Smart Bioinks for 4D Bioprinting: Requirements, Design, and Applications

Abstract

3D bioprinting is known for its high precision and reproducibility in fabricating complex and customized biomedical constructs. However, its applications are limited by their static nature; i.e., unlike native tissues, they cannot change shape or functionality over time. To overcome this, 4D bioprinting has emerged as a groundbreaking strategy by incorporating time as the fourth dimension, enabling dynamic structures that adapt in response to stimuli, thereby more accurately replicating living tissues. The success of 4D bioprinting hinges on the development of advanced smart bioinks, as their physicochemical properties uniquely dictate the shape-morphing behavior, functionality, and performance of bioprinted constructs. These bioinks must be precisely engineered to respond to specific stimuli. This review first introduces 4D bioprinting technologies for tissue engineering scaffolds. We then outline essential requirements for smart bioinks and highlight how AI, particularly machine learning, is revolutionizing their design. Additionally, we examine widely used biomaterials for 4D bioprinting and discuss promising candidates for 4D printing. We also present cutting-edge bioink applications in tissue engineering, drug screening, and disease modeling, showcasing their potential in regenerative medicine and personalized therapeutics. Finally, we discuss current challenges and future perspectives, underscoring the transformative impact of smart bioinks and 4D bioprinting on biomedical innovation.