Development of an In-Vitro Angiogenesis System

描述(由申请人提供)： 血管生长的失调(血管生成)是许多疾病的基础，包括癌症、糖尿病和关节炎。现有的体外血管生成模型是重要的实验工具，但不能从充满流动血液的“母”血管中复制出体内类似的血管生成。我们建议开发一种先进的体外血管生成模型，包括含有流动的腔液的组织工程化生物人工微血管(BMV)和将内皮细胞(EC)毛细血管萌发成支持细胞外基质的凝胶。BMV将通过在微径芯棒周围培养内皮细胞来构建，其末端紧密地贴合在聚合物微管道中。心轴的提取留下了一管内皮细胞，其中注入了营养介质。 目的1评价BMV管腔直径和管腔流速对发芽的影响。此外，还将产生复合BMV(被血管平滑肌细胞[SMCs]包围的ECs)。我们假设，来自复合BMV的一定比例的EC毛细血管将被SMC强化，形成动脉或静脉样的传导血管。在目标2中，两个相邻的BMV将被诱导形成一个相互连接的毛细血管网络。我们认为，BMV之间压力梯度的诱导将导致流体通过毛细血管网络在BMV之间流动，模拟体内具有动脉和静脉连接的毛细血管床。 我们相信，我们的新模型将对血管生成研究和重要的血管生成介导性疾病的治疗产生重大影响。此外，该模型有很大的潜力被转化为人造组织和器官的微血管系统。我们认为我们的研究计划非常适合R21机制。

DESCRIPTION (provided by applicant): Disregulation of vascular growth (angiogenesis) underlies many diseases that include cancer, diabetes, and arthritis. Existing models of angiogenesis in vitro are important experimental tools, but do not reproduce in vivo-like angiogenesis from a "parent" vessel filled with flowing blood. We propose to develop an advanced model of angiogenesis in vitro comprised of tissue-engineered bioartificial microvessels (BMVs) containing flowing luminal fluid and sprouting endothelial cell (EC) capillaries into a supportive gel of extracellular matrix. BMVs will be constructed by culture of ECs around a micro-diameter mandrel whose ends fit closely into polymer micro-tubing. Extraction of the mandrel leaves a tube of ECs which is perfused with nutritive media. Aim 1 evaluates the influence of BMV diameter and rate of luminal flow on sprout formation. Also, composite BMVs (ECs surrounded with vascular smooth muscle cells [SMCs]) will be generated. We hypothesize that a proportion of EC capillaries from composite BMVs will be reinforced by SMCs to form artery- or vein-like conducting vessels. In Aim 2, two adjacent BMVs will be induced to sprout a network of interconnected capillaries. We propose that induction of a pressure gradient between the BMVs will cause fluid to flow between the BMVs via the capillary network, simulating a capillary bed in vivo with arterial and venous connections. We believe our novel model will have a major impact on angiogenesis research and treatment of important angiogenesis-mediated diseases. Moreover, the model has a significant potential to be translated into microvascular systems for artificial tissues and organs. We consider our research program to be ideally suited to the R21 mechanism.