Cell Contractile Force-Mediated Morphodynamical Tissue Engineering via 4D Printed Degradable Hydrogel Scaffolds

Tissue morphogenesis is a critical aspect tissue development. Recent advances in four-dimensional (4D) cell scaffolds have shown promise for modeling morphogenic processes. While current 4D systems often rely on external stimuli, they tend to overlook the role of intrinsic cell-generated forces, such as cell contractile forces (CCFs), in driving tissue morphogenesis. The paradox between the inherent weakness of CCFs and the robustness of tissue scaffolds presents a significant challenge in achieving effective shape transformations. In this study, we introduce an easily printable, freestanding, cell-laden hydrogel platform 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 a significant advancement in biomimetic tissue engineering, offering new avenues for creating dynamic tissue models that closely replicate native morphogenesis.