Bioreactor application of fluid forces and influences on cell physiology for tissue engineering

无论是在体内还是在生物反应器系统中，液体流动都是细胞生理的强大调节器，并调节心血管疾病(CVD)的进展和干细胞的行为。心血管疾病往往发生在血流发生变化的地方(如动脉曲线或分支周围)，通常以血管的病变部分为特征，血管破裂可能导致中风或心脏病发作。内皮细胞(ECs)是受流体作用力影响的主要动脉细胞，它们执行多种调节血管特性和健康的功能。虽然有充分的证据表明流体流动在心血管疾病中的作用，但相对较少的人知道内皮细胞如何感知液体力并改变其生理功能。在完整的容器中很难分离出特定的流动效应，因为条件随着位置的变化而迅速变化。同样，干细胞为修复患病或受损的组织或器官提供了可行的选择。但在包含流体流动的生物反应器中，它们往往必须扩大到更大的数量。目前使用的系统包含复杂的流体力学，无法识别流体力对细胞的影响。需要模拟当地环境的实验系统来提供一种方法来研究暴露在流体流动中的细胞内部发生的事情。通过使用定制的生物反应器系统将内皮细胞暴露在不同的流动条件下，我们的实验室最近发现了一种新的机制，似乎参与决定流动依赖的结果。重要的是，我们的实验室已经发现，其他类型的细胞也有能力使用这种机制，包括干细胞。这项拟议的项目将确定不同类型的流体流动如何影响内皮细胞和干细胞中新机制的激活，以及这如何影响细胞对生物化学物质的反应。这些信息将定义生物反应器方案，以开发治疗心血管疾病的新方法，以及生成干细胞。这符合我们为细胞治疗、药物发现和测试以及医疗诊断创造设备和技术的长期目标。这些成果将通过促进疾病检测、药物发现和再生医学的现有技术和知识，对加拿大人的健康产生积极影响。

Fluid flow is a strong regulator of cell physiology, both in the body and in bioreactor systems, and modulates cardiovascular disease (CVD) progression and stem cell behavior. CVD tends to develop where blood flow changes (such as around artery curves or branches) and is typically characterized by diseased sections of blood vessels, which can rupture leading to strokes or heart attacks. Endothelial Cells (ECs) are the primary artery cells affected by fluid forces, and they perform a variety of functions that regulate blood vessel properties and health. While there is ample evidence of a role for fluid flow in CVD, relatively little is known about how ECs sense the fluid force and modify their physiology. It is difficult to isolate specific flow effects in intact vessels because conditions change rapidly with position. Similarly, stem cells offer viable options to repair diseased or damaged tissues or organs. But they often must be expanded to larger numbers in bioreactors that incorporate fluid flow. Currently employed systems contain complex hydrodynamics that do not enable identification of the effect of fluid forces on cells. Experimental systems mimicking the local environment are needed to provide a way to study what is going on inside the cells that are exposed to fluid flow. By using a customized bioreactor system to expose ECs to different flow conditions, our lab has recently discovered a new mechanism that appears to be involved in determining flow dependent outcomes. Importantly, our lab has discovered that other cell types also have the ability to use this mechanism, including stem cells. The proposed project will identify how different types of fluid flow affect activation of the new mechanism in both ECs and stem cells, and how this affects cell response to biochemicals. This information will define bioreactor schemes to enable development of novel treatments for CVD, as well as generation of stem cells. This fits into our long term goals of creating devices and technologies for cell therapy, drug discovery and testing, and medical diagnostics. These outcomes will have positive impact the health of Canadians by advancing the technology and knowledge available for disease detection, drug discovery and regenerative medicine.