Engineering vascular models to investigate disease at the microscale

Abstract: Early in development, our vasculature regulates the transport of biomolecules and fluid exchange throughout our tissues. The endothelium is dynamic and complex, changing in response to temporally and spatially regulated bio-chemical and mechanical cues within their local environments. When these signals go awry, the change from homeostasis first begets endothelial dysfunction, which can progress into pathologies such as cardiovascular disease or tumor metastasis. Investigating the nuances of endothelial dysfunction presents challenges in vivo, which can alternatively be addressed by exploiting tissue-engineered platforms. Adopting novel design principles, microfluidic and engineering techniques, it is possible to generate 3D capillary systems that closely mimic native in vivo systems. This talk will highlight several examples of these systems, where perfusable and self-assembled human capillaries are employed to investigate pathological conditions. First, we examine the potential for placental pericytes (stromal cells) to mediate vasculogenesis (vessel development) in a pathological model of placental vasculature. Second, we demonstrate how vascularized tumors generate local changes in the vessel microenvironment, and greatly impact chemotherapeutic delivery. As well, we also examine how luminal flow can impact microvessel growth and remodelling in comparison to ischemic-like (no flow) conditions. These in vitro capillaries are shown to be capable of recapitulating changes in morphological remodeling, cell signalling, gene expression and vascular transport, caused by altering the physical, chemical and mechanical environment. Our lab is currently employing similar strategies to vascularize larger organoids and tissues to model vascular pathogenesis, and to generate physiologic human preclinical models.