Abstract
Lung-on-a-chip (LoC) models hold the potential to rapidly change the landscape for pulmonary drug screening and therapy, giving patients more advanced and less invasive treatment options. Understanding the drug absorption in these microphysiological systems, modeling the lung-blood barrier is essential for increasing the role of the organ-on-a-chip technology in drug development. In this work, epithelial/endothelial barrier tissue interfaces were established in microfluidic bilayer devices and transwells, with porous membranes, for permeability characterization. The effect of shear stress on the molecular transport was assessed using known paracellular and transcellular biomarkers. The permeability of porous membranes without cells, in both models, is inversely proportional to the molecular size due to its diffusivity. Paracellular transport, between epithelial/endothelial cell junctions, of large molecules such as transferrin, as well as transcellular transport, through cell lacking required active transporters, of molecules such as dextrans, is negligible. When subjected to shear stress, paracellular transport of intermediate-size molecules such as dextran was enhanced in microfluidic devices when compared to transwells. Similarly, shear stress enhances paracellular transport of small molecules such as Lucifer yellow, but its effect on transcellular transport is not clear. The results highlight the important role that LoC can play in drug absorption studies to accelerate pulmonary drug development.
Highlights
Drug discovery is becoming slower and more expensive over time, a trend referred to as Eroom’s law (Moore’s law spelled backward), despite major progress in technologies such as high-throughput screening and computational drug design [1]
Epithelial A549 and endothelial human umbilical vein cells (HUVEC) cell were successfully co-cultured in a microfluidic membrane bilayer device to model the lung–blood barrier interface
The bilayer interface permeability for four different molecules was compared with the permeability in microfluidic devices, at steady state, and transwells, after two-hours incubation time, without and with either A549 or HUVEC cell monolayers
Summary
Drug discovery is becoming slower and more expensive over time, a trend referred to as Eroom’s law (Moore’s law spelled backward), despite major progress in technologies such as high-throughput screening and computational drug design [1]. While presenting in vivo tissue-level complexity, fail to provide the proper tissue microenvironment because animals do not possess the same anatomy or physiology as humans; these models have less than 8% successful translation to therapies in some cancer trials [5,6] These serious shortcomings underline the critical need to develop new in vitro biomimetic systems that better represent the in vivo human physiological conditions in effort of hastening medical innovation [7]. MPSs are used for modeling of diseases, such as cancer, which is emerging as a prominent application driving development of complex systems with higher-order tissue functions [11] In drug discovery, these models are utilized to perform high-throughput assays to assess drug viability, optimizing clinical trials, and potentially reducing R&D costs to develop new compounds [14]. Both epithelial and endothelial cell layers are submerged in liquid media for human lung models, an air-liquid interface is an important feature affecting molecular diffusion in the epithelial side of the interface and subsequently the permeability
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