Cellular Proliferation, Self-Assembly, and Modulation of Signaling Pathways in Silk Fibroin Gelatin-Based 3D Bioprinted Constructs.

Three-dimensional (3D) bioprinting is a highly innovative and promising technology to render precise positioning of biologics together with living cells and extracellular matrix (ECM) constituents. In spite of such enthralling potential, the fabrication of a clinically relevant engineered tissue is quite challenging. A constellation of factors simulating the complex architecture of the native tissue, selection of the "ideal bioink", optimization of the biochemical, mechanical, and topographical functions of the cell-laden printed construct, cellular differentiation, their self-assembly, and remodeling into the desired lineage postprinting present major complications. Keeping this in view, we have attempted to highlight the use of silk fibroin (SF) protein from silkworm as a promising biomaterial of choice for the formulation of bioink owing to its distinct characteristics involving rheology behavior, self-supporting filamentous extrusion, and a suitable biomaterial to achieve resolution printing. Further, we have elaborated on how SF gelatin bioink can in specific regulate the cellular differentiation pathway of progenitor cells, the mechanism of cellular self-assembly, cell migration, matrix remodeling, and self-orientation, leading to the desired tissue-specific construct. How features of bioink and fabrication design aspects can induce tissue patterning and anatomically relevant tissue organization have also been explored in this review. Importantly, we have tried to shift the understanding of bioprinted tissue regeneration from a cell-proliferation-centric and gene-expression-centric point of view to the complex role of the microenvironment present within the bioprinted constructs. We believe that shedding light on these factors would help in achieving the so-called "ideal 3D bioprinted construct" to meet the shortages of high-quality donor tissues for the regeneration of the damaged and diseased ones.