Collaborative Research: Understanding the Effects of Flow on Smooth Muscle Cells in an Arteriole-Sized Microchannel

这项研究将增加我们对在工程人体组织中调节血液流动的理解。体内微小的血管通过平滑肌细胞调节血液流向组织。这些平滑肌细胞自动调节血管直径，以应对不断变化的条件。当这个过程不能正常工作时，它会导致一系列严重的医疗问题，如高血压或脑功能障碍。目前的工程器官和组织无法模仿这种调节血液流动的能力，如果植入病人体内，可能会引起同样严重的医疗问题。为了应对这一挑战，这项工作将开发一种技术，将平滑肌细胞放入工程组织的微观血管中，并诱导这些细胞以与自然组织相似的方式组织和行为。然后，我们将测试这些细胞是否能以类似的方式调节工程显微血管的直径。从这些研究中获得的知识将增加工程组织的关键能力，并最终改善植入组织工程材料的未来患者的生活。随着组织工程领域从使用薄组织结构过渡到生产厚的、3D细胞装载的组织和器官，对嵌入式微血管的需求变得越来越明显。当研究人员专注于建立工程微血管维持细胞活力的能力时，微血管的一个关键功能被忽视了：调节局部血管阻力的能力。血管阻力是根据各种内外变化（温度变化、体位变化、各种组织的代谢需要等），通过调节血管管腔直径来局部调节的，并通过微血管壁内层平滑肌细胞的作用来完成。本研究的目的是建立在小动脉大小的微通道中形成可收缩的、向周定向的平滑肌细胞的功能内侧层所需的知识，从而使血管在适当的刺激下收缩或舒张。特别是，这项工作将研究脉动流维持收缩SMC表型和诱导微血管壁周向结构的能力，将细胞暴露于相关的血管活性物质，然后表征它们适当调节管腔直径的能力。我们在流动波形和细胞行为之间建立的关系将使微血管工程设计规则具有这一关键功能。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This research will increase our understanding of regulating blood flow in engineered human tissue. Microscopic blood vessels in the body regulate blood flow to tissues via smooth muscle cells. These smooth muscle cells automatically adjust vessel diameter in response to changing conditions. When this process does not work correctly, it can cause a wide range of serious medical problems such as hypertension or brain dysfunction. Current engineered organs and tissues are unable to mimic this ability to regulate blood flow and, if implanted in patients, are likely to cause the same serious medical problems. To address this challenge, this work will develop a technique for putting smooth muscle cells inside microscopic blood vessels in engineered tissue and coaxing these cells to organize and behave in a way that is similar to their behavior in natural tissue. We will then test to see whether the cells can adjust the diameter of the engineered microscopic blood vessels in a similar fashion. The knowledge gained from these studies will add a critical capability to engineered tissue, and will ultimately improve the lives of future patients implanted with tissue engineered materials. As the field of tissue engineering has transitioned from employing thin tissue structures to producing thick, 3D cell-laden tissues and organs, the need for an embedded microvasculature has become increasingly apparent. While researchers have focused on establishing the ability of engineered microvasculature to maintain cell viability, a critical function of the microvasculature has been ignored: the capability to regulate local vascular resistance. Vascular resistance is locally modulated by adjustments in vessel lumen diameter in response to various internal and external changes (changes in temperature, body position, metabolic needs of various tissues, etc.), and is accomplished by the action of smooth muscle cells in the medial layer of the microvessel wall. The objective of this research is to establish the knowledge needed to form a functional medial layer of contractile, circumferentially-oriented smooth muscle cells in an arteriole-sized microchannel, thereby enabling vasoconstriction or vasodilation in response to appropriate stimuli. In particular, this work will investigate the ability of pulsatile flow to maintain contractile SMC phenotype and induce circumferential architecture on the microvessel wall, expose the cells to relevant vasoactive agents, and then characterize their ability to appropriately modulate the lumen diameter. The relationships we establish between flow waveforms and cell behavior will enable design rules for engineered microvasculature with this critical functionality.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.