From Smart Hydrogel Design to 4D-Printed Scaffolds: Emerging Paradigms in Precision Drug Delivery and Regenerative...

Smart hydrogel systems with stimuli-responsive properties are increasingly being investigated in combination with advanced additive manufacturing techniques for targeted drug delivery and wound healing in regenerative medicine; however, their clinical translation remains limited by challenges related to material performance, design complexity, and manufacturing scalability. This review analyzes recent developments in smart hydrogel design and 4D-printed scaffolds, with emphasis on programmable and stimuli-responsive architectures. The literature is selectively evaluated based on relevance to (i) hydrogel structure-property relationships, (ii) 3D/4D printing strategies, and (iii) demonstrated performance in drug delivery and wound healing applications. The analysis highlights design approaches enabling spatiotemporal control of drug release and dynamic scaffold behavior, while also examining how fabrication methods influence functional outcomes. Major limitations are critically assessed, including issues of reproducibility, mechanical stability, long-term performance, and the gap between experimental studies and clinical application. Challenges in defining and implementing 4D printing in biomedical contexts are discussed as well. Overall, this review identifies current design trade-offs, outlines priorities for improving reliability and translational potential, and synthesizes emerging trends in 3D and 4D printed hydrogel scaffolds for precision drug delivery and regenerative wound therapy.