173 Current possibilities and future opportunities with three-dimensional lung ECM-derived hydrogels LUNG ECM-DERIVED HYDROGELS FOR MIMICKING CELL:MATRIX INTERACTIONS The in vivo mimicry of the composition and mechanics of the cellular microenvironment present in the lung ECM-derived hydrogels creates an ideal setting for culturing cells within a 3D spatial location. As soon as cells are seeded in hydrogels they begin to remodel their microenvironment [28, 31, 34]. Early reports of cells in lung ECM-derived hydrogels reflect findings in single component ECM hydrogels [28], indicating that cells remodel the ECM in which they are embedded, and the nature of the ECM that they encounter directs these remodelling events [69, 70]. This fact makes the use of lung ECM-derived hydrogels sourced from diseased lungs an ideal model to understand cellular responses within such a diseased microenvironment and to provide greater knowledge of the influence of the microenvironment to treatment effects. Initial studies using porcine lung ECM-derived hydrogels reported successful growth of human and rat mesenchymal stromal (stem) cells (MSCs) in 2016 [39]. Link et al then described successful culture of mouse MSCs, human alveolar epithelial cells (the cell line A549), human primary microvascular endothelial cells (HpuVECs), and human umbilical vein endothelial cells (HUVECs) in porcine lung ECM-derived hydrogels [58]. The field is now rapidly expanding with additional cells types including murine fibroblasts [53], Rat lung MSCs [50] and rat primary alveolar epithelial cells [71] being grown in porcine lung ECM-derived hydrogels. The use of human lung ECM-derived hydrogels is now also possible, with human fibroblasts and airway smooth muscle cells being grown both within and on top of these hydrogels [51, 56, 69]. The field is now moving forward with the cellular systems that are being explored, taking advantage of the values of lung ECM-derived hydrogels. Multi-cellular culture systems are being developed to enable cellular cross-talk in a 3D microenvironment to be examined [72], and lung ECM-derived hydrogels are being incorporated into other experimental systems (for example lung on chip or stretching/mechanical force setups) to bring the cell microenvironment in those systems also [73, 74]. The possibilities for 3D printing lung ECM-derived hydrogels are also being examined, suggesting greater scope for spatial arrangement of cells within their 3D microenvironment will be possible in the future [50, 51]. While the 3D model systems made possible with the use of lung ECM-derived hydrogels are rapidly advancing, the readouts that can be used to investigate end points within these systems are presenting some limitations (Figure 1). Traditional 7
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