ABSTRACT Extracellular vesicles, e.g., exosomes, derived from anti‐inflammatory M2 macrophages have emerged as potent mediators of tissue regeneration through their ability to modulate cellular behavior, immune responses, and angiogenesis. In this study, we developed a composite bioactive scaffold by integrating M2 macrophage‐derived EVs (M2‐EVs) into decellularized skin extracellular matrix (dSECM), and systematically evaluated its structural, biochemical, and regenerative properties. Bovine dermis was decellularized using chemical, enzymatic, and physical steps, yielding collagen‐rich, DNA‐depleted ECM matrices with preserved collagen content and tunable stiffness (15–40 kPa). M2‐EVs were isolated from IL‐10‐polarized RAW264.7 macrophages and characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS, mean diameter ∼151 nm), and Western blotting for CD81/CD63/TSG101/Calnexin expressions. Functional assays revealed that M2‐EVs enhanced the proliferation and migration of human dermal fibroblasts and keratinocytes, with 100 µg/mL achieving >90% wound closure at 48 h. When combined with dSECM, M2‐EVs further increased the expression of immunoregulatory genes such as TGF‐β (∼2.9‐fold) and IL‐10 (∼3.8‐fold), consistent with the scaffold's capacity to enhance anti‐inflammatory signaling. In the chick CAM model, dSECM/M2‐EVs significantly enhanced vascularization along with increased collagen deposition and vascular smooth muscle cell recruitment. These results highlight M2‐EVs as emerging biological effectors when incorporated into ECM‐based scaffolds for vascularized tissue repair.
Yazicioglu et al. (Thu,) studied this question.