Biomaterials to promote synapse formation after stroke

生物材料促进中风后突触形成

• 批准号: 10453306
• 负责人: Tatiana Segura
• 金额: $ 6.58万
• 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/10453306
• 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; Structure; 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.

总结 中风是美国成人残疾的主要原因。除了物理治疗之外，没有其他治疗选择 减少残疾负担;因此，非常需要新的治疗选择。行程腔是 中风后死亡的大脑不能自发再生。我们有兴趣设计可注射的 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 是理想的交货地点。我们设计了一种血管生成水凝胶， 腔，促进中风核心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都是了不起的。我们不能确定 由于这种新的组织形成或由于改善的梗塞周围可塑性，发生了行为改善。 然而，在12至16周之间观察到行为改善。我们相信，要实现这一目标 技术更接近临床实用性，我们必须能够将恢复时间轴缩短至术后4周 中风在这个建议中，我们将研究突触的形成和改进的机械支持作为一种方法， 改善皮质缺血性卒中后恢复时间轴。星形胶质细胞在突触形成中起关键作用， 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， 也是已知在突触形成中起作用的分泌的星形胶质细胞蛋白质的递送。这项建议 基于我们的初步数据多孔支架促进中风后星形胶质细胞浸润到材料中， 整合素结合可以决定神经祖细胞向星形胶质细胞的分化，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，我们将研究支架的微观结构 并且生物活性信号分子的掺入可以促进星形胶质细胞的浸润或分化， 祖细胞向星形胶质细胞谱系（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递送TSP-1， 支架影响脑卒中后的脑修复和行为改善。总的来说，我们的目标是设计一个亲- 突触材料，可以改善的时间轴和程度的行为改善中风后。