Biomaterials to promote synapse formation after stroke

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Summary Stroke is the leading cause of adult disability in the US. There are no therapeutic options beyond physical therapy to reduce disability burden; thus, new therapeutic options are highly needed. The stroke cavity is the region of the brain that dies after stroke and does not spontaneously regenerate. We are interested in designing injectable hydrogel formulations that can promote brain tissue repair after stroke and propose that intra core injection can be an ideal delivery location. We engineered an angiogenic hydrogel that re-vascularizes the necrotic stroke cavity, promotes vascular and neurological tissue formation within the stroke core, and promotes behavioral improvement. Achieving any type of brain repair in the stroke cavity is remarkable. We cannot be sure if behavioral improvement occurred because of this new tissue formation or due to improved peri-infarct plasticity. Nevertheless, behavioral improvement was observed between 12 and 16-weeks. We believe that to bring this technology closer to clinical utility, we must be able to improve the recovery timeline to closer to 4 weeks post stroke. In this proposal, we will investigate synapse formation and improved mechanical support as a way to improve recovery timeline after cortical ischemic stroke. Astrocytes play a critical role in synapse formation and pruning; thus, we will investigate several approaches to modulate this cell population in the brain post stroke and also the delivery of secreted astrocyte proteins that are known to play a role in synapse formation. This proposal builds upon our preliminary data that porous scaffolds promote astrocyte infiltration into the material post stroke, that integrin binding can dictate differentiation of neuroprogenitor cells into astrocytes, and that TSP-1 can promote similar levels of synapse formation as astrocytes. In particular, we will study how scaffold microstructure and incorporation of bioactive signaling molecules can promote astrocytic infiltration or differentiation of progenitor cells towards an astrocytic lineage (Aim 1), how the incorporation of our current angiogenic strategy into a porous scaffold impacts behavioral improvement (Aim 2), how the delivery of TSP-1 from our porous scaffolds influences brain repair and behavioral improvement post stroke. Overall, we aim to engineer a pro- synaptic material that could improve on the timeline and degree of behavioral improvement after stroke.