Strain‐Driven Topological Reorganization in Soft Fibrin Nanofibrous Networks Enabling Tissue‐Like Alignment

Abstract

ABSTRACT Programming long‐range anisotropy within soft, cell‐laden natural nanofibrous matrices remains a central challenge in soft matter and tissue engineering, as most alignment strategies rely on external templates or non‐physiological fields. Here, we demonstrate a gelation‐coupled strain‐induced alignment strategy that generates stable anisotropy in fibrin matrices by applying uniaxial deformation during a transient fibrillogenesis window. In partially crosslinked fibrin, stretching induces rapid fibril reorientation and pore elongation along the principal strain direction, with alignment saturation observed near 1.6× elongation under the present gelation and loading conditions. Structural and rheological analyses suggest that this post‐unloading alignment arises from balanced fibril mobility and network connectivity during gelation, while a simplified pore‐straightening model helps explain the observed strain‐saturation behavior. This strain‐guided response is further extended to uniaxial and multilayer tissue‐scale constructs by tuning scaffold geometry and boundary‐defined deformation. Aligned matrices improve cardiomyocyte structural organization, anisotropic contraction, electrical responsiveness, and calcium‐handling kinetics, with further functional enhancement achieved by integrating a deformable piezoelectric scaffold. These results establish a simple and biologically compatible strategy for generating directionally functional fibrin‐based tissues through gelation‐stage mechanical reorganization.