Diabetic foot ulcers remain one of the most difficult-to-treat complications of diabetes and may seriously threaten the life of patients since it frequently results in limb loss due to amputation, suggesting that an effective therapeutic strategy is still urgently needed. In this study, a chitosan-based heterogeneous composite hydrogel encapsulating perfluorocarbon emulsions, epidermal growth factor (EGF)-loaded chitosan nanoparticles, and polyhexamethylene biguanide (PHMB) named PEENPPCH was developed for diabetic wound healing. The PEENPPCH could sustainably release EGF and PHMB in an ion-rich environment to exert antibacterial effects and promote cell growth for wound repair. In addition, the PEENPPCH can provide anti-inflammatory effects functioned by its main constituent of chitosan. Moreover, the PEENPPCH can proactively offer oxygen delivery through the incorporation of perfluorocarbon and, therefore, is able to alleviate hypoxia conditions on diabetic wounds. These functionalities enabled a markedly enhanced wound healing efficacy on diabetic rats treated with the P(E)E(NP)PCHs, including thorough re-epithelization, a reduced inflammatory response, faster collagen deposition, and advanced collagen maturation resulting in a 95% of wound closure degree after 15 days that was 12.6% (p < 0.05) higher than the value of the group treated with the commercial dressing HeraDerm. Given the aforementioned advantages, together with the known merits of hydrogels, the developed PEENPPCH is anticipated to be a feasible tool for clinical diabetic wound treatment.
