Mechanisms underlying biomaterial-regulated macrophage polarization in bone tissue engineering: From interface sensing to immune microenvironment remodeling.

Traditional biomaterials commonly trigger a foreign body reaction after implantation, leading to fibrous encapsulation and poor osseointegration. Advances in osteoimmunology have enabled contemporary tissue engineering to redefine biomaterials as active modulators of the osteoimmune microenvironment rather than as passive scaffolds. At the core of this reconceptualization is the targeted control of macrophage polarization to establish an immune environment conducive to bone repair. The plasticity of macrophages reflects the dynamic balance between the M1 pro-inflammatory and M2 pro-regenerative states; this plasticity ultimately determines regenerative outcomes. This review offers a conceptual four-dimensional regulatory framework that extends from extracellular interface sensing to intracellular genome remodeling and progresses from material properties and signaling cascade stratification to mitochondrial reprogramming and non-coding RNA (ncRNA) networks. Within this framework, material interfaces function as platforms for activating, transducing, and integrating bioactive signals. These signals can be externally modulated to reshape intracellular metabolic organization and sustain mitochondrial function. At a finer regulatory tier, ncRNAs modulate signaling pathways to achieve the precise post-transcriptional regulation of gene expression. Central to this model is a bidirectional, spatiotemporally dynamic feedback loop linking intrinsic cellular machinery with extrinsic material systems. Linking material design parameters to dynamic biological responses lays a conceptual foundation for the development of biomaterials capable of the adaptive and programmable regulation of the osteoimmune microenvironment. Future research may focus on the precise temporal control of M1/M2 phenotypic switching and the coordinated presentation of multiple signals, thereby advancing the development of next-generation immunomodulatory biomaterials for bone repair.