Vascular mechanobioengineering

心血管疾病是社会的一个重要负担。动脉粥样硬化斑块早在儿童时期就会形成，并且已经确定了系统性危险因素，以及潜在的预防和治疗途径。鉴于目前的大流行，努力的目标是通过生物标记物识别和分子成像开发进行诊断，并通过开发新分子进行治疗。动脉粥样硬化发生在局部，并与内皮细胞的机械生物学有关。在体外、体外和体内的研究中，确定了动脉粥样硬化的特征，如炎症标志物的表达。动脉重塑通过基质金属蛋白酶及其抑制物的作用改变血管壁的几何形状以及细胞外基质的组成/取向，并通过迁移、增殖和凋亡改变细胞内容，从而潜在地影响进展和预后。了解重塑对机械生物学的影响可以为早期发现和改进治疗提供新的靶点。炎症标志物和基质金属蛋白酶的调节将在体外进行检测。主要目的是(1)设计和验证体外机械刺激系统，(2)研究均匀几何支架中壁切应力或循环应变下内皮细胞的炎症反应，以及(3)模拟动脉重建的支架中内皮细胞在复杂机械刺激(血流动力学剪切和机械应变)下的反应特征。开发的体外模型将为研究界提供机械生物学研究的工具，允许在其他细胞类型、药剂和其他病理情况下进行测试。已确定的生物标记物将提供制药业感兴趣的潜在新药疗法，以及正在开发的分子成像探针的靶标。机械生物学研究将提供有关生物标志物的关键信息，最终导致预期寿命/质量的提高，并使个人受益，这反过来将对加拿大产生积极的社会和经济影响。

Cardiovascular diseases represent an important burden for society. Atherosclerotic plaques develop as early as childhood and systemic risk factors have been identified, along with potential preventative and therapeutic avenues. Given the current pandemic, efforts are targeted towards diagnosis, through biomarker identification and molecular imaging development, and treatment, by developing novel molecules. Atherosclerosis develops focally and is linked to endothelial mechanobiology. In vitro, ex vivo and in vivo studies identified hallmarks of atherosclerosis such as expression of inflammatory markers. Arterial remodelling alters vessel wall geometry, as well as extracellular matrix composition/orientation, through the action of matrix metalloproteinases and their inhibitors, and cellular content, through migration, proliferation and apoptosis, potentially affecting progression and outcome. Understanding the effects of remodelling on mechanobiology can provide novel targets for earlier detection and improved treatments. Regulation of inflammatory markers and matrix metalloproteinases will be examined in vitro. The main objectives are to (1) design and validate in vitro systems for mechanical stimulation, (2) study inflammatory response of endothelial cells exposed to wall shear stress or cyclic strain in uniform geometry scaffolds, and (3) characterize endothelial cell response under complex mechanical stimuli (both hemodynamic shear and mechanical strain) in scaffolds mimicking remodelled arteries. The developed in vitro models will provide tools to the research community for mechanobiological studies, allowing tests on other cell types, pharmaceutical agents and in other pathological contexts. The biomarkers identified will provide potential new drug therapies, of interest to the pharmaceutical industry, and targets for molecular imaging probes that are being developed. Mechanobiological studies will provide crucial information on biomarkers, eventually leading to increased life expectancy/quality and benefiting individuals which in turn will have both a positive social and economic effect on Canada.