Biomaterials to promote synapse formation after stroke

生物材料促进中风后突触形成

• 批准号: 10295783
• 负责人: Tatiana Segura
• 金额: $ 51.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295783
• 关键词: Acute; Adult; Area; Astrocytes; Axon; Behavioral; Biocompatible Materials; Biomedical Engineering; Birth; Blood Vessels; Brain; Brain region; Cells; Cerebral cortex; Clinical; Data; Development; Engineering; Environment; Formulation; Generations; Goals; Heparin; Human; Hyaluronic Acid; Hydrogels; Immune response; Infarction; Infiltration; Inflammatory Response; Injectable; Injections; Integrin Binding; Ischemic Stroke; Lead; Location; Mechanics; Medical; Monitor; Mus; Natural regeneration; Necrosis; Neurologic; Neurons; Physical Medicine; Physical therapy; Play; Population; Proteins; RGD (sequence); Recovery; Repair Material; Robotics; Role; Signaling Molecule; Speed; Stroke; Synapses; Technology; Therapeutic; Thrombospondin 1; Time; TimeLine; Tissues; Vascular Endothelial Growth Factors; axon growth; base; brain repair; brain tissue; clinically translatable; design; disability; disability burden; experimental study; improved; in vivo; inflammatory modulation; interest; nanoparticle; nerve stem cell; neurological rehabilitation; new technology; novel therapeutics; particle; post stroke; programs; repaired; response; scaffold; stem cells; synaptogenesis; tissue repair

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.

概括 中风是美国成人残疾的主要原因。除了物理治疗之外，没有治疗选择 减轻残疾负担；因此，急需新的治疗选择。中风腔是 中风后死亡并且不会自发再生的大脑。我们有兴趣设计注射型 水凝胶制剂可以在中风后促进脑组织修复并提出核心注入可以 成为理想的送货地点。我们设计了一种血管生成水凝胶，该水凝胶重新血管化坏死性中风 腔，促进中风核内的血管和神经组织形成，并促进行为 改进。在中风腔中实现任何类型的脑修复是显着的。我们不能确定是否 行为改善是由于这种新的组织形成或由于侵入周期可塑性的改善而发生的。 然而，在12至16周之间观察到行为改善。我们相信要带这个 技术更接近临床公用事业，我们必须能够改善恢复时间表，以接近接近4周后 中风。在此提案中，我们将调查突触形成和改善机械支持的方法 改善皮质缺血性中风后的恢复时间表。星形胶质细胞在突触形成中起着至关重要的作用 修剪；因此，我们将研究几种在中风后脑中调节该细胞群体的方法， 同样，已知在突触形成中发挥作用的分泌星形胶质细胞蛋白的递送。这个建议 基于我们的初步数据，多孔脚手架会促进星形胶质细胞渗透到中风后的材料中， 整联蛋白结合可以决定神经元基因细胞分化为星形胶质细胞，而TSP-1可以 促进与星形胶质细胞相似的突触形成水平。特别是，我们将研究脚手架微观结构 并掺入生物活性信号分子可以促进星形胶质细胞浸润或分化 祖细胞向星形胶质细胞谱系（AIM 1），我们当前的血管生成策略如何纳入 变成多孔脚手架会影响行为的改善（AIM 2），如何从我们的多孔中传递TSP-1 脚手架会影响脑修复和行为改善。总体而言，我们旨在设计专业 突触材料可以改善中风后的时间表和行为改善程度。