The proposed work aims at the development of an enhanced organoid-based in vitro pre-clinical drugscreening 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 ofhuman physiology, thus behave differently from their in vivo and human counterparts in many keycharacteristics of cellular behavior, limiting our ability to accurately model brain diseases. Thanks toadvancements in human induced pluripotent stem cell (hiPSC) technology, complex structures resemblingdeveloping organs, named organoids, have been generated for many types of organs, including brainorganoids. These human organoids replicate critical organ and tissue-specific features not observed in animalmodels or 2D cell cultures, thus providing a unique opportunity to model human organ structure and functionunder healthy and disease conditions. A major limitation for brain organoid research is the lack of adequateinstrumentation to monitor spatial and temporal organization of neural networks. Specifically, organoids arespherical whereas commercial microelectrode arrays (MEAs) are flat, which reduces the accuracy to determineneural network organization because the cellular surface area for recording neural signals is limited andorganoids remodel on flat surfaces. To enhance the value of brain organoids for preclinical research anddisease modeling, an MEA technology is needed that enables monitoring of neural signals across as much ofthe 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 createpockets of variable sizes to contain the organoid, retain its shape and physiological function, and envelope itwith 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 thepockets 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 theneed for organoids research. The second specific aim is the evaluation of the electrical and mechanicalproperties of the platform. The third specific aim is the validation of the OBSuRVE platform for drug screeningand disease modeling using brain organoids. The focus of this proposal are human brain organoids becauseneurological 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 beapplicable to other types of organoids, e.g., cardiac spheroids, for cardiovascular disease models as well.
Public Health Relevance Statement: Project Narrative
Brain organoids replicate critical organ and tissue-specific features not observed in animal models or 2D cell
cultures to model human organ structure and function under healthy and disease conditions. A major limitation
for the utility of brain organoids for pre-clinical drug development is the lack of adequate instrumentation to
monitor spatial and temporal neural network organization across the surface of physiologically intact organoids.
The proposed 3D model platform will solve this problem, thus improving the efficacy to assess drug candidates
in pre-clinical research to treat neurological and neurodegenerative diseases.
Project Terms: Affect ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Animals ; Brain ; Brain Nervous System ; Encephalon ; Brain Diseases ; Brain Disorders ; Encephalon Diseases ; Intracranial CNS Disorders ; Intracranial Central Nervous System Disorders ; Cardiovascular Diseases ; cardiovascular disorder ; Cell Culture Techniques ; cell culture ; Cell physiology ; Cell Function ; Cell Process ; Cellular Function ; Cellular Physiology ; Cellular Process ; Subcellular Process ; Disease ; Disorder ; Electrodes ; Electrophysiology (science) ; Electrophysiology ; Neurophysiology / Electrophysiology ; electrophysiological ; Equipment ; Human ; Modern Man ; In Vitro ; instrumentation ; Microelectrodes ; Miniaturized Electrodes ; Neurological Models ; Neurologic Models ; Names ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; Noise ; Organoids ; Parkinson Disease ; Paralysis Agitans ; Parkinson ; Parkinson's disease ; Parkinsons disease ; Primary Parkinsonism ; Physiology ; pressure ; Problem Solving ; Research ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Societies ; Suction ; Mechanical Aspiration ; Suction Drainage ; Technology ; Tissues ; Body Tissues ; Vacuum ; Work ; Measures ; Morphologic artifacts ; Artifacts ; Health Care Costs ; Health Costs ; Healthcare Costs ; electric impedance ; Electrical Impedance ; Impedance ; base ; Organ ; improved ; Site ; Area ; Surface ; Phase ; Physiological ; Physiologic ; Neurologic ; Neurological ; Evaluation ; Plant Roots ; root ; Shapes ; mechanical ; Mechanics ; Dimensions ; Complex ; Protocol ; Protocols documentation ; elastomeric ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; electrical property ; membrane structure ; Membrane ; drug efficacy ; voltage ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; neural ; relating to nervous system ; Stretching ; Structure ; Nerve Impulse Transmission ; Nerve Transmission ; Neuronal Transmission ; axon signaling ; axon-glial signaling ; axonal signaling ; glia signaling ; glial signaling ; nerve signaling ; neural signaling ; neuronal signaling ; neurotransmission ; novel ; disorder model ; Disease model ; UV laboratory microscope ; Ultraviolet Microscopes ; fluorescence/UV microscope ; fluorescent microscope ; laboratory fluorescence light microscope ; fluorescence microscope ; Modeling ; Property ; drug development ; Brain Trauma ; traumatic brain damage ; Traumatic Brain Injury ; model development ; Thickness ; Thick ; Autism ; Autistic Disorder ; Early Infantile Autism ; Infantile Autism ; Kanner's Syndrome ; autistic spectrum disorder ; autism spectrum disorder ; Pre-clinical Drug Testing/Development ; Preclinical Drug Testing/Development ; pre-clinical drug development ; Preclinical Drug Development ; Preclinical Models ; Pre-Clinical Model ; Reproducibility ; Resolution ; in vitro Model ; in vivo ; Validation ; Monitor ; Characteristics ; Cardiac ; Development ; developmental ; cellular imaging ; cell imaging ; Image ; imaging ; pre-clinical ; preclinical ; three-dimensional modeling ; 3-D modeling ; 3D modeling ; Outcome ; innovation ; innovate ; innovative ; pre-clinical research ; preclinical research ; drug testing ; drug detection ; cell behavior ; cellular behavior ; induced pluripotent stem cell ; iPS ; iPSC ; iPSCs ; therapy development ; develop therapy ; intervention development ; treatment development ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; drug candidate ; mechanical properties ; Drug Screening ; human model ; model of human ; neural network ; induced pluripotent stem cell technology ; iPSC technology ;
