The selective permeation of molecules and nanomedicines across the diseased vasculature dictates the success of a therapeutic intervention. Yet, in vitro assays cannot recapitulate relevant differences between the physiological and pathological microvasculature. Here, a double-channel microfluidic device was engineered to comprise vascular and extravascular compartments connected through a micropillar membrane with tunable permeability. The vascular compartment was coated by endothelial cells to achieve permeability values ranging from 0.1 um/sec, following a cyclic adenosine monophosphate (cAMP) pre-treatment (25 ug/mL), up to 2 um/sec, upon exposure to Mannitol, Lexiscan or in the absence of cells. Fluorescent microscopy was used to monitor the vascular behavior of 250 kDa Dextran molecules, 200 nm polystyrene nanoparticles (PB), and 1,000-400 nm discoidal polymeric nanoconstructs (DPN), under different permeability and flow conditions. In the proposed on-chip microvasculature, it was confirmed that permeation enhancers could favor the perivascular accumulation of ~ 200 nm, in a dose and time dependent fashion, while have no effect on larger particles. Moreover, the microfluidic device was used to interrogate the role of particle deformability in vascular dynamics. In the presence of a continuous endothelium, soft DPN attached to the vasculature more avidly at sub-physiological flows (100 um/sec) than rigid DPN, whose deposition was larger at higher flow rates (1 mm/sec). The proposed double-channel microfluidic device can be efficiently used to systematically analyze the vascular behavior of drug delivery systems to enhance their tissue specific accumulation.
|Titolo della tesi:||Microfluidic organ-on-chip for assessing the transport of therapeutic molecules and polymeric nanoconstructs|
|Data di discussione:||12-mag-2021|
|Appare nelle tipologie:||Tesi di dottorato|