# Air Quality Effects on Human Health and Approaches for Its Assessment through Microfluidic Chips
## 5 OoC for Assessing Health Effects  
### OoC Technology for Modeling Healthy and Pathological Lung Function  
Inhalation studies using animals are the current gold standard when potential risks of airborne pollutants need to be assessed. However, the translation of results gained in animal studies to humans is hampered by differences in lung physiology and ventilation characteristics. These parameters can influence the rate of particle deposition, and thus, the cellular (effective) dose [147]. For better comparability and the identification of safety thresholds, humanized systems that allow for control of the applied dose and exact determination of the cellular dose would be needed. Here, OoC technology might be added as a valuable tool in the animal-free testing of short and long-term effects on the respiratory system by exposure to airborne pollutants. The lung is a tissue with a highly complex physiology. The trachea, bronchi, and bronchioles form the conductive airways, while the alveoli can be regarded as the smallest functional unit facilitating the actual gas exchange. The paranasal sinuses are also considered to be part of the human airways, yet they are not involved in the process of breathing and gas exchange. The distinct compartments of the lung have different structural characteristics, such as stiffness and cellular composition, that determine their respective function [148]. Furthermore, the lung has features that are quite distinctive from other tissues. These include a high elasticity that facilitates air exchange through breathing, an air-liquid interface, and high gas permeability for gas exchange in the alveoli. The lung is also a barrier tissue that is meant to prevent foreign bodies and pathogens from entering the body while ensuring the exchange of O\({}_{2}\) and CO\({}_{2}\). Rather large particles and pathogens are removed through mucociliary transport, while pollutants such as very small particles and pathogens that reach smaller compartments, like the alveoli, are removed by macrophages [149]. The alveoli are the lung compartment that is of key importance for gas exchange, but also, the transfer of airborne pollutants into the blood stream. Hence, most published OoC do not try to recapitulate the complexity of the whole lung, but rather, the alveoli as the interface between air and blood stream. First attempts to recreate the alveolar interface focused on engineering principles, rather than an exact recapitulation of biology, while later systems show a higher sophistication on the cellular level. For example, [PERSON] and colleagues introduced an early approach to recreate the alveolar air-liquid interface. Here, A549 human alveolar basal epithelial cells were cultured on top of a membrane with 0.4 um pore size, while the lower side of the membrane had access to a fluid channel filled with media (Figure 2A). The cells themselves had direct contact with ambient air, which resulted in the formation of a surfactant layer, similar to the physiologic situation in the alveoli [150]. Building on similar design considerations, others have introduced designs that encompass the use of epithelial and endothelial cells separated by a porous membrane (Figure 2B). The membrane itself divides two channels, with the upper one experiencing air flow, and the lower one, media flow [151; 152; 153]. This general design can be further developed to enable cyclic stretching of the separating membrane, therefore simulating alveolar stretching in response to breathing movements (Figure 2C) [154]. While being an elegant example of an organ-on-a-chip system, the lung-on-a-chip of [PERSON] and colleagues is still an approximation of the physiological counterpart, due to different dimensions, the use of cell lines, and an artificial membrane for keeping apart the two cell layers. Also, the unilateral stretching of the membrane only partially represents the 3D mechanical strain found in spherically shaped alveoli [155].