Viscoelasticity, a time-scale mechanical feature of the native extracellular matrix (ECM), is reported to play crucial roles in plentiful cellular behaviors, whereas its effects on neuronal behavior and the underlying molecular mechanism still remain obscure. Challenges are faced in the biocompatible synthesis of neural ECM-mimicked scaffolds solely controlled with viscoelasticity and due to the lack of suitable models for neurons-viscoelastic matrix interaction. Herein, we report difunctional hyaluronan-collagen hydrogels prepared by a static-dynamic strategy. The hydrogels show aldehyde concentration-dependent viscoelasticity and similar initial elastic modulus, fibrillar morphology, swelling as well as degradability. Utilizing the resulting hydrogels, for the first time, we demonstrate matrix viscoelasticity-dependent neuronal responses, including neurite elongation and expression of neurogenic proteins. Then, a motor-clutch model modified with a tension dissipation component is developed to account for the molecular mechanism for viscoelasticity-sensitive neuronal responses. Moreover, we prove enhanced recovery of rat spinal cord injury by implanting cell-free viscoelastic grafts. As a pioneer finding on neurons-viscoelastic matrix interaction both in vitro and in vivo, this work provides intriguing insights not only into nerve repair but also into neuroscience and tissue engineering.
Keywords: biomedical application; cell niche manipulation; cellular response to material; hydrogel; imine bonding; viscoelasticity.