Mechanisms underlying the cell-matrixed nerve grafts repairing peripheral nerve defects.

Decellularized extracellular matrix (dECM), with its distinct biological properties, has gained significant attention as a natural biomaterial. Leveraging its potentials, we successfully developed a three-dimensional matrix-based oriented nerve graft by encapsulating a fibrous scaffold with multilayered conformationally intact and biologically active human bone marrow mesenchymal stem cell-derived decellularized extracellular matrix (hBMSC-dECM). Convincingly, the hBMSC-dECM group exhibited comparable functional recoveries to the autograft group by postoperative week 12. In the comprehensive analysis, the molecular regulations in the hBMSC-dECM group were more intricate and nuanced compared to the autograft group. Nevertheless, both groups displayed similar molecular regulatory processes in terms of vascularization and extracellular matrix. Notably, the hBMSC-dECM group demonstrated sustained high levels of regulation in axon and myelin regeneration at week 12, while the immunomodulation returned to the normal levels after peaking at week 2. Collectively, our findings illustrated the satisfactory construction of a cell-matrixed nerve graft that established a microenvironment conducive to nerve regeneration, and elucidated the distinct molecular regulation patterns and characteristics associated with different repair modes.