139 3D lung models – 3D extracellular matrix models yields type A gelatin, negligibly affects amide groups. Conversely, alkaline hydrolysis converts glutamine and asparagine to glutamate and aspartate residues respectively, resulting in type B gelatin [99]. Gelatin is less immunogenic compared to collagen due to fewer aromatic groups. Moreover, it retains the RGD sequence and MMP degradation sites of the parent collagen molecule that plays an indispensable role in orchestrating cell-matrix adhesion and enabling migration and cellular remodeling respectively [99, 100]. Gelatin is both biodegradable and a biocompatible material and is economical to produce and abundantly extractable from porcine skin, fish, bovine hides, and porcine and bovine bones [101]. Given the above enticing properties, gelatin is one of the most extensively used polymers in the food, pharmaceutical, cosmetic, and biomedical industry and is a generally regarded as safe material. Gelatin is thermo-reversible and forms a hydrogel as the temperature decreases below 30-35°C [102]. This occurs as gelatin sustains a conformation change from a random coil to triple helix and rearrangement of the triple helices gives rise to a huge polymer network. However, these non-covalent (hydrogen and van der Waals) interactions are broken as the temperatures rise above 30-35°C. In fact, gelatin dissolves in water at 37°C and as a result, native gelatin hydrogels have low stability and elasticity and poor mechanical properties [102]. These limitations are often assuaged by covalently crosslinking gelatin either in its native form or following functionalization of its side chains [103]. Native gelatin can be crosslinked chemically or enzymatically, while modified gelatin is commonly crosslinked thermally, enzymatically or using photo-initiators [103-106] (Figure 2). Gelatin has been used for a myriad of biomedical applications such as to produce micro or nanoparticles, polymeric fibers and hydrogels for tissue-engineered scaffolds and bioadhesives [107]. 3D bioprinting has especially proven to be an extremely valuable technique in terms of recreating organs with complex architectures, such as lungs, as it enables layer-by-layer deposition of biomaterials and/or cells [108]. Several studies have used gelatin as a bio-ink to print lung scaffolds. For instance, a sodium alginategelatin hydrogel, encapsulating non-small cell lung carcinoma patient-derived xenograft cells and cancer associated lung fibroblasts, was 3D printed to model tumor microenvironment in vitro [109]. The printed scaffold supported the development of 3D co-culture spheroids up to 25 days. Additionally, tumor-stromal crosstalk was demonstrated by increased expression of vimentin, α-SMA (smooth muscle actin), and loss of E cadherin in co-culture spheroids [109]. This composite sodium alginate-gelatin hydrogel has also been used to support culture of lung cancer cells (A549 and 95D) for at least 2 weeks. Furthermore, 3D culture of these cancer cells enhanced their migratory properties and invasiveness compared to their 2D cultured counterparts [110]. 6
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