Immunized Microspheres Engineered Hydrogel Membrane for Reprogramming Macrophage and Mucosal Repair

Abstract The “double‐edged sword” effect of macrophages under the influence of different microenvironments determines the outcome and prognosis of tissue injury. Accurate and stable reprogramming macrophages (Mφ) are the key to rapid wound healing. In this study, an immunized microsphere‐engineered GelMA hydrogel membrane is constructed for oral mucosa treatment. The nanoporous poly(lactide‐co‐glycolide) (PLGA) microsphere drug delivery system combined with the photo‐cross‐linkable hydrogel is used to release the soybean lecithin (SL)and IL‐4 complexes (SL/IL‐4) sustainedly. In this way, it is realized effective wound fit, improvement of drug encapsulation, and stable triphasic release of interleukin‐4 (IL‐4). In both in vivo and in vitro experiments, it is demonstrated that the hydrogel membrane can reprogram macrophages in the microenvironment into M2Mφ anti‐inflammatory types, thereby inhibiting the local excessive inflammatory response. Meanwhile, high levels of platelet‐derived growth factor (PDGF) secreted by M2Mφ macrophages enhanced neovascular maturation by 5.7‐fold, which assisted in achieving rapid healing of oral mucosa. These findings suggest that the immuno‐engineered hydrogel membrane system can re‐modulating the biological effects of Mφ, and potentiating the maturation of neovascularization, ultimately achieving the rapid repair of mucosal tissue. This new strategy is expected to be a safe and promising immunomodulatory biomimetic material for clinical translation.