Synthetic Mesenchymal Stem Cell Niches for Vascular Therapy

项目摘要 巨大且未满足的临床需求与血液透析血管通路功能障碍相关， 目前被认为是临床血管移植的最具挑战性的形式之一。高失败率 与所有类型的透析血管通路相关，包括动静脉瘘和动静脉移植物，结果 在发病率、死亡率和经济成本方面。尽管这个临床问题的严重性，没有有效的 解决方案是可用的。血液透析患者的终末期肾病和其他健康状况 不利的环境，如尿毒症、炎症和由小和/或非顺应性血管引起的血流紊乱， 在血管通路周围，这至少部分地解释了通路失败。核心假设是 该建议是在血液透析相关条件下开发的精确细胞龛， 临床设置透析血管通路，预防透析通路失败。为了验证这个假设，我们将 在精确的细胞龛中引入细胞保护，再生信号，使间充质干细胞功能化 细胞（MSC）来克服不利的环境影响并协调动脉再生，导致专利， 强大的血管通路。该项目将使用我们的新型生物材料平台，该平台允许细胞龛和 使用临床输入例如尿毒症、血流、血管顺应性 和直径，目的是优化靶向动脉再生以减少通路失败。 为了实现研究目标，本文提出了三个目标。AIM 1专注于将精密单元 壁龛进入血管周围包裹，并确定其对动静脉瘘动脉化的影响， 模拟血液透析条件。AIM 2寻求建立和空间整合独特的精确细胞生态位 旨在促进动静脉移植物动脉化。AIM 3将评估精确定位设计如何 辅助基于MSC的动脉再生，用于患病猪模型中的血管通路。如果成功， 这里开发的精密血管通路平台可以改变传统的临床护理模式， 透析血管通路。我们设想，在不久的将来，肾脏病学家可以获得一系列的 血管通路装置源自精确的细胞龛设计。

Project Summary A huge and unmet clinical need is associated with hemodialysis vascular access dysfunction, which is currently considered to be one of the most challenging forms of clinical vascular grafting. The high failure rates associated with all types of dialysis vascular access, including arteriovenous fistulae and arteriovenous graft, result in significant morbidity, mortality and economic cost. Despite the magnitude of this clinic problem, no effective solutions are available. The end-stage renal disease and other health conditions of hemodialysis patients present a hostile milieu, such as uremia, inflammation and flow disturbance caused by small and/or non-compliant vessel, around the vascular access, which account for, at least partially, the access failure. The central hypothesis for this proposal is that precision cell niches, developed under hemodialysis-relevant conditions and when applied to the clinical setting of dialysis vascular access, prevent dialysis access failure. To test this hypothesis, we will introduce cell-protective, regenerative signals in the precision cell niches, which functionalize mesenchymal stem cells (MSCs) to override the hostile milieu impact and orchestrate the arterial regeneration, leading to patent, robust vascular access. This project will use our novel biomaterials platform, which allows both the cell niche and the niche-containing structure to be tailored using clinical inputs such as uremia, blood flow, vessel compliance and diameter, with a goal of optimizing targeted arterial regeneration to reduce access failure. To pursue the research goal, three aims are proposed here. AIM 1 focuses on incorporating the precision cell niches into a peri-vascular wrap and determining its effect on the arterialization of arteriovenous fistula under simulated hemodialysis conditions. AIM 2 seeks to establish and spatially integrate distinct precision cell niche designs to promote arteriovenous graft arterialization. AIM 3 will evaluate how the precision niche design can assist MSC-based arterial regeneration for vascular access in a diseased swine model. If successful, the precision vascular access platforms developed here could transform traditional clinical care paradigms for dialysis vascular access. We envision that in the near future, nephrologists could have the access to a range of vascular access devices derived from precision cell niche designs.