磁引导超声靶向磁性高分子微泡在经皮血管成形术后增效干细胞移植中的研究

Incidence of restenosis after percutaneous transluminal angioplasty (PTA) is very high. Endothelial cells are injured and vascular smooth muscle cells directly expose to blood flow.That is an important cause of restenosis. Transplanted stem cells can help rebuilding the endothelial cells, but the rate of homing is low. Ultrasound irradiation combined with targeted magnetic polymer microbubbles which are guided by magnetic could help transplanted stem cells adhere, aggregate and stay a long time to the injured vascular, increase the rate of stem cell homing, reduce incidence of postoperative restenosis. Therefore, taking these advantages of the targeted magnetic polymer microbubbles and magnetic guidance, we propose a novel agent and method in order to achieve the aim of ultrasound-assisted stem cell transplantation after PTA. In this project, targeted magnetic polymer microbubbles，in which magnetic particles are enclosed in the shell , supplemented by magnetic guidance, will be used to improve stem cell transplantation effect after PTA . Targeted microbubbles which gather by magnetic guidance in the injured vascular could be observed through the real-time ultrasound imaging, and then destroyed. The cavitation effect and changed microenvironment could increase the rate of the stem cell homing. This project will further combine ultrasound molecular imaging and ultrasound-assisted stem cell transplantation to achieve visual stem cell transplantation which is guided by ultrasound imaging and increase the rate of the stem cell homing after PTA.

经皮血管成形术(PTA)术后再狭窄发生率高。内皮细胞损伤后血管平滑肌细胞直接暴露于血流是其重要原因。干细胞移植有助于内皮细胞重建，但归巢率低。磁引导超声靶向磁性高分子微泡，有助于干细胞在血管损伤区粘附、聚集、较长时间停留，提高干细胞归巢率，减少术后再狭窄。本项目提出一种基于靶向磁性高分子微泡和磁引导来实现PTA术后超声成像引导干细胞移植的超声可视化增效移植的方法，拟通过构建磁性微粒包裹在微泡壳层中的靶向磁性高分子微泡，辅以磁引导，应用于PTA术后的增效干细胞移植研究。通过超声成像实时观察其在磁引导和靶向的作用下在血管损伤区的聚集，再通过超声破坏微泡的空化效应和细胞微环境的改变，提高干细胞归巢率。本项目的研究将进一步把超声分子成像与超声辅助的干细胞移植结合起来，有望实现PTA术后的超声成像引导的可视化干细胞移植并提高干细胞归巢率。

细胞疗法在再生医学和组织工程领域具有广阔的应用前景，因其在修复损伤组织结构的同时可以恢复组织的正常功能。骨髓间充质干细胞（Bone marrow mesenchymal stem cells，BMSCs）具有自我更新，多向分化和免疫调控的潜能，在再生医学应用领域引起了广泛关注。然而，细胞疗法的效果很大程度上依赖于细胞是否能归巢和滞留在损伤部位。实时影像引导和磁靶向递送是增强细胞归巢和滞留的有效手段。在此，本课题组采用自组装的方法构建磁性脂质-高分子聚合物杂合微泡（Magnetic lipid-polymer hybrid microbubbles，Mag-LPMs）。高分子聚合物材料具有较高的结构完整度和硬度；并且，高分子聚合物微泡的外壳比脂质微泡的外壳厚，更有利于装载Fe3O4磁性材料。脂质与生物膜相似，因而具有较好的生物相容性，然而脂质微泡的缺点是不稳定，容易破裂。由于Mag-LPMs的外壳由高分子聚合物和脂质杂合而成，因而Mag-LPMs具备了高分子聚合物材料和脂质体的优点。研究结果表明，Mag-LPMs标记BMSCs后，不影响BMSCs的细胞活力和分化功能。在磁场引导下，超声影像可实时示踪Mag-LPMs标记的BMSCs归巢至血管损伤部位。通过构建磁性微泡-干细胞复合体，即Mag-LPMs标记BMSCs，在磁场的作用下，有利于提高干细胞归巢率；同时，磁性微泡-干细胞复合体可被超声影像示踪，从而实现干细胞超声可视化，可为磁性微泡—干细胞复合体归巢至靶区提供超声影像依据，也为后续定量干细胞以及了解干细胞数量与组织修复间的关系提供新思路。