Immunomodulatory All-Natural Kelp Decellularized Scaffold Prepared Using Deep Eutectic Solvent with Angiogenic Properties for Accelerating Diabetic Wound Healing

Excessive oxidative stress, chronic inflammation, and impaired vascularization are the main barriers to diabetic wound repair. A decellularized extracellular matrix (dECM) with a native ECM structure is a promising biomaterial candidate for diabetic wound healing. However, the traditional decellularization process (reagents) can diminish the structural stability, mechanical properties, and bioactive components of dECM. To address these issues, we developed an intrinsically bioactive kelp decellularized scaffold (Im-Gly2) using natural and gentle deep eutectic solvents (DES) for accelerating diabetic wound healing. Im-Gly2 had a stable porous 3D structure (80.7 μm) and suitable mechanical properties, which could support cell growth, proliferation, and migration. Due to the retention of fucoidan, polyphenols (735.3 μg/g), and flavonoids, Im-Gly2 demonstrated intrinsic antioxidant and immunomodulatory effects. It effectively reduced reactive oxygen species (ROS) production in RAW264.7 macrophages and promoted their differentiation into the M2 phenotype. Notably, Im-Gly2 promoted tube formation through paracrine mechanisms by inducing the expression of transforming and proliferative cytokines from the RAW264.7 macrophage. In vivo, Im-Gly2 accelerated the healing of diabetic wounds by alleviating inflammation, angiogenesis, granulation tissue formation, collagen deposition, and re-epithelialization. Taken together, our study provides a novel strategy for fabricating a bioactive kelp dECM without cross-linking with exogenous substances for accelerating chronic diabetic wound healing.