146 Chapter 6 porcine lung ECM hydrogels have seeded cells on top of the hydrogel. Human lung fibroblasts, mesenchymal stromal cells and pulmonary vascular endothelial cells were able to survive and grow on the porcine lung ECM hydrogel [163]. The mechanical properties of human lung ECM hydrogels, both healthy and diseased (IPF and COPD) were compared to those of intact whole lung tissue pieces [58]. The differences in stiffness seen between healthy, COPD and IPF tissues were still present, albeit to a lesser degree, in the corresponding ECM hydrogels. The stiffness of ECM hydrogels resembled that of whole tissue while their viscoelasticity differed. Lung ECM hydrogels are still a very novel tool and there remains a lot to optimize and discover; however, incorporating these in 3D co-culture models will allow researchers to ask and answer more complex questions about the physiology and pathophysiology of the lung and the role of the ECM in disease pathogenesis. Application of these lung ECM-derived hydrogels in disease-specific models can be further specialized by several different means. While using the pepsinsolubilized ECM as the bulk hydrogel [58, 173] already improves the biomimicry of the 3D ECM-based in vitro lung models, using such in combination with other biopolymers could also provide extensive versatility. Although used in a 2D culture model, the combination of solubilized decellularized ECM from control or IPF lungs with polyacrylamide hydrogels with defined stiffness values was shown to form hydrogels with disease-specific compositions [145]. Similarly, reinforcing the solubilized decellularized ECM with alginate resulted in the possibility of finetuning the mechanical properties of the resulting hydrogels [171]. The same study also elegantly demonstrated the application of the reinforced ECM hydrogel as a bioink for bioprinting of 3D lung models. Chemically modifying the solubilized ECM to modulate the biochemical and biomechanical properties provides another alternative to improve the applicability of these hydrogels in 3D models. By functionalizing the solubilized ECM with thiol groups (thiolation) and combining this with methacrylated PEG (PEGMA) molecules, Petrou et al. generated ECM-derived hydrogels with tunable mechanical properties in two separate steps [172]. While the initial stiffness values were adjusted by changing the concentration of the modified ECM in the solution, a second step of stiffening these hydrogels was achieved using photo-crosslinking the PEGMA molecules, resulting in great variability in the stiffness values (soft: 3.63 ± 0.24 kPa, stiff: 13.35 ± 0.83 kPa). The exciting opportunity of utilizing (disease-specific) lung ECM-derived hydrogels brings various levels of innovation to the development of novel 3D in vitro models for lung diseases. While alternatives to pepsin digestion have yet to be discovered to prepare solubilized ECM, ECM-derived hydrogels enhance the biomimicry of in
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