141 3D lung models – 3D extracellular matrix models disaccharides (glucuronic acid and N-acetyl glucosamine) [120]. While most studies focus on drug delivery approaches using HA [121], the use of this flexible biomaterial as an in vitro model in hydrogel form has also been explored. In its native form, HA does not form viable hydrogels; however, chemical functionalization (additions of methacrylate [122], thiol [123], furan [124]) of HA, as well as combining HA hydrogels with other biopolymers (gelatin [125, 126], fibronectin [127], methylcellulose [124]) results in hydrogel formation (Figure 2). Varying the concentration of HA and the degree of modification of HA molecules results in great variability in the mechanical properties of the resultant hydrogel: (0.35 ± 0.05 kPa – 1613.0 ± 248.5 kPa) [122, 128] . Considering the high range, it would be possible to use such models in fibrotic lung disease research, where hydrogels with higher stiffness can be used to mimic the fibrotic microenvironment. Other ECM components have been used to construct 3D ECM-based in vitro models. Fibronectin, an important ECM glycoprotein, was modified with the addition of polyethylene glycol (PEG) molecules to form mechanically tunable hydrogels that could support sprouting of human umbilical vein endothelial cells (HUVECs) in an in vitro model [129]. Similarly, fibrinogen was used in combination with collagen to formulate in vitro models with varying stiffness [130]. Fibrin hydrogels were used to create a 3D in vitro model for fibroblast-epithelial cell co-culture to mimic the airway [131, 132], or even a tri-culture model for epithelial cells, fibroblasts and endothelial cells [133]. Just like in collagen, gelatin or HA hydrogels, it is possible to modulate the mechanical properties of fibrin hydrogels within an extensive range (1.1 ± 0.3 kPa – 31 ± 2.8 kPa), which increases the applicability of these hydrogels to a variety of lung diseases as well as representing specific locations within lung tissue [134]. 3D MODELS – 2: ECM MODELS WITH COMPLEX ECM MIXTURES Decellularized lung scaffolds Decellularization is the process of removing cells from tissue or whole organs while minimizing the damage to and preserving the biological integrity, composition, and mechanical properties of the ECM [135]. This technique has enabled generation of acellular, native, and 3D ECM in vitro and ex vivo models that are useful to study tissue-specific cell-ECM component interactions in healthy and diseased states, and the dynamic reciprocity between cells and their microenvironment [136-138]. Moreover, decellularization of allogeneic and xenogeneic ECM grafts followed by recellularization can ideally provide an unlimited supply for clinical applications such as tissue reconstruction and transplantation [137-139]. Although this has 6
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