Multifunctional Collagen–Hyaluronic Acid Scaffolds Loaded with Propranolol as Platforms for Accelerated Diabetic Wound Healing

Effective management of diabetic wounds requires multifunctional biomaterials capable of regulating inflammation, preventing infection, promoting angiogenesis, and sustaining a favorable microenvironment for tissue regeneration. In this study, collagen/hyaluronic acid (COL/HA) scaffolds loaded with propranolol (Pr) were developed as bioactive wound dressings that combine extracellular matrix–mimicking architecture with localized pharmacological modulation. The scaffolds were fabricated via EDC/NHS-mediated cross-linking followed by freeze-drying and systematically characterized in terms of chemical structure, morphology, swelling behavior, mechanical performance, and drug-release kinetics. Scanning electron microscopy revealed an interconnected porous architecture with pore sizes ranging from 77 to 133 μm, suitable for nutrient diffusion and cellular infiltration. Propranolol incorporation markedly influenced scaffold performance, with the COL/HA/Pr 2 formulation exhibiting the highest swelling capacity (2914%) while maintaining adequate compressive strength (35.2 N·mm), ensuring optimal hydration and structural integrity. Drug-release studies demonstrated biphasic behavior, consisting of an initial burst followed by sustained release over 120 h. In vitro biological evaluation confirmed excellent cytocompatibility toward BJ-1 fibroblasts (>90% viability) and significant anti-inflammatory activity in LPS-stimulated RAW 264.7 macrophages, as evidenced by pronounced inhibition of nitric oxide production. Fibroblast scratch assays revealed accelerated cell migration, achieving 92.3% wound closure within 24 h for the COL/HA/Pr 2 scaffold. In vivo assessment using a streptozotocin-induced diabetic rat model demonstrated markedly enhanced wound healing in propranolol-loaded groups. The COL/HA/Pr 2 scaffold achieved rapid wound contraction, exceeding 84% closure by day 7 and reaching near-complete healing (99.7%) by day 20. Histopathological and immunohistochemical analyses further confirmed improved collagen deposition, enhanced VEGF expression, and significant downregulation of pro-inflammatory markers (TNF-α and NF-κB), indicating effective immunomodulation and angiogenic stimulation. Collectively, these findings demonstrate that propranolol-loaded COL/HA scaffolds function as multifunctional therapeutic platforms that actively regulate inflammation, suppress infection, and promote vascularized tissue regeneration. The optimized COL/HA/Pr 2 formulation shows strong potential as an advanced scaffold for accelerating diabetic wound healing and managing chronic, nonhealing wounds.