseases, such as Autism, Alzheimer’s Disease, and Parkinson’s Disease, are among...