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 the most prevalent and costly health problems facing our society. However, the results will be
applicable to other types of organoids, e.g., cardiac spheroids, for cardiovascular disease models as well.
