Biomaterial-based microenvironment remodeling for functional regeneration of scarred uterus tissue

Cesarean section-induced uterine scar defects represent a growing global clinical challenge characterized by fibrosis-dominated healing, mechanical dysfunction, and impaired reproductive outcomes. Current surgical interventions fail to restore the structural and functional integrity of the myometrium, highlighting the urgent need for regenerative strategies. Biomaterials have emerged as a promising solution; however, their success remains limited by the pathological microenvironment at the implantation site. Here, the uterine scar is conceptualized as a coupled disequilibrium system driven by three interdependent factors: mechanical microenvironment mismatch, immune dysregulation, and vascular insufficiency. Representative biomaterial systems, including biomimetic extracellular matrix scaffolds, mechanically active constructs, and functionalized modified platforms, are systematically evaluated, highlighting that spatiotemporal matching between material degradation and tissue regeneration is a critical determinant of therapeutic efficacy. Furthermore, the key biological mechanisms underlying functional regeneration are discussed, including macrophage-mediated immune remodeling, vascular network reconstruction, and directed organization of smooth muscle cells. Major translational challenges are also addressed, including limitations of current animal models, the lack of standardized evaluation systems, and long-term biosafety concerns. Finally, future directions are proposed, emphasizing smart responsive biomaterials, multimodal regenerative matrices, and mechanism-driven design strategies. It is proposed that successful uterine regeneration is governed not by individual material properties but by the ability of biomaterials to reprogram the coupled mechanical-immune-vascular microenvironment, thereby shifting healing from fibrosis toward functional regeneration.