Bioactive scaffolds for treatment of diabetic wounds with bone infections.

Diabetes is a prevalent disease worldwide, and every year millions of people undergo amputations due to untreated or severe diabetic wounds that progress to bone involvement. Although many strategies have been applied to overcome the diabetic wound burden, most are limited by high cost and prolonged treatment duration. Hence, an effective solution is needed for complex diabetic wounds with bone infections. In the present study, a dual therapeutic strategy targeting both skin wounds and underlying bone infections was applied to treat diabetic wounds with bone involvement. A clinically relevant animal model was established by creating a skin wound on the tibial surface along with a bone infection just below the skin wound to mimic real-world conditions. Skin wounds were treated with functionalized cryogel scaffolds with nitric oxide (NO)-releasing and oxygen-releasing properties, while bone infection was treated with hydroxyapatite based nanocement loaded with rifampicin. Exosomes were impregnated in both the scaffolds to enhance therapeutic efficacy. The cryogel scaffolds had a pore size around 40-60 µm and a high water uptake capacity of ∼93-97%. Slow and sustained release of NO and oxygen was also observed, reaching ∼86% over 10 days and 67% over 7 days, respectively. The scaffolds also showed good biocompatibility and promoted fibroblast cell migration in vitro. Exosomes showed high antioxidant activity and enhanced cell migration in vitro. In the animal studies, scaffolds showed healed wound and restoration of skin and bone ultrastructure after 8 weeks of treatment, as depicted by radiological and histological analyses. Overall, the proposed dual-targeted strategy demonstrated excellent potential for treatment of diabetic wounds with bone infections and will pave ways for clinical translation.