Three-dimensional niche-like porous structure locoregionally regulating macrophage immunosenescence rejuvenates aged bone repair.

Abstract

The decreased reconstruction potential of aging bone marrow mesenchymal stem cells (BMMSCs) fails to resist compromised bone healing, and strategies to remodel the regeneration capacity of senescent BMMSCs are urgently needed. A depletion of ARG1⁺ macrophages in aging murine exacerbates the impaired reconstructive functionality of BMMSCs, eventually becomes a critical obstacle for aged osteointegration. Herein, we fabricated a niche-like multiscale porous Titanium (p-Ti) implant using a vapor-phase-assisted alloying-dealloying strategy for in-situ manipulating the regenerative repair potential of BMMSCs while alleviating immunosenescence during bone reconstruction. This versatile method can be used to fabricate a porous surface layer on commercial implants with complex geometries. As benchmarked with commercial Ti, the <i>in vitro</i> and <i>in vivo</i> results of rabbits and rats show our niche-like p-Ti efficiently promotes BMMSCs to engender an osteogenic phenotype and attune the areas of bone defect. Moreover, niche-like multiscale porous structure yields rejuvenated ARG1⁺ macrophages in tandem with BMMSCs osteogenic differentiation at the bone-implant interface, modulating the immunosenescence, and synergistically promoting the osteointegration. Our findings establish that the macrophage can be re-engineered to be youthful for maintaining immune homeostasis, thereby providing a reversible treatment strategy for bone reconstruction of old people with broad applications in other senescence-related diseases.