Tunable viscoelastic collagen/polyethylene glycol composite hydrogels modulate neural and tumor cell behavior in 3D microenvironments.

Three-dimensional (3D) cell culture systems provide a more physiological environment than traditional two-dimensional cultures by better mimicking the complex interactions within the extracellular matrix (ECM). Among the key properties of the ECM, viscoelasticity is essential for regulating cell behaviors, such as proliferation, differentiation, and migration. However, many present 3D culture systems are complex and technically demanding, which limits their broad application. In this study, we developed two hydrogel systems with identical stiffness but distinct viscoelastic properties, designed to serve as ECM-based 3D culture platforms. These hydrogels were constructed through the cross-linking reaction between type I collagen and functionalized polyethylene glycol derivatives, resulting in either reversible (dynamic) or stable (static) network structures. This platform effectively simulated ECM-like mechanical cues, enabling the investigation of viscoelastic effects on both neural and cancer cell responses. Our results demonstrated that dynamic hydrogels, characterized by rapid stress relaxation, enhanced PC12 cell elongation, promoted neural stem cell differentiation, and significantly facilitated the invasiveness and tumorigenic capacity of DU145 cells in vitro and in vivo. These findings highlight the critical importance of matrix viscoelasticity in modulating cell behavior and underscore the potential of this hydrogel-based system as a versatile and accessible tool for applications in neural tissue engineering, cancer research, and mechanobiology.