Engineering Next-generation Drug Delivery Systems Via 4-D Printing: A Paradigm Shift Toward Precision Medicine.

Four-dimensional (4-D) printed constructs have recently become clinically relevant platforms for customized and precise drug delivery due to their bio-programmability, bio-responsiveness, and spatiotemporal transformative potential. The 4-DP bio-constructs are highly bio-interactive and dynamically evolving as per therapeutic requisite. In this review, we aim to provide a detailed discourse on the key mechanisms that drive 4-D transformations of a broad spectrum of materials-ranging from shape-memory (SM) systems, liquid crystalline elastomers (LCEs), self-healing and multi-responsive polymers, metamaterials, and select bio-derived materials. The review also summarizes various conventional and advanced additive manufacturing strategies that have been employed for 4-DP of various bio-constructs. Contemporary representatives of various 4-DP drug delivery devices such as smart hydrogels and scaffolds, implants, stents, prosthetics, microneedles, responsive biomedical devices, and dynamic organ- and tumor-on-chip platforms have also been highlighted. Characterization methodologies, preclinical considerations, translational challenges, and the evolving patent and industrial landscape have also been recapitulated. The review also intends to provide critical perspectives on the expanding horizons and translational glitches of 4-DP while elucidating the key bottlenecks to its commercial large-scale integration and clinical translation.