81 Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research research on the chip [71, 72]. Diseases like asthma and COPD have been modelled in LOC mimicking small airways [73, 74]. In addition, a stromal layer can be included, combining LOC technology with hydrogel culture [75]. LOC technology has evolved further and recently, a LOC with a stretch regimen that is closer to physiological stretch was developed. This platform uses a micro-diaphragm that stretches the cell culture membrane in three-dimensions [76, 77]. It can be used with immortalised primary alveolar cells for nanoparticle exposure and lipopolysaccharide challenge [78]. To create a more in vivo-like environment, the polymer membrane of the LOC was replaced by a collagen-elastin membrane spread by surface tension on an ultra-thin grid with holes the size of alveoli enabling the creation of an array of alveoli [79]. Lung microvasculature and vascular diseases are also modelled with microfluidics. For example, side effects of the IPF drug Nintedanib [80], effects of physiological stretch on the endothelium [81], or combined effects of hypoxia and cyclic stretch [82] have been investigated. A challenge with LOC experiments is the incorporation of primary material that presents wide heterogeneity. This has been tackled by generating type II alveolar epithelial cells (AECII) organoids to enable expansion of primary lung alveolar cells in hydrogels before culture in a LOC [42]. Another challenge is the complicated fabrication of LOC devices, which often requires highly specialised equipment. A recent study showed that it is possible to develop a LOC to study ventilation-induced injury solely by using a simple 3D printer and syringe pump [83]. In spite of these challenges, LOC as a technology has been successfully commercialised by multiple startups, such as Emulate [71], AlveoliX [78], and Mimetas [84] that support research on a wide-range of human (lung) diseases. Often, these companies offer customization of chips allowing easy technology transfer and adaptation of LOC systems, thus enabling rapid uptake of LOC without the limitation of the requirement of development and manufacture in-house by various research groups. However, the scalability and costs of these systems remain an important challenge. The LOC field is still young and exciting with new developments continuously occurring. Overall, LOC technology is promising for modelling lung diseases and drug efficacy/safety screening with the advantage of being able to model the complexity of the different compartments of the lung in one system. PERSPECTIVES AND FUTURE DIRECTIONS A summary of recent applications of the use of PCLS, organoids, ECM-derived hydrogels and LOC as in vitro systems for lung disease modelling is presented in Table 1. Excitingly, the development of lung in vitro models continues to rapidly advance. In 4
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