Development‐based In Vivo Bioreactor Strategy for Challenging Senescent Bone Reconstruction

ABSTRACT Critical segmental bone defects in elderly patients pose a formidable clinical challenge due to limited autograft availability, senescent bone dysfunction, and compromised healing from fibrous tissue invasion. Here, we present a development‐based in vivo bioreactor strategy wherein BMP‐2‐loaded biomaterials trigger the body's intrinsic developmental programs, using the organism as a bioreactor to engineer bone. Distinct from classical developmental engineering, this in vivo bioreactor‐derived bone (vBR‐Bone) recapitulates native osseous architecture, including vasculature, cortical bone, trabeculae, and bone marrow niche. In aged murine models, the vBR‐Bone exhibits a rejuvenated restoration of bone bioactivity lost in aging, with reduced senescence, elevated remodeling, and improved stem cell functionality. Capitalizing on its restored remodeling capacity of high bone turnover, the vBR‐Bone fragments enclosed in an asymmetric biomimetic periosteum achieved 6‐week repair of critical‐sized 1/3 femoral shaft segmental defects. Through a “compartmentalized” approach that partitions the defect into manageable fragments, vBR‐Bone progressively remodeled and integrated into functional trabecular bone, ultimately restoring bone mineral density, volume, and microstructure in defects of aged mice. The biomimetic periosteum inhibits fibrous invasion while permitting vascular ingrowth, thereby creating a space for regeneration. Mechanistically, the multifactors within vBR‐Bone reconstitute a bone‐remodeling microenvironment, wherein matrix‐released TGF‐β1 activates the PI3K/AKT/mTOR signaling axis via TRAF6‐dependent ubiquitylation to promote robust osteogenesis. This strategy overcomes autograft shortage and senescence‐associated dysfunction, offering a clinically translatable solution for critical age‐related segmental bone defects.