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

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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.