Smart biomaterials in 4D printing: from tissue engineering to translational applications

Recent advances in tissue engineering and reconstruction demand scaffold systems capable of dynamically adapting to complex physiological environments. Conventional 3D-printed scaffolds, although structurally precise, remain static and often fail to replicate the responsive remodeling behavior of native tissues. In this context, 4D printing has emerged as a next-generation biofabrication strategy that integrates stimuli-responsive “smart” biomaterials capable of undergoing programmed changes in shape, mechanical properties, or functionality over time. This review presents a comprehensive overview of recent advances and translational applications of 4D-printed smart scaffolds in tissue engineering and reconstruction. Progress in smart polymers, hydrogels, nanocomposites, and multifunctional bioinks has enabled the development of constructs that respond to physiological triggers such as temperature, pH, moisture, magnetic fields, and light, thereby improving scaffold adaptability after implantation. Emerging fabrication strategies, including multi-material printing, integration of cell-laden bioinks, and advanced crosslinking approaches, have further expanded the design of biomimetic and patient-specific regenerative constructs. Clinically relevant applications are increasingly being explored in bone and cartilage regeneration, wound healing and skin reconstruction, vascular repair, and neural tissue engineering, demonstrating enhanced functional integration and regenerative outcomes in preclinical studies. Despite promising progress, key challenges remain, including precise control of in vivo transformations, long-term biocompatibility, scalability for clinical translation, and the lack of standardized evaluation protocols. Continued interdisciplinary innovation and regulatory advancement are expected to accelerate the development of adaptive, personalized implants and establish 4D printing as a transformative platform in reconstructive regenerative medicine.