In Situ Forming Hypoxia-Induced Exosome-Loaded Hydrogel for Enhanced Diabetic Wound Healing

Diabetic wound healing presents unique challenges, including impaired angiogenesis, prolonged inflammation, and delayed re-epithelialization. Advancements in tissue engineering offer promising solutions through cell/drug-based therapies. Exosomes (Exo) derived from hypoxia-preconditioned adipose-derived stem cells (ADSCs) have gained attention for their potential to address these complex issues in diabetic wounds. Existing strategies for Exo delivery aim to overcome drawbacks associated with conventional administration methods, including rapid loss of activity, frequent dosing, and off-target effects. However, complexities in fabrication, undesirable components within the delivery system, and unforeseen outcomes have hindered the efficacy of these approaches. Thus, an in situ formed hydrogel is engineered using click chemistry to facilitate the convenient encapsulation of hypoxia-induced Exo. The hydrogel swiftly transitioned into a gel state upon mixing and facilitated the controlled release of Exo at various loading dosages. Through systematic screening of Exo-hydrogel formulations, it is demonstrated that the encapsulated Exo retained their bioactivity, exhibits therapeutic efficacy in vitro via scratch and tube formation assays. Further, the optimal Exo-hydrogel promotes accelerated wound healing while preventing scar formation in a diabetic rat wound model. The Exo-loaded hydrogel represents a promising approach for efficient Exo delivery in wound healing applications and holds potential for broader applications in diverse medical fields.