Topologically aligned fibrous biopolymeric hydrogel orchestrates sequential cellular responses for accelerated scarless wound healing

Abstract

While the importance of biomaterial topology in wound healing is widely recognized, how precisely controlled anisotropic hydrogel architectures regulate the cellular dynamics of skin regeneration remains poorly understood. Here, photochemically crosslinked collagen–chitosan hydrogels with controlled anisotropic fiber architectures are developed to investigate how topological cues influence wound repair outcomes. By modulating the sequence of photocrosslinking and collagen self-assembly, non-fibrous (L), randomly fibrous (T + L), and aligned anisotropic fibrous (C + L) hydrogels are generated, with the latter achieved through additional plastic compression. In vitro, aligned fiber topography promotes fibroblast alignment, early myofibroblast differentiation, and macrophage polarization toward an anti-inflammatory M2 phenotype. In vivo, C + L hydrogel accelerates healing, achieving complete re-epithelialization within 7 days while minimizing scar formation through coordinated regulation of cellular responses. The aligned anisotropic architecture orchestrates an optimal healing sequence beginning with myofibroblast-driven contraction followed by M2 macrophage-dominated regeneration, ultimately producing scar-free repair with restored epidermal structure, physiological tissue thickness and functional vascular networks. These findings demonstrate that precise control of collagen fiber organization can optimize the entire healing cascade, offering a promising topological strategy for advanced wound dressings that simultaneously promote rapid closure and high-quality tissue regeneration.