Inflammation environment-adaptive matrix confinement for three-dimensional modulation of macrophages†

The balance of macrophages in immune reactions is crucial for tissue repair. Despite some studies on responsive surfaces for immunomodulation regulation of macrophage phenotypes via external stimuli, 2D and manual interventions are limited. Herein, to address these limitations, we developed an inflammation environment-responsive macrophage-laden hydrogel-filled scaffold for investigating the impact of matrix confinement on macrophage phenotypes adaptively. We fabricated gelatin scaffolds with a controllable pore size and found that macrophages within smaller pores tended to have an anti-inflammation phenotype. We prepared poly(vinyl alcohol) (PVA)-based hydrogels crosslinked with phenylboronic acid (PBA)-based linkers. The hydrogels possessed shear-thinning, cell-loading, and ROS-sensitive-degradation abilities. Subsequently, a macrophage-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 that with a weaker one. Meanwhile, with the change in matrix confinement, the macrophages upregulated the expressions of Arg-1 and IL-10 and downregulated the expressions of IL-1β, TNF-α, and IL-6, indicating polarization toward the anti-inflammatory phenotype. The inflammation environment-adaptive modulation of macrophage phenotypes in 3D provides a smart and biomimetic strategy for immunomodulation and regenerative medicine.