The role that small volume regions of dead brain tissue (microinfarcts) play in neurological dysfunction and cognitive impairment is not well understood. Analysis of dementia patients' brains has linked the presence of numerous and wide-spread microinfarcts, in some cases thousands in a single brain, to increased cognitive impairment. Animal studies support this finding. While a causal link has been established, the cellular, molecular, and physiological events that occur during small blood vessel stroke and their role in neurological impairment remain unknown. Performing high-resolution cellular experiments in humans or animal brains is extremely challenging. To overcome this limitation, this project focuses on the development and validation of a tissue-engineered, microfluidic, in vitro, microstroke model that accurately recapitulates the cascade of events that occur in vivo. Development and validation of this fluidized, in vitro, microstroke model has the potential to provide significant insights into the fundamental biological changes induced by microstrokes. It is envisioned that the biological discoveries achieved with this model could significantly impact human health and potentially lead to the development of intelligently designed therapies to treat microstroke and dementia in future applications. To increase exposure across a broad range of students, from elementary to undergraduate, an educational plan has been developed that aims to spark interest in students to pursue science, technology, engineering and math education through Art in Science Exhibits, hands-on Art in Science Modules, laboratory research experiences, as well as to incorporating research in microphysiological systems into existing undergraduate courses.
The project focuses on developing and validating a tissue-engineered, microfluidic, in vitro, microstroke model that can be used to study the cellular, molecular and physiological events that occur during microstroke-induced neurological impairment occlusion- and reperfusion-induced changes. The model overcomes challenges in performing high-resolution, spatiotemporal cellular/molecular experiments in animal brains. The Research Plan is organized under 3 specific aims: 1) Quantify the influence of capillary occlusion and reperfusion on cerebrovascular flow in a 3D synthetic, biomimetic, vascular network based on a 3D image stack of the vascular system of an entire mouse brain that was generated by high-resolution imaging, via knife edge scanning microscopy, of perfused india ink; 2) Quantify the influence of capillary occlusion and reperfusion on human stem cell derived brain microvascular endothelial cells (BMECs) and 3) Quantify the influence of capillary occlusion and reperfusion on microinfarct progression by spatiotemparally monitoring the progression of a capillary occlusion- and reperfusion induced microinfarct in hydrogel encapsulated human astrocytes and neurons. Fulfillment of these aims requires further development and implementation of advanced biofabrication techniques (two-photon hydrogel degradation and polymerization), advanced biomaterials (enzymatically-degradable constructs and semi-synthetic blood clots), and incorporation of differentiated human neural stem cells (BMECs, astrocytes, and neurons) to create a microphysiological ìstroke model using all human cells.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
