Diabetes mellitus (DM)-associated impairments in wound healing include prolonged inflammation, the overexpression of matrix metalloproteases (MMPs), and low levels of growth factors at the wound site. To this end, a layer-by-layer scaffold (SL‑B‑L) made of cross-linked silk fibroin and hyaluronic acid is developed to deliver chlorhexidine, an antimicrobial agent and an MMP-9 inhibitor, along with the PDGF-BB protein. SL‑B‑L exhibited highly porous morphology. Diabetic rats treated with SL‑B‑L demonstrated an early wound closure, a fully reconstructed epithelial layer by 14 days, and reduced levels of IL-6, TNF-α, TGF-β1, and MMP-9. Interestingly, SL‑B‑L treatment increased angiogenesis, the bioavailability of collagen, DNA content, and VEGF-A levels. Furthermore, enhanced keratinocyte–fibroblast interaction along with ordered collagen deposition was observed in SL‑B‑L-treated rats. Most interestingly, when compared with a clinically used scaffold SEESKIN+, SL‑B‑L outperformed in promoting wound healing in a diabetic rat model by regulating the inflammation while delivering growth factor and the MMP-9 inhibitor.

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