Engineered Hierarchical Porosity in Three-Dimensional-Printed Hydrogel Scaffolds Enhances Mesenchymal Stem Cell Therapy for Chronic Diabetic Wounds

Abstract

Abstract Unhealing chronic diabetic wounds is a major clinical challenge, as it is rooted in the complex pathological microenvironment, including neuropathy, angiopathy, and chronic inflammation. Traditional treatment methods cannot fundamentally solve these problems. Inspired by outdoor rock climbing, this study developed a multifunctional bioactive hydrogel scaffold with hierarchical pore sizes (CSP hydrogel) to remodel the wound microenvironment and boost regenerative repair. Fabricated through 3D printing and photopolymerization from methacryloylated chitosan (CSMA) and methacryloylated silk fibroin (SiMA), the hydrogel has controlled properties: multi-scale porous structure (macropores ≥100 μm, mesopores 1–50 μm, micropores <1 μm), ∼15 kPa mechano-instructive stiffness, strong tissue adhesiveness, and intrinsic broad-spectrum antibacterial ability. In vitro, MSC-loaded CSP@MSC promoted the fibroblast-like pro-regenerative functions of MSCs, including enhanced migration, extracellular matrix synthesis, angiogenic factor expression, and protection against oxidative stress under simulated high-glucose conditions. In diabetic mice with full-thickness skin defects, CSP@MSC accelerated wound closure and guided organized tissue regeneration. This work demonstrates that this hydrogel can enhance the potential of mesenchymal stem cells, repair the pathological conditions of diabetic wounds, and provide a comprehensive solution for non-healing wounds.