Novel silver and nanoparticle-encapsulated growth factor co-loaded chitosan composite hydrogel with sustained antimicrobility and promoted biological properties for diabetic wound healing

Diabetic foot ulcer, one of the most common diabetic complications, is a progressive wound occurred on the skin with irregularly delayed wound healing rate due to impaired metabolism and weak immune responses. Such chronic wound remains a serious healthcare burden to the diabetics since it is often associated with high risk of limb loss due to amputation and leads to a reduced survival consequently. To improve the efficiency of diabetic wound healing, a synthetic chitosan-based composite hydrogel named SNP_ECHG incorporating silver ions (Ag⁺) and nanoparticle-encapsulated epidermal growth factor (EGF) was developed in this study. The optimal effective dosages of 24-mM Ag⁺ and 60-μg mL^-1 EGF for the SNP_ECHG manufacture were first determined based on the results of antibacterial, cytotoxicity, and cell growth examinations. We then characterized the optimized SNP_ECHG and found that the composite hydrogel was able to provide sustained release of Ag⁺ and EGF, and exhibited a significantly higher hydration capacities, including the swelling degree and equilibrium water content, in PBS than those in deionized water, showing that the developed SNP_ECHG is highly applicable in the ion-rich environment such as chronic wound site. According to the results of in vivo study using diabetic rats, the one with SNP_ECHG exhibited a markedly enhanced wound healing effect compared with the other settings since day 3, and may reach a degree of wound closure of 97% at day 14 that was 7.4% (P < 0.05) and 18.9% (P < 0.05) higher than the values gained from the groups with the commercial dressing HeraDerm and gauze, respectively. Moreover, the wound treated with the SNP_ECHG exhibited thorough re-epithelization, sufficient collagen deposition, and accelerated collagen maturation confirmed by the histological analysis. Taken all together, we anticipate that the SNP_ECHG is highly advantageous for use in the clinical diabetic/chronic wound treatment.