Abstract
At the onset of life in utero, the respiratory system begins as a liquid-filled tubular organ and undergoes significant morphological changes during fetal development towards establishing a respiratory organ optimized for gas exchange. As airspace morphology evolves, respiratory alveolar flows have been hypothesized to exhibit evolving flow patterns. In the present study, we have investigated flow topologies during increasing phases of embryonic life within an anatomically inspired microfluidic device, reproducing real-scale features of fetal airways representative of three distinct phases of in utero gestation. Micro-particle image velocimetry measurements, supported by computational fluid dynamics simulations, reveal distinct respiratory alveolar flow patterns throughout different stages of fetal life. While attached, streamlined flows characterize the shallow structures of premature alveoli indicative of the onset of saccular stage, separated recirculating vortex flows become the signature of developed and extruded alveoli characteristic of the advanced stages of fetal development. To further mimic physiological aspects of the cellular environment of developing airways, our biomimetic devices integrate an alveolar epithelium using the A549 cell line, recreating a confluent monolayer that produces pulmonary surfactant. Overall, our in vitro biomimetic fetal airways model delivers a robust and reliable platform combining key features of alveolar morphology, flow patterns, and physiological aspects of fetal lungs developing in utero.