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.

项目总结 中风是成人致残的主要原因，美国每年新增80万中风患者。 缺血性中风脑血管和神经严重受损，导致神经功能障碍。 这会导致残疾。尽管更好的患者预后与血管生成的增加和总体 卒中区域的再灌流，目前没有治疗方法来增强卒中腔内的血管生成以 推进修缮。尽管水凝胶微结构可以被设计成促进体内血管生成，即使在 缺乏生长因子，目前促进大脑修复的支架不是多孔的，因此，它们的 微观结构是无法设计的。这项研究的目的是设计和合成一种可注射的 水凝胶配方，可具有用户定义的微观结构，以促进集体迁移到 支架，导致促进血管生成和神经前体(NPC)细胞迁移到病变部位。在……里面 特别是，我们建议向卒中腔内注射微孔退火颗粒(MAP)水凝胶，该水凝胶 释放血管内皮生长因子-A 165(VEGF)、血小板衍生生长因子-BB(PDGF)，以及 基质衍生因子1(SDF-1)具有控释动力学促进神经血管形成 中风腔内的壁龛。我们相信，这个神经血管利基的产生将促进 卒中后功能恢复。拟议研究的目标1调查了不同的 微结构和MAP水凝胶微结构在血管形成中的作用。目标2将调查 可控动力学释放血管内皮生长因子和血小板衍生生长因子的MAP水凝胶的制备及性能研究 显微结构和生化信号传递的综合效应。最后，在目标3中，我们将设计 从MAP水凝胶中持续释放SDF-1，并研究神经干细胞向病变部位的迁移。 综上所述，我们的目标是(I)了解水凝胶微观结构与生物活性信号之间的关系 释放及其组合对体外和脑内血管构型的影响和(Ii)招募内源性神经前体细胞 并通过SDF-1梯度和活跃的血管生成促进修复。