A lung-on-a-chip platform for improved tissue maturation

Until a few years ago, in vitro models could only poorly mimic the processes observed in the human body. During drug development, their inability to mimic complex physiological processes was an essential reason for drug withdrawals. The combination of 3D in vitro models with an engineered microenvironment, resulting in the so-called “organ-on-a-chip” technology, allows these limitations to be overcome. The exposure of 3D models to a more physiological environment has been demonstrated several times to increase their resemblance with human organs. With the aim of creating a bronchial and small airway model better resembling the human lung, Philip Morris International has recently developed a new chip system allowing for an improved maturation of air-liquid interface lung tissues. The chip consists of four circuits, each composed of eight interconnected wells that can accommodate Transwell™ inserts. A specially designed peristaltic pump ensures a continuous medium circulation within the circuits. To demonstrate the benefits of maturing tissues within the chip, bronchial and small airway tissues were characterized every week for four weeks using the following assays: transepithelial electrical resistance (TEER) and cilia beating frequency (CBF), metabolism (CYP1A1/1B1 activity) and morphology (histological analysis and whole insert immunostaining). We found that the continuous medium recirculation decreased tissue thickness improving homogeneity, pseudostratification, and cell polarization when compared with tissues matured in standard plates. Cell differentiation was also improved leading to the formation of a denser ciliation. At the functional level, the tissues matured in the chip had a similar CBF but a higher TEER than those matured in the standard plates. Our results demonstrated that the maturation of bronchial and small airway tissues with a continuous medium recirculation can be beneficial for the tissue characteristics.