Development of an In-Vitro Angiogenesis System

描述（由申请人提供）： 血管生长（血管生成）的失调是许多疾病的基础，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“母体”血管中复制体内血管生成。我们建议开发一种先进的模型血管生成在体外组成的组织工程生物人工微血管（BMV）含有流动的管腔流体和发芽的内皮细胞（EC）毛细血管成支持凝胶的细胞外基质。将通过围绕微直径心轴培养EC来构建BMV，所述心轴的端部紧密配合到聚合物微管中。心轴的提取留下灌注有营养培养基的EC管。 目的1评价BMV直径和管腔流速对芽形成的影响。此外，还将生成复合BMV（血管平滑肌细胞[SMC]包围的EC）。我们推测，复合BMV的EC毛细血管的比例将被SMC加强，形成动脉或静脉样的传导血管。在目标2中，两个相邻的BMV将被诱导发芽互连毛细血管的网络。我们建议，诱导BMV之间的压力梯度将导致流体通过毛细血管网络之间的BMV流动，模拟体内的毛细血管床与动脉和静脉连接。 我们相信我们的新模型将对血管生成研究和治疗重要的血管生成介导的疾病产生重大影响。此外，该模型具有很大的潜力，可以转化为人工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.