Stage-Mimicking Assembly Strategy Enables Processable and Biomimetic Collagen Nanofiber Materials

Abstract

Collagen-based hydrogels are promising scaffolds for regenerative medicine due to their inherent bioactivity and biocompatibility. However, their clinical translation is hindered by the trade-off between injectability and fibrillar structural fidelity. Herein, we present a dynamic collagen hydrogel via a stage-mimicking assembly strategy that decouples rapid in situ crosslinking from subsequent fibrillogenesis. Methacrylated collagen (ColMA) was first crosslinked with dithiothreitol (DTT) through a visible light-induced thiol-ene reaction, forming an amorphous gel within seconds (Stage Ⅰ). Upon physiological incubation, the system spontaneously reconstructed into a fibrous matrix (Stage Ⅱ) with tunable mechanics and redox activity. The formed collagen nanofibers recapitulated extracellular matrix features, supported cell adhesion and orderly migration, while DTT-derived thiol groups conferred reactive oxygen species (ROS) scavenging capacity. In a diabetic wound model, the fibrillar hydrogel significantly promoted wound closure and epithelial regeneration, outperforming non-fibrillar or non-antioxidant controls. Histological and transcriptomic analyses confirmed enhanced M2 macrophage polarization, integrin β1-mediated adhesion, and activation of redox-responsive and cell–matrix interaction pathways. This study provides a versatile injectable collagen platform that integrates structural biomimicry, dynamic remodeling, and redox modulation, demonstrating high potential for chronic wound repair and broader bioresponsive scaffold design.

Keywords

Collagen hydrogel / Stage-mimicking assembly / Fibrillogenesis / ROS scavenging / Cell–matrix interactions

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Funding

the National Key Research and Development Program(2025YFA0921400)

the National Natural Science Foundation of China (32425031)

the Science and Technology Innovation Project of Shanghai Science and Technology Committee(25CL2900700)

the Zhejiang Natural Science Foundation(Z25E030005)

Basic Public Welfare Scientific Research Projects of Wenzhou (Y20240111)

National Key R&D Program of China (2024YFA1108405)

Clinical Key Discipline Project of Shanghai; Shanghai Top Priority Research Center Project(2023ZZ02013)

the Excellent Academic Leader Project of Shanghai Science and Technology Committee(23XD1425000)

RIGHTS & PERMISSIONS

Donghua University, Shanghai, China