80 Chapter 4 used to solubilise milled ECM of porcine trachea [60], as an alternative to pepsin digestion, which also solves the unsolved challenge of leftover pepsin in the lung ECM-derived hydrogels. Despite these rigorous treatments, ECM-derived hydrogels retain most of the native composition and reflect mechanical properties of the lung ECM both in healthy and diseased states [54]. Interestingly, a recent report illustrates organ-specific elasticity, viscoelastic relaxation and gelling properties of ECM-derived hydrogels [56]. These studies highlight the importance of mimicking the underlying architectural and mechanical properties of the ECM that are disease and organ-specific and can thus differentially regulate cellular responses. To this end, multiple studies have demonstrated alterations in cellular morphology or phenotype [61, 62], differentiation [63, 64] and gene and protein expression [61, 65] in cells cultured on or harvested from within ECM-derived hydrogels. Further investigation into individual biomechanical properties in studies using novel tools such as click chemistry for modulating elastic modulus [66], ECM-derived and synthetic material hybrid hydrogels to modulate stiffness [67], or applying fibre cross-linking to native lung ECM-derived hydrogels to increase stiffness and decrease viscoelastic stress relaxation [68], have provided novel insights as to the role of the lung microenvironment in driving disease processes. Lung ECM-derived hydrogels are an innovative and powerful tool that can be manipulated. Through the addition of cyclic stretch to mimic breathing, this model has the potential to further mimic the lung microenvironment in vivo [62, 69], thus being among the models that most closely represent physiological conditions. A challenge yet to be addressed effectively is the capacity to mimic the physiological architecture of peripheral lung tissue. Through the employment of this model system, the outcomes of cell-ECM interactions in the lung are slowly becoming evident. LUNG-ON-CHIP (LOC) LOC devices are microphysiological systems that model part of the lung and provide the possibility to combine physiological flow, mechanical stretching, multicompartment co-culture, drug/particle exposure and ECM material in an in vitro system. The LOC models began with 2 or 2.5D systems, however, they have now advanced to multicellular and multidimensional 3D systems. Microfluidic devices offer many possibilities that have recently been used to develop different LOC devices and some relevant LOC devices are highlighted here. The first LOC with physiological flow and mechanical stretch was developed by the Ingber group [70]. This alveoluson-chip, with lung epithelial cells and endothelial cells, was perfused with neutrophils to mimic an infection, and later expanded to initiate coronavirus disease (COVID-19)
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