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调节人体组织中血流的理解。体内的微观血管通过平滑肌细胞调节流向组织的血液。 这些平滑肌细胞自动调整血管直径以应对不断变化的条件。 当这个过程不正常工作时，它可能会导致广泛的严重医疗问题，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流的能力，如果植入患者体内，可能会导致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，将平滑肌细胞置于工程组织中的微观血管内，并诱使这些细胞以类似于它们在自然组织中行为的方式组织和行为。 然后，我们将测试这些细胞是否可以以类似的方式调整工程化微观血管的直径。 从这些研究中获得的知识将为工程组织增加关键能力，并最终改善未来植入组织工程材料的患者的生活。随着组织工程领域已经从采用薄组织结构转变为产生厚的3D细胞负载组织和器官，对嵌入式微脉管系统的需求变得越来越明显。 虽然研究人员专注于建立工程微血管系统维持细胞活力的能力，但微血管系统的一个关键功能却被忽视了：调节局部血管阻力的能力。 血管阻力通过响应于各种内部和外部变化（温度、身体位置、各种组织的代谢需求等的变化）调节血管腔直径来局部调节，并通过微血管壁中间层中平滑肌细胞的作用实现。 本研究的目的是建立在小动脉大小的微通道中形成收缩性、周向平滑肌细胞的功能性中间层所需的知识，从而使血管收缩或血管舒张响应于适当的刺激。 特别是，这项工作将调查脉动流的能力，以保持收缩SMC表型和诱导微血管壁上的周向架构，暴露的细胞相关的血管活性剂，然后表征其能力，适当地调节管腔直径。 我们建立的流量波形和细胞行为之间的关系，将使设计规则的工程微vasculature与此关键functional.This奖项反映了NSF的法定使命，并已被认为是值得的支持，通过评估使用基金会的智力价值和更广泛的影响审查标准。

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.