Fibrous Viscoelastic Extracellular Matrix Assists Precise Neuronal Connectivity

Abstract Synapse formation in complex neuronal network is a pivotal process for normal functioning of nervous system. Although intense research has been conducted, how neurons and axons are guided toward the target remains largely unclear. In traditional opinions, axons are directed through chemotaxis, while recently mechanotaxis has been brought up as a potential complementary mechanism, as it can provide delicately controlled signals in addition to the random diffusive chemical cues. To further explore the path‐finding mechanism, a quasi‐3D in vitro model for neuronal cells is constructed by integrating hydrogel collagen I as extracellular matrix (ECM), and primary mouse cortical neurons and PC12 cells are tested. It is strikingly found out that axons and neuronal cells can be precisely guided toward target neurites via ECM. By developing a label‐free traction force microscopy technique, the force networks among neurons are presented, validating that the fibrous matrix‐transmitted paratensile signals can assist the axon pathfinding. This precise axon guidance is related to the activation of mechanosensitive ion channels, calcium signaling, and probably the following F‐actin assembly. This mechanism can potentially assist developing clinical applications and designing biomaterials in near future.