3D-exosomes laden multifunctional hydrogel enhances diabetic wound healing via accelerated angiogenesis

Impaired vascular networks, local insufficiency of neovascularization, and tissue inflammation caused by the accumulation of reactive oxygen species (ROS) and bacterial infections contribute to the delayed healing of wounds in patients with diabetes. Thus, an urgent need is to develop effective diabetic wound treatments that promote angiogenesis, inhibit bacterial infections, and reduce oxidative damage and tissue inflammation. Exosome therapy promotes angiogenesis and wound healing. However, traditional exosomes have limitations such as low yield and rapid release. Compared with two-dimensional (2D) cell culture, three-dimensional (3D) cell culture results in a higher yield of exosomes and better healing effects. In this study, we designed a multifunctional hydrogel with 3D-exosome-sustained release features to improve diabetic wound healing. Chitosan-grafted-dihydrocaffeic acid (CS-DA) and benzaldehyde-terminated Pluronic®F127 (PF127-CHO) were combined using a dynamic Schiff base bond to form a dynamic hydrogel network and simultaneously fused tannic acid (TA) and 3D adipose-derived mesenchymal stem cells-derived exosomes (3D ADSCs-Exos, referred to in this study as 3D-Exo). The phosphoric acid groups of 3D-Exo combine with the polyphenol groups of DA/TA through reversible interactions, enabling the sustained release of 3D-Exo. The CS-DA/PF/TA/3D-Exo hydrogel exhibited tissue-adhesive, self-healing, antibacterial, anti-inflammatory, and antioxidant properties. The CS-DA/PF/TA/3D-Exo hydrogel significantly accelerated the recovery of diabetic wounds by promoting angiogenesis and collagen deposition in vivo. Furthermore, rapid hemostasis was achieved owing to the wet tissue adhesion and platelet activation of the hydrogel. In general, this multifunctional hydrogel could be used as a wound dressing for diabetic wound management.