Engineering a Multiresponsive Injectable Hydrogel via a Double-Injection Strategy for Diabetic Wound Healing

Diabetic wounds are typical chronic wounds hindered by hyperglycemia, oxidative stress, and persistent inflammation, often failing to transition from inflammation to proliferation. Standard dressings fall short in intelligently regulating this complex microenvironment. Here, we report a facile double-injection strategy to fabricate an injectable, self-healing, and multiresponsive hydrogel (hydrogel@MIC&bFGF). This system employs dynamic boronic ester bonds formed between phenylboronic acid (PBA)-grafted alginate (APBA) and poly(vinyl alcohol) (PVA), integrated with gelatin for biocompatibility. It co-encapsulates anti-inflammatory acetyl-11-keto-beta-boswellic acid (AKBA) within hyaluronic acid-cholesterol micelles (MIC) and basic fibroblast growth factor (bFGF). The hydrogel exhibits smart responsiveness to glucose, reactive oxygen species (ROS), and acidic pH, enabling the on-demand, sustained release of AKBA and bFGF to mitigate inflammation and promote angiogenesis. In vitro experiments confirmed excellent cytocompatibility and enhanced cell migration. In a full-thickness skin defect model in diabetic rats, hydrogel@MIC&bFGF significantly accelerated wound closure and re-epithelialization. Histological and immunohistochemical staining demonstrated that the treatment remarkably suppressed inflammation (reducing tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and myeloperoxidase (MPO)) while promoting collagen deposition and angiogenesis (upregulating vascular endothelial growth factor (VEGF)). This versatile hydrogel platform offers a promising on-demand therapeutic strategy for regulating the diabetic wound microenvironment.