4-octyl itaconate-functionalized dextran-polyethylene glycol hydrogel prevents postoperative peritoneal adhesion via regulating macrophage function and mesothelial differentiation.

Hydrogel barrier is considered to be a promising strategy to prevent postoperative peritoneal adhesion (PPA) formation. However, a simple physical barrier alone might not satisfactorily prevent adhesion. Herein, four-octyl itaconate (4-OI), a cell-permeable itaconate derivative with antiinflammatory and antioxidant properties, was encapsulated into micelles and then loaded into the dextran-polyethylene glycol hydrogel via the Schiff's base reaction between the aldehyde group of oxidized dextran and the amino group of four-arm polyethylene glycol amine (4-arm-PEG-NH2). The fabricated hydrogels exhibited excellent physico-chemical properties including good injectability, optimal gelation time adjustability, appropriate biodegradation rate, and desirable antiadhesive property, as well as excellent biocompatibility in vitro and in vivo. Furthermore, 4-OI micelles possessed antiinflammatory, antioxidant, mesothelial to mesenchymal transition (MMT) inhibition, and pro-healing abilities. Mechanistically, they could regulate macrophage function and mesothelial cell differentiation. Specifically, 4-OI micelles inhibited MMT differentiation of mesothelial cells via ROS-HIF-1α-EMT-TF pathway regulation. In the mouse PPA model, the physical antifouling barrier and the encapsulated bioactive 4-OI synergistically inhibited PPA formation. All of the performance made this 4-OI-functionalized antifouling hydrogel be a potential candidate as PPA prevention in clinical settings.