A physiologically relevant pre-clinical drug screening platform for Alzheimer's Disease and Traumatic Brain Injury with integrated stretchable microelectrodes

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Abstract The proposed work aims at the commercialization of a microfluidic chip-based platform for modeling Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) for preclinical in vitro mechanistic studies and drug testing. AD/ADRD are a growing health concern, accounting for 50-75% of all dementia cases, and currently affecting an estimated 5.8 million Americans. In addition to the human suffering, the annual cost of AD/ADRD is $290 billion. Current FDA approved treatments only help manage the symptoms of the disease. However, there is no treatment to stop or reverse its progression despite hundreds of clinical trials. A major obstacle to successful treatment development is the dearth of suitable preclinical models. In addition, there is substantial epidemiological evidence of an intricate relationship between traumatic brain injury (TBI), longer-term AD/ADRD pathology, and cognitive decline. However, the exact link between AD and TBI is not known. This application aims to solve both of these problems by developing a novel microfluidics- based 3D in vitro AD model, and merging this chip with BMSEED’s existing in vitro TBI model platform, the MicroElectrode Array Stretching Stimulating und Recording Equipment (MEASSuRE), to meet the needs for pre-clinical AD/ADRD research. This new platform presents an efficient and physiologically relevant pre-clinical drug screening platform for AD treatments. The platform is also well-suited to investigate the effects of a TBI on a person with or without a pre-existing genetic disposition to develop AD. The key innovations are the use of a stretchable microelectrode array for functional assessment of neuronal health in a microfluidics drug screening platform, and the capability to investigate the mechanistic links and similarities between AD and TBI using this stretchable microelectrode array in a 3D cell culture matrix (3D-sMEA). This 3D-MEASSuRE platform provides a more realistic in vitro facsimile of the natural in vivo biochemical and biomechanical microenvironment of the cells compared to existing 2D systems. Phase I is focused on demonstrating Proof-of- Concept (PoC) using a single-well (SW) 3D-MEASSuRE platform with cells derived from genetically modified (3xTg, 5xFAD) and wild type mice. Phase II is directed towards (a) improving efficiency by developing a high throughput multi-well (MW) 3D-MEASSuRE platform, and (b) increasing relevance to clinical translation by evaluating the platform using human cells derived from induced-pluripotent stem cells (hiPSCs) from AD patients and age matched controls. The capability of the 3D-MEASSuRE platform for research on the genetic pre-disposition to develop AD and the role of crosstalk between different cell types in the brain in mediating neuronal health after TBI-relevant strain injury will be evaluated and validated. The focus of this proposal is the development of a pre-clinical drug screening platform for AD/ADRD, however, the products developed in this research will also be applicable in drug screening for other neurodegenerative diseases, e.g., Parkinson’s Disease. At the end of Phase II, the 3D-MEASSuRE platform will be ready for the marketplace.