The strategies concerning modification of the complex immune pathological inflammatory environment during acute spinal cord injury remain oversimplified and superficial. Inspired by the acidic microenvironment at acute injury sites, a functional pH-responsive immunoregulation-assisted neural regeneration strategy was constructed. With the capability of directly responding to the acidic microenvironment at focal areas followed by triggered release of the IL-4 plasmid-loaded liposomes within a few hours to suppress the release of inflammatory cytokines and promote neural differentiation of mesenchymal stem cells in vitro, the microenvironment-responsive immunoregulatory electrospun fibers were implanted into acute spinal cord injury rats. Together with sustained release of nerve growth factor (NGF) achieved by microsol core-shell structure, the immunological fiber scaffolds were revealed to bring significantly shifted immune cells subtype to down-regulate the acute inflammation response, reduce scar tissue formation, promote angiogenesis as well as neural differentiation at the injury site, and enhance functional recovery in vivo. Overall, this strategy provided a delivery system through microenvironment-responsive immunological regulation effect so as to break through the current dilemma from the contradiction between immune response and nerve regeneration, providing an alternative for the treatment of acute spinal cord injury.

The stiffness of the extracellular matrix (ECM) plays an important role in regulating the cellular programming. However, the mechanical characteristics of ECM affecting cell differentiation are still under investigated. Herein, we aimed to study the effect of ECM substrate stiffness on macrophage polarization. We prepared polyacrylamide hydrogels with different substrate stiffness, respectively. After the hydrogels were confirmed to have a good biocompatibility, the bone marrow-derived macrophages (BMMs) from mice were incubated on the hydrogels. With simulated by the low substrate stiffness, BMMs displayed an enhanced expression of CD86 on the cell surface and production of reactive oxygen species (ROS) in cells, and secreted more IL-1β and TNF-α in the supernatant. On the contrary, stressed by the medium stiffness, BMMs expressed more CD206, produced less ROS, and secreted more IL-4 and TGF-β. In vivo study by delivered the hydrogels subcutaneously in mice, more CD68+CD86+ cells around the hydrogels with the low substrate stiffness were observed while more CD68+CD206+ cells near by the middle stiffness hydrogels. In addition, the expressions of NIK, phosphorylated p65 (pi-p65) and phosphorylated IκB (pi-IκB) were significantly increased after stimulation with low stiffness in BMMs. Taken together, these findings demonstrated that substrate stiffness could affect macrophages polarization. Low substrate stiffness promoted BMMs to shift to classically activated macrophages (M1) and the middle one to alternatively activated macrophages (M2), through modulating ROS-initiated NF-κB pathway. Therefore, we anticipated ECM-based substrate stiffness with immune modulation would be under consideration in the clinical applications if necessary.

Bone metabolism is tightly regulated by the immune system. Accelerated bone destruction is observed in many bone diseases, such as rheumatoid arthritis, fracture, and particle-induced osteolysis. These pathological conditions are associated with inflammatory responses, suggesting the contribution of inflammation to bone destruction. Macrophages are heterogeneous immune cells and are polarized into the proinflammatory M1 and antiinflammatory M2 phenotypes in different microenvironments. The cytokines produced by macrophages depend on the macrophage activation and polarization. Macrophages and macrophage-derived cytokines are important to bone loss in inflammatory bone disease. Recent studies have shown that macrophages can be detected in bone tissue and interact with bone cells. The interplay between macrophages and bone cells is critical to bone formation and repair. In this article, we focus on the role of macrophages in inflammatory bone diseases, as well as discuss the latest studies about macrophages and bone formation, which will provide new insights into the therapeutic strategy for bone disease.