Biomaterials to promote synapse formation after stroke

摘要 在美国，中风是导致成年人残疾的主要原因。除了物理治疗，没有其他的治疗选择。 以减轻残疾负担；因此，迫切需要新的治疗选择。卒中空洞是 中风后死亡且不会自发再生的大脑。我们对设计注射剂很感兴趣 可以促进中风后脑组织修复的水凝胶制剂，并提出核心内注射可以 成为一个理想的送货地点。我们设计了一种血管生成水凝胶，可以使坏死性中风重新血管化。 空洞，促进中风核心内血管和神经组织的形成，并促进行为 进步。在中风腔内实现任何类型的大脑修复都是了不起的。我们不能确定是否 由于这种新组织的形成或由于梗塞周围可塑性的改善，行为得到了改善。 然而，在12到16周之间观察到了行为改善。我们相信，要带来这一点 更接近临床实用的技术，我们必须能够将恢复时间表缩短到接近4周后 卒中。在这项提案中，我们将研究突触的形成和改进的机械支持作为一种方式 改善皮质缺血性卒中后的恢复时间表。星形胶质细胞在突触形成和 因此，我们将研究几种方法来调节中风后大脑中的这种细胞群，并 此外，已知在突触形成中起作用的分泌的星形胶质细胞蛋白的输送。这项建议 基于我们的初步数据，多孔支架促进星形胶质细胞在中风后渗入材料， 整合素结合可以决定神经前体细胞向星形胶质细胞的分化，而TSP-1可以 促进与星形胶质细胞相似水平的突触形成。特别是，我们将研究支架的微观结构 而生物活性信号分子的掺入可促进星形胶质细胞的浸润或分化。 祖细胞朝向星形细胞谱系(目标1)，如何纳入我们目前的血管生成策略 进入多孔支架影响行为改善(目标2)，如何从我们的多孔支架输送TSP-1 支架影响中风后的大脑修复和行为改善。总体而言，我们的目标是设计一种专业- 突触物质可以改善卒中后行为改善的时间线和程度。

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.