Engineering Capillary Networks

描述(申请人提供)：缺血性疾病仍然是美国和世界范围内发病率和死亡率的主要原因，在糖尿病患者中尤其严重。细胞疗法已经在各种模型中被证明可以增强局部血管形成和灌流，但到目前为止，临床试验中患者的改善并不明显。这可能与移植细胞成功植入并参与重建血管系统的比例较小有关，以及目前对细胞发挥作用的机制的有限了解(S)。这个项目要解决的具体假设是，通过提供适当启动的细胞从生物材料载体持续释放到缺氧组织中，移植内皮祖细胞建立血管网络和缓解组织缺血的能力可以显著增强。将针对下列目标评估这一假说：(1)确定适当设计的载体微环境是否能调节内皮祖细胞基因的表达、在材料中的迁移以及向周围组织的弥散；(2)定量检测内皮祖细胞在缓解SCID小鼠急慢性外周缺血方面的持续输送和组织再聚集能力，并确定其作用机制(S)；以及(3)利用链脲佐菌素诱导的小鼠和四氧嘧啶诱导的兔糖尿病模型，研究材料介导的内皮祖细胞载体在糖尿病周围缺血中促进康复的能力。这些研究产生的数据和系统可能会影响生物学和工程研究的几个领域，并导致临床策略对缺血组织进行血管重建。也许最重要的是，该项目将开发一种新的方法，旨在有效地将具有协调新生血管能力的细胞重新填充到缺血组织中。这种方法将在外周缺血的情况下进行研究，但这种方法也将在治疗冠状动脉疾病和其他涉及组织缺血的情况下发现有用。我们预计，自体细胞最初将用于这些应用，迄今为止在内皮祖细胞分离和扩增方面开发的临床经验将直接应用于该方法的细胞来源方面。这些研究还将提高目前对两种细胞群体--内皮祖细胞和嗅鞘细胞在血管形成中作用的理解，这可能导致未来新的血管形成策略。

DESCRIPTION (provided by applicant): Ischemic disease remains a major cause of morbidity and mortality in the USA and worldwide, and is particularly problematic in diabetics. Cell therapies have been demonstrated to enhance local vascularization and perfusion in a variety of models, but patient improvement in the clinical trials to date has been modest. This likely relates to the small percentage of transplanted cells that engraft successfully and participate in rebuilding the vasculature, and the current limited knowledge of the mechanism(s) by which the cells exert their effects. The specific hypothesis to be addressed in this project is that the ability of transplanted endothelial progenitor cells to build a vascular network and relieve tissue ischemia can be dramatically enhanced by providing a sustained release of appropriately primed cells into the hypoxic tissue from a biomaterial vehicle. This hypothesis will be evaluated with the following set of aims: (1) Determine if appropriate design of a vehicle microenvironment can regulate endothelial progenitor cell gene expression, migration through the material and dispersion into the surrounding tissue, (2) Quantify the ability of a sustained delivery and tissue repopulation by endothelial progenitor cells to relieve acute and chronic peripheral ischemia in SCID mice, and determine the mechanism(s) of this effect, and (3) Examine the ability of material-mediated endothelial progenitor cell delivery to enhance recovery from peripheral ischemia in the context of diabetes, using a STZ induced mouse and an alloxan-induced rabbit model of diabetes. The data and systems arising from these studies may impact several areas of biology and engineering research, and lead to clinical strategies to revascularize ischemic tissue. Perhaps most importantly, a new approach will be developed in this project that aims to effectively repopulate ischemic tissues with cells competent to orchestrate neovascularization. This approach will be investigated in the context of the peripheral ischemia, but this approach would also find utility in the treatment of coronary artery disease and other situations involving tissue ischemia. We anticipate that autologous cells would initially be used in these applications, and the clinical experience developed to date in endothelial progenitor isolation and expansion will directly apply to the cell source aspects of this approach. These studies will also improve the current understanding of the role of the two cell populations - EPCs and OECs in vascularization, and this may lead to completely new strategies of neovascularization in the future.