Development of a microfluidic platform to emulate the human microvasculature
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2022
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Doctoral Thesis
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Abstract
The human body employs a tube-like system calledblood vessels for transporting molecules such as oxygen or cells. These pipes are lined with endothelial cells that are phenotypically different and thus very heterogenous. Due to its important role in maintaining homeostasis, every organ and tissue is heavily relying on thorough vascularization. Thus, with intravenous drug administration every target within the human body can be reached effectively. The gold standard in drug development is still animal experiments.However, besides ethical reasons, species to species differences can lead to unnecessary clinical trials or failure of clinical transition due to false negative results within the animal experiments. Microfluidics allow for overcoming this difference by utilizing human and even patient-derived cells while also saving resources due to miniaturization. Channels and compartments can be imprinted into biocompatible polymers such as poly(dimethylsiloxane) (PDMS), thus spatial confined co-culture is possible in 2D and even 3D. Additionally, mechanical and chemical stimuli can be applied on demand and very parallelized, which makes it all together a strong tool in drug discovery. Thus, we developed a microfluidic platform that utilizes primary endothelial cells as a tool to mimic the human blood vessel system. To emulate in-vivo conditions as accurately as possible, the vascular heterogeneity was exploited. Both human arterial (HUAECs) and venous cells (HUVECs) were integrated in our system together with flow cultivation in 3D and pericytes to form a biologically relevant barrier. Due to the on-chip generated human microvasculature being perfusable, the device can be used for a widerange of applications in fundamental and applied sciences as we could show with molecule permeation, bead perfusion,and studying T cell trafficking across the endothelial barrier. Also, the microfluidic platform allows for varying the perivascular space by fine tuning the extracellular matrix (here: fibrin), where the microvasculature forms over time. Thus, the vasculature can be exposed to important extravascular cues, e.g., different cells or molecules, and their impact on vascular development can thereby be investigated. By embedding pre-polarized macrophages within our extracellular matrix, we could show distinct influences of the polarization state onto network and sprout formation. This successful realization of an on-chip microvasculature model is a first step to address further crucial questions in vascular biology and can be employed to understand endothelial‐immune crosstalk better in the future.
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Examiner: Dittrich, Petra S.
Examiner : Filippova, Maria
Examiner : Reddy, Sai
Examiner: Treutlein, Barbara
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ETH Zurich
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03807 - Dittrich, Petra / Dittrich, Petra