Pushing the Natural Frontier: Progress on the Integration of Biomaterial Cues toward Combinatorial Biofabrication and Tissue Engineering

Abstract The engineering of fully functional, biological‐like tissues requires biomaterials to direct cellular events to a near‐native, 3D niche extent. Natural biomaterials are generally seen as a safe option for cell support, but their biocompatibility and biodegradability can be just as limited as their bioactive/biomimetic performance. Furthermore, integrating different biomaterial cues and their final impact on cellular behavior is a complex equation where the outcome might be very different from the sum of individual parts. This review critically analyses recent progress on biomaterial‐induced cellular responses, from simple adhesion to more complex stem cell differentiation, looking at the ever‐growing possibilities of natural materials modification. Starting with a discussion on native material formulation and the inclusion of cell‐instructive cues, the roles of shape and mechanical stimuli, the susceptibility to cellular remodeling, and the often‐overlooked impact of cellular density and cell–cell interactions within constructs, are delved into. Along the way, synergistic and antagonistic combinations reported in vitro and in vivo are singled out, identifying needs and current lessons on the development of natural biomaterial libraries to solve the cell–material puzzle efficiently. This review brings together knowledge from different fields envisioning next‐generation, combinatorial biomaterial development toward complex tissue engineering.