Breathing in vitro: Designs and applications of engineered lung models

Abstract

The aim of this review is to provide a systematic design guideline to users, particularly engineers interested in developing and deploying lung models, and biologists seeking to identify a suitable platform for conducting in vitro experiments involving pulmonary cells or tissues. We first discuss the state of the art on lung in vitro models, describing the most simplistic and traditional ones. Then, we analyze in further detail the more complex dynamic engineered systems that either provide mechanical cues, or allow for more predictive exposure studies, or in some cases even both. This is followed by a dedicated section on microchips of the lung. Lastly, we present a critical discussion of the different characteristics of each type of system and the criteria which may help researchers select the most appropriate technology according to their specific requirements. Readers are encouraged to refer to the tables accompanying the different sections where comprehensive and quantitative information on the operating parameters and performance of the different systems reported in the literature is provided.

Keywords: Lung models; aerosol exposure; fluidic systems; in vitro models; stretching systems.

Figure 1.

Toward physiological relevance—main elements of the lung microenvironment that are desirable in an in vitro model.

Figure 2.

Different configurations of bioreactors designed to operate with millifluidics. Representations are not at scale. The photograph in panel C shows the MALI chamber with nebulizer.

Figure 3.

Schematic representation of the: (a) alveolar, (b) in vitro in-plane, and (c) in vitro out-of-plane stretching. Black arrows represent the deformation directions, while red arrows the corresponding strain on the cells.

Figure 4.

Scheme of the most common principles of actuation for stretching elastic cell culture supports in lung in vitro models. In pneumatic actuation, the support can be deformed either by inflowing air at controlled over pressure (a), or by applying a negative pressure (b), and (c) motor-driven convex surfaces or indenters cyclically deform the support.

Figure 5.

Schematic representation of two different working principles of breathing chips: (a) Huh et al. working principle: the microfabricated device uses compartmentalized PDMS microchannels to mimic the lung breathing sequence, and (b) Stucki et al.^, working principle: a micro-diaphragm actuated by an electro-pneumatic set-up leads to the cyclic motion of the cells.