Advances in the Fabrication of Biomaterials for Gradient Tissue Engineering

Natural tissues and organs exhibit an array of spatial gradients, from the polarized neural tube during embryonic development to the osteochondral interface present at articulating joints. The strong structure–function relationships in these heterogeneous tissues have sparked intensive research into the development of methods that can replicate physiological gradients in engineered tissues. In this Review, we consider different gradients present in natural tissues and discuss their critical importance in functional tissue engineering. Using this basis, we consolidate the existing fabrication methods into four categories: additive manufacturing, component redistribution, controlled phase changes, and postmodification. We have illustrated this with recent examples, highlighted prominent trends in the field, and outlined a set of criteria and perspectives for gradient fabrication. There has been a recent surge in the number of tissue-engineering protocols that use gradient biomaterials to replicate key developmental processes or functional roles.Recent advances in additive manufacturing (e.g., 3D bioprinting, microfluidics) have led to increased structural complexity in bottom-up gradient biomaterial fabrication.A growing number of reports are seeking to use applied forces that redistribute components of homogeneous systems to fabricate biomaterials with well-integrated gradients.A small number of recent studies have fabricated gradient biomaterials by controlling the temperature or light exposure during hydrogel crosslinking.Recent reports have demonstrated the fabrication of gradient biomaterials by postmodifying precast hydrogels or solid scaffolds using mechanisms based on temperature, light, or diffusion.