Harnessing Macromolecular Chemistry to Design Hydrogel Micro- and Macro-Environments

Cell encapsulation within three-dimensional hydrogels is a promising approach to mimic tissues. However, true biomimicry of the intricate microenvironment, biophysical and biochemical gradients, and the macroscale hierarchical spatial organizations of native tissues is an unmet challenge within tissue engineering. This review provides an overview of the macromolecular chemistries that have been applied toward the design of cell-friendly hydrogels, as well as their application toward controlling biophysical and biochemical bulk and gradient properties of the microenvironment. Furthermore, biofabrication technologies provide the opportunity to simultaneously replicate macroscale features of native tissues. Biofabrication strategies are reviewed in detail with a particular focus on the compatibility of these strategies with the current macromolecular toolkit described for hydrogel design and the challenges associated with their clinical translation. This review identifies that the convergence of the ever-expanding macromolecular toolkit and technological advancements within the field of biofabrication, along with an improved biological understanding, represents a promising strategy toward the successful tissue regeneration. The faithful replication of the tissue's native micro- and macroenvironmental biophysical and biochemical heterogeneity is a key challenge within tissue engineering. This review describes how macromolecular chemistry and biofabrication are used to replicate relevant tissue features. The strategic convergence of the macromolecular toolkit and biofabrication technology is identified as a promising strategy toward engineering the next generation of tissue mimics.image