Brain Health Consortium: Multiplex Biosensing of Neural Organoids Modeling Traumatic Brain Injury - Frank DeLuna

In the U.S. alone, 2.8 million people sustain a traumatic brain injury (TBI) each year and seek medical care.1,2 However, there are no FDA approved therapies for effective treatment of TBI (or concussion) patients. Current medications are limited to only reducing secondary damage to the brain following TBI, such as using diuretics to reduce the pressure inside the brain by increasing urine output. Despite the enormous medical costs for TBI (~$77 billion annually in the U.S.), the outcome of treatments is limited, especially in controlling the long-term effects of TBI on neurodegenerative disorders and diseases. The overarching goal of the proposed project is to develop an in vitro TBI model that is dynamically monitored with an innovative biosensing system for rapid, low-cost, long-term (scale of weeks) evaluation of the therapeutic effects of a novel neuroprotective agent (AST-004) on the molecular level. In contrast to previous unsuccessful studies that were focused primarily on neuronal targets, AST-004 targets astrocytes, the major supporting cell in the brain that has been largely understudied for the development of therapeutics. As reactive astrogliosis is a complex and multifaceted process following TBI that results in both beneficial and detrimental effects, we will demonstrate the importance of controlling the timing of intervention of astrogliosis in order to develop an effective treatment of TBI. The in vitro model creates an open system that can be closely monitored with a unique biosensor and a confocal microscope to investigate the interaction of the drug with 3D cerebral organoids containing human astrocytes and neurons. The optimal time window for applying AST-004 will be determined through the proposed study. This in vitro molecular study will provide information complementary to the in vivo studies of the drug effects on controlling the cellular and physiological processes following TBI (conducted by our collaborator Dr. James Lechleiter at UTHealth SA). The neuroprotective efficacy of AST-004 is likely to decrease at delayed treatment times. However, quantification of the efficacy at the later time points will still be of high significance. We note that many patients suffering from TBI frequently do not have treatments until days or months after the initial trauma. After proving the concept of monitoring TBI via optical biosensing with the BHC grant support, we will move forward to larger grant (i.e. R01) applications for the development of an all-inclusive microfluidic/neural organoid system for high-throughput screening of potential TBI therapeutics.