An Injectable Ibuprofen Sustained-Release Composite Hydrogel System Effectively Accelerates Diabetic Wound Healing via Anti-Inflammatory Effects and Angiogenesis

Zhibin Li,1 Haijiang Dong,1 Shenyu Yang,2 Ximei Wang,1 Zhen Li3 1Department of Plastic and Aesthetic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2Medical 3D Printing Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 3Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of ChinaCorrespondence: Zhen Li, Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China, Email [email protected]: Excessive inflammation in diabetic wounds, driven by hyperglycemia, prolongs healing, increases the risk of non-healing ulcers, and can lead to severe complications such as amputation or life-threatening infections. Recurrent wound infections and prolonged treatment impose significant economic and psychological burdens, drastically reducing patients’ quality of life. Modulating the inflammatory response is a promising strategy to accelerate diabetic wound healing. Ibuprofen (IBU), a widely used anti-inflammatory and analgesic agent, has the potential to promote healing by mitigating excessive inflammation and alleviating wound-associated pain. However, its clinical application is hindered by poor water solubility and a short half-life. Therefore, a controlled and sustained-release system for IBU could enhance its therapeutic efficacy in diabetic wound management.Materials and Methods: Here, we present an in situ multi-crosslinked composite hydrogel system that integrates oxidized alginate (OSA), methacryloylated gelatin (GelMA), and an ibuprofen/amino-modified β-cyclodextrin inclusion complex (IBU/CD-NH2) via ion crosslinking, photocrosslinking, and Schiff-base reactions.Results: The optimized hydrogel formulation was synthesized at 35°C, with a P/A molar ratio of 2 and an methacrylamide(MA) volume fraction of 20%. Physicochemical and biocompatibility analyses demonstrated that the IBU-loaded composite hydrogel exhibits enhanced mechanical strength, favorable biocompatibility, tunable degradation, and injectability. This system effectively addresses IBU’s solubility and absorption challenges while conforming to wounds of varying shapes and sizes, enabling controlled and sustained drug release. Cellular and animal studies confirmed that the hydrogel continuously and uniformly releases IBU, exerting anti-inflammatory effects while promoting angiogenesis and fibroblast migration. This leads to enhanced granulation tissue formation, collagen deposition, and epidermal regeneration, significantly accelerating wound closure within 14 days.Conclusion: By simultaneously suppressing inflammation and stimulating tissue regeneration through controlled IBU release, this hydrogel system offers a highly effective strategy for diabetic wound healing and holds strong potential for clinical application.Keywords: ibuprofen, diabetic wound healing, sustained-release, injectable composite hydrogel system, inflammation