ROS‐Responsive Hydrogel Enables Drug/Ion/Gas Co‐Delivery for Improving Survival of Multi‐Territory Perforator Flap in Diabetes

Abstract The multi‐territory perforator flap is a widely used microsurgical technique for repairing skin and tissue defects in diabetes. In the diabetic microenvironment, oxidative stress and inflammation from reactive oxygen species (ROS) lead to compromised blood supply to the flap, resulting in challenges for survival. The common complication of multi‐territory perforator flap is distal necrosis, which is primarily attributed to the Choke zone, the critical location characterized by delayed blood supply and inadequate neovascularization. To address this issue, a ROS‐responsive MSL@Z/G hydrogel is developed by encapsulating metformin‐Sr‐L‐Arg@ZIF‐90 (MSL@Z) nanoparticles into gelatine methacrylamide (GelMA), enabling the release of metformin, Sr ions and NO. The enhanced deformation resistance and compressive strength properties of the MSL@Z/G hydrogel make it suitable for tissue reconstruction and drug delivery. Additionally, the MSL@Z/G hydrogel exhibits antioxidant and anti‐inflammatory effects, thereby modulating the vascular microenvironment. In the dorsal multi‐territory perforated flap model of type 2 diabetic rats, the MSL@Z/G hydrogel demonstrates the ability to alleviate inflammation and promote neovascularization of the Choke zone, reducing distal necrosis, which holds great promise for improving flap survival in diabetes.