Recapitulating physiological and pathological shear stress and oxygen to model vasculature in health and disease

Abstract

Studying human vascular disease in conventional cell cultures and in animal models does not effectively mimic the complex vascular microenvironment and may not accurately predict vascular responses in humans. We utilized a microfluidic device to recapitulate both shear stress and O2 levels in health and disease, establishing a microfluidic vascular model (μVM). Maintaining human endothelial cells (ECs) in healthy-mimicking conditions resulted in conversion to a physiological phenotype namely cell elongation, reduced proliferation, lowered angiogenic gene expression and formation of actin cortical rim and continuous barrier. We next examined the responses of the healthy μVM to a vasotoxic cancer drug, 5-Fluorouracil (5-FU), in comparison with an in vivo mouse model. We found that 5-FU does not induce apoptosis rather vascular hyperpermeability, which can be alleviated by Resveratrol treatment. This effect was confirmed by in vivo findings identifying a vasoprotecting strategy by the adjunct therapy of 5-FU with Resveratrol. The μVM of ischemic disease demonstrated the transition of ECs from a quiescent to an activated state, with higher proliferation rate, upregulation of angiogenic genes, and impaired barrier integrity. The μVM offers opportunities to study and predict human ECs with physiologically relevant phenotypes in healthy, pathological and drug-treated environments.

Glioblastoma adhesion in a quick-fit hybrid microdevice

“…Under the 5.4 mL h − 1 shear flow stimulation alone, the 1 Pa shear stress induced classical parallel alignment of HUVECs (Fig. 9d), consistent with prior observations (Buchanan et al 2014; Abaci et al 2014). Without any shear flow, the HUVECs exhibited no alignment preference (Fig.…”

Fabrication of 3-dimensional multicellular microvascular structures

“…Therefore, to create vessels with a larger diameter, there has to be a system to guide the formation of cylindric vascular structures in the order of hundreds of micrometers. Microfluidic channels have been used extensively to study microvascular development processes, yet most of these studies are done in channels with a square cross section or in nonimplantable devices (37, 38).…”

Engineering tissue‐specific blood vessels

“…Vascular cell types can sense and adapt to these changes in oxygen levels through different mechanisms exhibiting various responses including angiogenesis, proliferation, apoptosis, and migration. Microfluidic culture platforms developed using different approaches and design principles helped circumvent this problem by finely tuning the oxygen concentration at the cellular level and allowed for recapitulation of healthy and diseased conditions …”

“…Historically, shear-stress and cyclic strain exerted by blood flow were first recreated in vitro using large-scale perfusion culture systems, 5 including parallel plate flow systems and cyclic-stretch devices, which later transformed into microfluidic systems containing microchannels typically made of plastics such as Polydimethylsiloxane (PDMS) or polycarbonate. [34][35][36] More recently, microchannels were created in 3D reconstructed ECM and hydrogels that permitted studying the permeability of molecules through the endothelial barrier and for incorporating other vascular cell types (e.g., smooth muscle cells), paving the way for generating high-fidelity microvascular tissues. 6,37 The surrounding ECM in these models can also provide mechanical signals, which affect various cellular responses responsible for homeostasis and angiogenesis.…”

“…Microfluidic culture platforms developed using different approaches and design principles helped circumvent this problem by finely tuning the oxygen concentration at the cellular level and allowed for recapitulation of healthy and diseased conditions. 34,49 These advancements on recreating the vascular milieu in vitro allow for restoring the physiological relevance of vascular cells in culture. Notably, some of the physical and chemical cues discussed above also show variations between organs.…”