An overview of recent advancements in 4D printing of alginate hydrogels for tissue regeneration.

Abstract

4D printing of alginate hydrogels has emerged as a transformative strategy in tissue engineering, enabling the fabrication of stimuli-responsive scaffolds that recapitulate the temporal and spatial complexities of native tissues. Leveraging alginate's tunable crosslinking, biocompatibility, and easy modification, recent research has demonstrated the successful design of constructs capable of programmable shape morphing in response to physiological stimuli. This review highlights recent advances in polymer design, including methacrylated, oxidized, and ligand-functionalized alginate derivatives, and cutting-edge 4D printing technologies such as extrusion-based and photopolymerization-based printing technologies. Notably, these systems have shown promising outcomes in regenerating cartilage, bone, vascular, and neural tissues. However, key challenges remain, including the standardization of shape-morphing quantification, enhancement of mechanical robustness, improvement of host tissue integration, and the replication of native tissue complexity. This review concludes with a critical evaluation of current limitations and future directions, highlighting the potential of integrating 4D alginate hydrogel systems with emerging technologies such as artificial intelligence, machine learning, organoid models, and bioelectronic interfaces to accelerate innovation and broaden their application in tissue engineering. By synthesizing recent advancements and offering insights into the implementation of 4D alginate hydrogels, this review aims to stimulate continued progress in this rapidly evolving field.