Advances in Gelatin Bioinks to Optimize Bioprinted Cell Functions.

Gelatin is a widely utilized bioprinting biomaterial due to its cell-adhesive and enzymatically-cleavable properties, which improve cell adhesion and growth. Gelatin is often covalently crosslinked to stabilize bioprinted structures, yet the covalently-crosslinked matrix is unable to recapitulate the dynamic microenvironment of the natural extracellular matrix (ECM), thereby limiting the functions of bioprinted cells. To some extent, a double network bioink can provide a more ECM-mimetic, bioprinted niche for cell growth. More recently, gelatin matrices are being designed using reversible crosslinking methods that can emulate the dynamic mechanical properties of the ECM. In this review, we analyze the progress in developing gelatin bioink formulations for 3D cell culture, and critically analyze the bioprinting and crosslinking techniques, with a focus on strategies to optimize the functions of bioprinted cells. We discuss new crosslinking chemistries that recapitulate the viscoelastic, stress-relaxing microenvironment of the ECM, and enable advanced cell functions, yet are less explored in engineering the gelatin bioink. Finally, we present our perspective on the areas of future research and argue that the next generation of gelatin bioinks should be designed by considering cell-matrix interactions, and bioprinted constructs should be validated against currently established 3D cell culture standards to achieve improved therapeutic outcomes. This article is protected by copyright. All rights reserved.