GelMA–GelDopa–Sr double-network hydrogel promotes skin regeneration by enhancing angiogenesis and macrophage polarization

Yuxuan Su^1,2,3,4,5Fang Zhao^1,2,3,4,5,6Shuang Liu^2,3,4,5,7*Zheqin Dong^2,3,4,5,8Dongxu Liu^1,2,3,4,5*

• ¹Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
• ²Shandong University Cheeloo College of Medicine, Jinan, China
• ³Shandong University Shandong Dental Tissue Regeneration Key Laboratory, Jinan, China
• ⁴Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration, Jinan, China
• ⁵Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China
• ⁶Department of Orthodontics, Tai'an Stomatological Hospital, Tai'an, China
• ⁷Shandong University, Jinan, China
• ⁸Department of Additive Manufacturing, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China

Chronic skin defects typically exhibit persistent inflammation, damaged cell regeneration, and insufficient vascularization, all of which severely impede the healing process. Traditional skin dressings merely serve to cover the wound and do not actively promote wound healing. They lack anti-inflammatory capabilities and only minimally regulate immune cells, and their poor biocompatibility can lead to foreign body reactions. Some traditional dressings adhere to the defect area, and during dressing changes, they may cause secondary trauma, resulting in pain and tearing of new tissue. To address these challenges, we combined gel methacrylamide (GelMA), gel dopamine (GelDopa), and strontium ions (Sr2+) to create a multifunctional dual-network composite hydrogel, GelMA-GelDopa-Sr hydrogel. This dual-network design provided several functional advantages: the photopolymerization properties of GelMA enabled rapid and controllable gelation; the catecholamine derived from GelDopa imparted antioxidant capabilities, thereby reducing oxidative stress; and Sr2+ promoted angiogenesis. In vivo evaluations demonstrated that the fabricated GelMA-GelDopa-Sr hydrogel significantly promoted fibroblast proliferation (assessed by CCK-8 and live/dead cell staining assays), accelerated cell migration (assessed by scratch and transwell assays), and promoted the formation of stable vascular networks (evaluated by tube formation experiments). In a full-thickness skin defect rat model, the GelMA-GelDopa-Sr hydrogel significantly upregulated levels of CD31 (an endothelial cell marker) and CD163 (a macrophage marker promoting regeneration), indicating that the hydrogel enhanced angiogenesis and regulated the immune environment, which accelerated wound healing. This study provides a promising approach to designing multifunctional hydrogels that overcome the challenges of inflammation and insufficient vascularization during skin tissue regeneration.