The role of the endothelium extends beyond acting just as a barrier, and vascular endothelial cells are actively involved in almost all disease pathophysiologies [Aird, 2007]. The subject of this proposal is related to endothelial damage brought on as a result of persistent activation of the endothelium by cardiovascular risk factors such as diabetes mellitus [Rabelink 2015]. Glycocalyx function in patients with diabetes, obesity, or chronic kidney disease is diminished, leading to enhanced albumin excretion from blood vessels, which in turn drives vascular inflammation and progressive organ function loss. Experimental studies have suggested that glycocalyx dysfunction is reversible, rendering the glycocalyx a promising therapeutic target.
We propose to develop new in vitro models for the glycocalyx to better be able to investigate this component of the vascular system as a target for potential therapeutic intervention in renal and cardiovascular disease. These models will be based on microfluidics, as this technology enables ultra-small-volume liquid handling in the femtoliter to microliter range in tiny channels having effective diameters from 1 to 1000 micrometers [Whitesides 2006]. Micofluidics has been applied to a multitude of life-science research questions, including those involving biochemical reactions and bioanalysis in the absence of cells (cell-free) [Mross 2015], as well as microperfusion cell culture (e.g. organs-on-a-chip). Organs-on-a-chip are microfabricated devices incorporating microchambers in which cells or tissue are cultured under continuous perfusion and other biochemical and physical stimuli to simulate tissue or organ physiology [Bhatia 2014]. These devices, currently under development for many different organs, enable the engineering of in vivo-like cellular microenvironments. It is also possible to implement dynamic experimental conditions to mimic the temporal changes to these microenvironments experienced by tissue in vivo. Microfluidic devices designed for both cell-free and cell-culture applications can provide real-time insight into physiological processes under different conditions, and the opportunity to test the efficacy of pharmacological interventions under varying circumstances.