Tailored Hydrogels for 3D Bioprinting: Matching Tissue Viscoelasticity to Enhance Resident Cell Functionality

Abstract The development of biomaterials that reconcile print fidelity with cellular functionality remains a major challenge in extrusion‐based 3D bioprinting. Here, a viscoelastic hydrogel featuring a small‐molecule‐mediated crosslinking dynamic network, enabling precise tuning of viscoelastic properties to mimic the mechanical properties of diverse tissues is introduced. The hydrogel's unique combination of high viscosity and rapid shear‐thinning characteristics reduced extrusion‐induced cell damage while maintaining structural integrity. Meanwhile, the hydrogel mimicking the viscoelasticity of bone marrow significantly promotes the proliferation, spreading, migration and stemness maintenance of bone marrow‐derived mesenchymal stem cell (BMSC) in 3D culture via an integrin/p‐FAK/Lamin/YAP signaling pathway, with an enhanced bone regeneration efficacy both in vitro and in vivo. The molecular mechanisms underlying viscoelastic hydrogel‐mediated osteogenic differentiation are also uncovered, revealing a novel phenomenon of nuclear co‐localization and interaction between Wnt1 and YAP. Moreover, designed viscoelastic hydrogels enable the establishment of disease models by replicating the mechanical parameters of pathological matrices relevant to colon cancer, pulmonary fibrosis, and liver cancer. Overall, this work establishes a unique strategy for bioink design, merging regenerative medicine and disease modeling by integrating tunable viscoelasticity with biological functions, offering broad translational potential for future 3D bioprinting.