Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis

Abstract

Therapeutic and diagnostic nanomaterials are being intensely studied for several diseases, including cancer and atherosclerosis. However, the exact mechanism by which nanomedicines accumulate at targeted sites remains a topic of investigation, especially in the context of atherosclerotic disease. Models to accurately predict transvascular permeation of nanomedicines are needed to aid in design optimization. Here we show that an endothelialized microchip with controllable permeability can be used to probe nanoparticle translocation across an endothelial cell layer. To validate our in vitro model, we studied nanoparticle translocation in an in vivo rabbit model of atherosclerosis using a variety of preclinical and clinical imaging methods. Our results reveal that the translocation of lipid-polymer hybrid nanoparticles across the atherosclerotic endothelium is dependent on microvascular permeability. These results were mimicked with our microfluidic chip, demonstrating the potential utility of the model system. nanotechnology | cardiovascular disease | microfluidics | noninvasive imaging

Biomimetic channel modeling local vascular dynamics of pro-inflammatory endothelial changes

“…There are a few in vitro reports using microfluidic chips to study vascular functions. [3][4][5][6][7][8][9][10][11][12] Work by Tsou et al employed soft lithography based flow chamber to study how endothelial cells sense a gradient of flow shear stress (FSS) and tumor necrosis factor-alpha (TNF-a) triggering to transduce signals that regulate membrane expression of cell adhesion molecules and monocyte recruitment. 13 Sato et al used a microfluidic model separated by a membrane containing both blood and lymphatic vessels for examining vascular permeability.…”

“…13 Sato et al used a microfluidic model separated by a membrane containing both blood and lymphatic vessels for examining vascular permeability. 9 Kim et al 4 studied cytokine mediated controlled permeability on endothelial cell layers through nanoparticle (NP) extravasation. However, this study was performed under static conditions without consideration of the FSS conditions to which the endothelium would have been exposed in vivo.…”

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

“…A couple of recent works used an endothelial cell layered microfluidic device to study permeability, but these works were performed on a cell layer not exposed to physiologically relevant flow. 17,18 Another work uses an endothelial cell layer to study monocyte adhesion and transmigration. 19 Blood vessel endothelium is constantly exposed to FSS at its apical side due to blood flow.…”

A Membrane-integrated Microfluidic Device to Study Permeation of Nanoparticles through Straight Micropores toward Rational Design of Nanomedicines

“…9,10 The size of a microfluidic channel can be adjusted to that of a microvessel, and various vascular cells can be cultured in the channel under blood flow-like flow conditions. [11][12][13] In one approach, a porous membrane was integrated into a microfluidic device and utilized to evaluate the permeability of an endothelial monolayer on the membrane against fluorescein isothiocyanatelabeled bovine serum albumin (FITC-BSA) [14][15][16] and lipid-coated nanoparticles. 16 However, the pores within the monolayer are irregular in size and shape, as shown in previous studies.…”

“…[11][12][13] In one approach, a porous membrane was integrated into a microfluidic device and utilized to evaluate the permeability of an endothelial monolayer on the membrane against fluorescein isothiocyanatelabeled bovine serum albumin (FITC-BSA) [14][15][16] and lipid-coated nanoparticles. 16 However, the pores within the monolayer are irregular in size and shape, as shown in previous studies. [5][6][7] Therefore, from a different point of view, we have proposed an assay of nanoparticles utilizing the porous membrane with straight micropores with a defined pore size (without cells).…”