140 Chapter 6 Interestingly, gelatin has been used to produce microbubble-scaffolds, using specialized microfluidic devices, to mimic alveoli structure [111, 112]. A two-channel fluid jacket microfluidic device yielded 3D gelatin microbubble scaffolds that were seeded with mouse pulmonary stem/progenitor cells (mPSCs) and supported the differentiation of mPSCs into alveolar pneumocytes [111]. Additionally, a four-channel microfluidic device has been used to generate disc-shaped gelatin microbubble scaffolds with a uniform pore size of 100µm resembling the alveoli structure [112]. A549 cells seeded in these scaffolds had higher drug resistance compared to their 2D controls and hence the 3D hydrogels are better models for anticancer drugs screening [112]. Microfluidic devices for in vitro modeling of the lung microenvironment have also gained traction. Recently, gelatin methacrylate (GelMA) was used to mimic the lung microenvironment in an airway-on-chip model [113]. In this model, the biological properties of GelMA were further enhanced by resuspending Matrigel particulates and encapsulating lung fibroblasts within the GelMA solution [113]. Furthermore, the alveolar-capillary barrier microenvironment was modeled to study the influence of the ECM structure and mechanics on epithelial cell injury during cyclic airway reopening during mechanical ventilation [114]. Another novel use of gelatin has been in the development of prosthetics for tracheal reconstruction [115, 116]. Recently, it has been demonstrated that gelatin-based scaffolds are compatible with techniques such as electrospinning, micro-molding, and photolithography to produce micro- and nano- patterned topographical features to mimic native ECM [117, 118]. The mucosal folding of the respiratory track was mimicked in cell laden GelMA hydrogels that were bonded to pre-stretched tough hydrogel substrates composed of interpenetrating polymer networks of polyacrylamide and alginate. Relaxation of the substrate induced controlled patterns in the GelMA layer [119]. In another study, the microarchitecture of ECM fibers of healthy and diseased lung tissue was mimicked using PCL-gelatin electrospun fibers [114]. In conclusion, gelatin’s ability to support cellular activity, modifiable mechanical properties, and several functional groups for chemical modifications make it a highly desirable biomaterial for the generation of 3D models for cell culture with versatile potential for tissue engineering and regenerative medicine particularly in pulmonary diseases. Other ECM components Other ECM components and their derivatives have also been used for generating 3D in vitro lung models, although model types and the applications of these systems are limited. One of the most applied ECM components is hyaluronic acid (HA), also called hyaluronan: a linear polysaccharide composed of repeating units of
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