Inflammation environment-adaptive matrix confinement for three-dimensional modulation of macrophages
The balance of macrophages in immune reaction is crucial to tissue repair. Despite some studies, responsive surfaces for immunomodulation regulated macrophage phenotypes by external stimuli, there would be limit to 2D and manual intervention. Here, to address these limitations, we developed an inflammation environment-responsive macrophage-laden hydrogel-filled scaffold for investigating the impact of matrix confinement on macrophages phenotypes adaptively. We fabricated gelatin scaffolds with controllable pore size and found that macrophages within smaller pores tend to anti-inflammation phenotype. We prepared poly (vinyl alcohol) (PVA)-based hydrogels which were crosslinked with phenylboronic acid (PBA) -based linkers. The hydrogels have the abilities of shear thinning, cell lading, and ROS-sensitive degradation. Then, a macrophages-laden hydrogel-filled scaffold was fabricated by filling the hydrogels into the porous scaffold under vacuum. With the degradation of the hydrogels under the overexpression of ROS in an inflammation environment, the macrophages were transferred from a state with strong matrix confinement to weaker ones. Meanwhile, with the change of matrix confinement, macrophages upregulated the expressions of Arg-1 and IL-10, and downregulated the expressions of IL-1β, TNF-α, and IL-6, indicating the polarization toward to anti-inflammatory phenotype. The inflammation environment-adaptive modulation of macrophages phenotypes in 3D provides a smart and biomimetic strategy for immunomodulation and regenerative medicine.
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