Novel Engineered Particle Platform for Endothelium Regeneration

尽管血管成形术等经皮冠状动脉介入治疗(PCI)方法经常被用作 心血管疾病是美国头号死亡原因，治疗心血管疾病的标准程序，他们 有许多局限性，包括晚期再狭窄和血栓形成。术后内皮再生延迟 经皮冠状动脉介入治疗对血管的损伤被认为是造成这些缺陷的主要原因，尤其是晚期血栓形成。 事实上，内皮层是动脉的天然屏障，在 防止血小板黏附和平滑肌细胞的增殖和迁移。因此，我们的长期目标是 设计新型多功能靶向纳米粒子(MTN)，可特异性地结合到受伤的人身上 动脉部位作为临时屏障，防止血小板黏附和平滑肌细胞迁移 招募干细胞，如内皮祖细胞(EPC)，以促进内皮再生。这个 新型工程MTN将防止血小板黏附并促进受伤患者的快速内皮愈合 部位，允许原位再内皮化的可能性。 为了达到我们的目标，我们提出了三个具体的目标：(1)对小说进行综合和表征 可生物降解、生物相容和血液相容的生物材料，包括氨基甲酸酯掺杂聚酯(UPE) 用于血管组织工程应用。(2)制定MTN，其由UPE制成，装载有 治疗试剂包括生长因子，并与损伤的动脉壁结合靶向 配体和EPC结合分子。MTN的各种性质，包括对血小板的影响 血管内皮细胞在体外的沉积和再生有待进一步研究。(三)确定效力 利用动物模型研究新型MTN在体内对经皮冠状动脉介入治疗损伤后内皮细胞原位再生的作用。 这项研究有几个创新方面。我们设计的MTN，基于 组织工程和纳米技术的最新进展提供了一个独特的战略来促进 可促进血管内皮细胞再生，从而促进经皮冠状动脉介入治疗后的血管愈合，同时防止血小板粘连。 我们研究的另一个新方面是，工程MTN利用(1)靶向的组合 损伤的动脉，(2)通过充当临时屏障来减少血小板的粘连，(3)在 靶向部位，间接减少受损区域的血小板沉积；以及(4)促进 使用工程化组织纳米支架的内皮再生。拟议的MTN将带来显著的 冠状动脉介入治疗相关血管损伤治疗的改进，应产生高度科学性和 心血管疾病治疗中的经济影响。

Although percutaneous coronary intervention (PCI) modalities such as angioplasty are often used as the standard procedure for treatment of cardiovascular disease, the number one cause of death in the U.S., they have many limitations including late restenosis and thrombosis. Delayed endothelium regeneration after vascular injury by PCI has been indicated as a major cause for these drawbacks, especially late thrombosis. Indeed, endothelium layer serves as a nature barrier for the artery and plays an important role in the prevention of platelet adhesion and smooth muscle cell proliferation and migration. Thus our long-term goal is to engineer novel multifunctional targeting nanoparticles (MTNs) that can bind specifically onto the injured arterial site to serve as a temporary barrier to prevent platelet adhesion and smooth muscle cell migration while recruiting stem cells such as endothelial progenitor cells (EPCs) for enhancing endothelium regeneration. The novel engineered MTNs will prevent platelet adhesion and encourage rapid endothelium healing at the injured site, allowing the potential of re-endothelialization in situ. To reach our goal, three specific aims are proposed: (1) To synthesize and characterize novel biodegradable, biocompatible, and hemo-compatible biomaterials including urethane-doped polyesters (UPEs) for vascular tissue engineering applications. (2) To formulate MTNs, which are made of UPEs, loaded with therapeutic reagents including growth factors, and conjugated with both the injured arterial wall targeting ligands and the EPC binding molecules. Various properties of MTNs including the effects of MTNs on platelet deposition and endothelium regeneration in vitro will be further investigated. (3) To determine the effectiveness of novel MTNs in vivo for endothelium regeneration in situ following PCI injury using animal models. There are several innovative aspects associated with this research. Our engineered MTNs, based on recent advances in both tissue engineering and nanotechnology, provide a unique strategy to promote endothelium regeneration and hence to stimulate vascular healing after PCI while preventing platelet adhesion. Another novel aspect of our research is that the engineered MTNs utilize the combination of (1) targeting injured arteries, (2) reducing platelet adhesion by serving as a temporary barrier, (3) capturing EPC at the targeted sites, which indirectly reduce platelet deposition on the damaged areas, and (4) promoting endothelium regeneration using engineered tissue nanoscaffolds. The proposed MTNs will bring in a significant improvement in the treatment of PCI-associated vascular injury and should generate highly scientific and economic impacts in cardiovascular disease therapy.