4D bioprinting: Materials, mechanisms, and mathematical modeling for next-generation tissue engineering

Advances in 3D bioprinting have enabled the fabrication of synthetic tissues with complex architectures that closely mimic natural ones. However, 3D bioprinting faces challenges in generating fully functional bioconstructs using biocompatible materials and cells. To overcome this limitation, the emerging technology of 4D bioprinting offers a novel solution. Unlike its 3D counterpart, 4D bioprinting enables structures to change shape in response to both intrinsic and external stimuli. This dynamic capability of 4D bioprinting has the potential to surpass the limitations of 3D bioprinting while more accurately replicating the adaptive nature of living tissues. By leveraging 4D bioprinting, it becomes feasible to produce highly intricate and dynamic structures with exceptional resolution, which would be challenging to achieve using conventional biofabrication methods such as 3D printing or bioprinting. This review highlights the applications of stimuli-responsive materials in 4D bioprinting. It delves into the chemistry and mechanism of action of advanced 4D materials. Additionally, this review discusses the diverse applications of 4D bioprinted tissues and organs, emphasizing their impact on regenerative medicine. The integration of mathematical modeling as a predictive tool for the printing process and final structural outcomes is also examined. Furthermore, the article addresses essential testing protocols for evaluating the functionality and safety of bioprinted tissues. Finally, it discusses current challenges and future directions in this rapidly evolving field, particularly its implications and potential breakthroughs in tissue engineering.