Engineering Injectable Microporous Hydrogels for Brain Repair

用于脑修复的工程可注射微孔水凝胶

• 批准号: 9270092
• 负责人: Tatiana Segura
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270092
• 关键词: Adult; Area; Biochemical; Biomedical Engineering; Blood Vessels; Brain; Cells; Cellular Infiltration; Cerebrovascular system; Chemicals; Data; Encapsulated; Endothelial Cells; Engineering; Formulation; Gel; Generations; Goals; Grant; Growth Factor; Hydrogels; In Situ; In Vitro; Infarction; Injectable; Ischemic Stroke; Kinetics; Lesion; Link; Mechanics; Mediating; Modeling; Molecular; Morphology; Movement; Nerve; Neurobiology; Neurologic; Neurologic Deficit; Patients; Pattern; Perfusion; Plasticizers; Porosity; Protocols documentation; Publishing; Recovery of Function; Recruitment Activity; Research; Role; Saline; Signal Transduction; Site; Skin; Skin wound; Stem cells; Stroke; Structure; Structure-Activity Relationship; Testing; Tissue Engineering; Tissues; United States; VEGFA gene; Vascular Endothelial Growth Factors; Vascularization; Ventricular; Wound Healing; Wounds and Injuries; angiogenesis; base; blood vessel development; brain repair; capsule; cell motility; controlled release; density; design; diabetic; disability; healing; implantation; in vivo; migration; nanocapsule; nerve stem cell; neurovascular; osmotic minipump; outcome forecast; particle; platelet-derived growth factor BB; porous hydrogel; pre-clinical; regenerative; repaired; scaffold

Project summary Stroke is the leading cause of adult disability with 800,000 new stroke patients per year in the US 1. After ischemic stroke both the brain vasculature and nerves are severely damaged leading to the neurological deficit that causes disability. Although better patient prognosis has been linked to increased angiogenesis and overall re-perfusion of the stroke area, no therapy currently exists to enhance angiogenesis within the stroke cavity to promote repair. Although hydrogel microstructure can be engineered to promote angiogenesis in vivo even in the absence of growth factors, current scaffolds to promote repair in the brain are not porous and, thus, their microstructure cannot be engineered. The studies in this grant aim to design and synthesize an injectable hydrogel formulation that can have a user defined microstructure to promote collective migration into the scaffold, leading to enhanced angiogenesis and neuroprogenitor (NPC) cell migration to the lesion site. In particular, we propose to inject into the stroke cavity a microporous annealed particle (MAP) hydrogel that releases vascular endothelial growth factor-A 165 (VEGF), platelet derived growth factor-BB (PDGF), and stromal derived factor 1 (SDF-1) with controlled release kinetics to promote the formation of a neurovascular niche within the stroke cavity. We believe that the generation of this neurovascular niche will promote functional recovery after stroke. Aim 1 of the proposed research investigates the generation of different microstructures and the role of MAP hydrogel microstructure on vascularization. Aim 2 will investigate the generation of MAP hydrogels that can release VEGF and PDGF with controlled kinetics and study the combined effects of microstructure and biochemical signal delivery. Last, in Aim 3, we will engineer the sustained release of SDF-1 from the MAP hydrogel and study the migration of NPCs towards the lesion site. Taken together we aim to (i) understand the relationship between hydrogel microstructure, bioactive signal release ad their combination on vascular patterning in vitro and in the brain and (ii) recruit endogenous NPCs to the stroke cavity and promote repair through SDF-1 gradients and active angiogenesis.

项目摘要 中风是成人残疾的主要原因，在美国，每年有80万名新中风患者1。 缺血性中风脑脉管系统和神经都受到严重损害，导致神经缺陷 这会导致残疾。尽管更好的患者预后与血管生成增加有关 重新灌注中风区域，目前尚无治疗可以增强中风腔内的血管生成 促进维修。尽管可以设计水凝胶微结构以促进体内血管生成 没有生长因素，目前促进大脑修复的脚手架不是多孔的，因此 微观结构无法设计。这项赠款的研究旨在设计和合成注射剂 水凝胶配方可以具有用户定义的微观结构，以促进集体迁移到 脚手架，导致血管生成增强和神经元元素（NPC）细胞迁移到病变部位。在 特别是，我们建议将微孔退火颗粒（MAP）水凝胶注入中风腔 释放血管内皮生长因子A 165（VEGF），血小板衍生的生长因子BB（PDGF）和 带有受控释放动力学的基质衍生因子1（SDF-1），以促进神经血管的形成 中风腔内的利基。我们认为，这种神经血管生态位的产生将促进 中风后的功能恢复。拟议研究的目标1调查了不同的生成 微观结构以及MAP水凝胶微结构在血管化中的作用。 AIM 2将调查 生成可以用受控动力学释放VEGF和PDGF的地图水凝胶的生成，并研究 微结构和生化信号传递的综合效应。最后，在AIM 3中，我们将设计 从地图水凝胶中持续释放SDF-1，并研究NPC向病变部位的迁移。 综上所述，我们的目的是（i）了解水凝胶微结构，生物活性信号之间的关系 在体外和大脑中释放AD在血管图案上的组合，以及（ii）募集内源性NPC 通过SDF-1梯度和活性血管生成来促进中风腔并促进修复。