Tunable Fast Relaxation in Imine-Based Nanofibrillar Hydrogels Stimulates Cell Response through TRPV4 Activation

As a key mechanical signal of natural extracellular matrix (ECM), stress relaxation plays an essential role in cell fate decision. However, the biomimetic matrix with fast stress relaxation and its cellular response mechanism have received little attention. Meanwhile, the nanofibrillar architecture which is conductive to mechanical transduction has invariably been ignored in the previous viscoelastic matrix design. Herein, by introducing a dynamic covalent imine bond into a physically cross-linked collagen hydrogel, we prepared bionic fast-relaxing nanofibrillar hydrogels with relaxation time less than 10 s. Through a single control of imine bond content, we realized fine-tuning of the relaxation rate while maintaining a constant initial modulus and fiber density. Using MC3T3-E1 cells as a model, we then proved that the nanofibrillar matrix with fast relaxation mechanics can effectively promote cell spreading and differentiation. In particular, TRPV4 as a molecular sensor of matrix viscoelasticity was demonstrated to regulate cell fate on the nanofibrillar hydrogels by mediating calcium influx. It is expected that the material design principle combining both nanofibrillar structure and tunable fast-relaxation can provide a more broadly adaptable materials platform for simulating natural ECM mechanical cues, and the investigation of the TRPV4 ion channel mediated cellular response will facilitate discovery of more fundamental mechanisms in tissue growth and development.