Cell Contractile Force‐Mediated Morphogenetic Tissue Engineering via 4D Printed Degradable Hydrogel Scaffolds

Through the actuation of cell contractile forces, geometrically complex structures are formed via a bioprinted, rapidly degrading cell‐laden hydrogel system, resulting in cell‐only condensation within a few days of culture. This system supports stem cell differentiation down different lineages and new tissue formation, such as chondrogenesis and osteogenesis, while undergoing shape transformations simultaneously, demonstrating its potential for 4D tissue engineering applications. Abstract Tissue morphogenesis is a critical aspect of tissue development. Recent advances in 4D cell scaffolds have shown promise for modeling morphogenetic processes. While current 4D systems often rely on external stimuli, they frequently overlook the role of intrinsic cell‐generated forces, such as cell contractile forces (CCFs), in driving tissue morphogenesis. The paradox between the inherently weak nature of CCFs and the robustness of tissue scaffolds presents a significant challenge in achieving effective shape transformations. In this study, an easily printable, freestanding, cell‐laden hydrogel platform is designed to harness CCFs for 4D shape morphing. These hydrogels initially provide mechanical support to maintain structural integrity, followed by rapid degradation that amplifies CCFs through enhanced cell–cell interactions and increased local cell density, thereby inducing tissue morphogenesis. This platform enables the formation of scaffold‐free constructs with programmed shape transformations. By modulating the initial printed geometries, complex and large tissue constructs can be generated via controlled global shape transformations. Furthermore, the platform supports 4D tissue engineering by facilitating tissue differentiation coupled with dynamic shape evolution. This CCF‐4D system represents an important advancement in biomimetic tissue engineering, offering new avenues for creating dynamic tissue models that partially recapitulate native morphogenesis. Through the actuation of cell contractile forces, geometrically complex structures are formed via a bioprinted, rapidly degrading cell-laden hydrogel system, resulting in cell-only condensation within a few days of culture. This system supports stem cell differentiation down different lineages and new tissue formation, such as chondrogenesis and osteogenesis, while undergoing shape transformations simultaneously, demonstrating its potential for 4D tissue engineering applications. Abstract Tissue morphogenesis is a critical aspect of tissue development. Recent advances in 4D cell scaffolds have shown promise for modeling morphogenetic processes. While current 4D systems often rely on external stimuli, they frequently overlook the role of intrinsic cell-generated forces, such as cell contractile forces (CCFs), in driving tissue morphogenesis. The paradox between the inherently weak nature of CCFs and the robustness of tissue scaffolds presents a significant challenge in achieving effective shape transformations. In this study, an easily printable, freestanding, cell-laden hydrogel platform is designed to harness CCFs for 4D shape morphing. These hydrogels initially provide mechanical support to maintain structural integrity, followed by rapid degradation that amplifies CCFs through enhanced cell–cell interactions and increased local cell density, thereby inducing tissue morphogenesis. This platform enables the formation of scaffold-free constructs with programmed shape transformations. By modulating the initial printed geometries, complex and large tissue constructs can be generated via controlled global shape transformations. Furthermore, the platform supports 4D tissue engineering by facilitating tissue differentiation coupled with dynamic shape evolution. This CCF-4D system represents an important advancement in biomimetic tissue engineering, offering new avenues for creating dynamic tissue models that partially recapitulate native morphogenesis. Advanced Science, Volume 12, Issue 48, December 29, 2025.