Hierarchically Porous Implants Orchestrating a Physiological Viscoelastic and Piezoelectric Microenvironment for Bone Regeneration

The extracellular matrix microenvironment of bone tissue comprises several physiological cues. Thus, artificial bone substitute materials with a single cue are insufficient to meet the demands for bone defect repair. Regeneration of critical-size bone defects remains challenging in orthopedic surgery. Intrinsic viscoelastic and piezoelectric cues from collagen fibers play crucial roles in accelerating bone regeneration, but scaffolds or implants providing integrated cues have seldom been reported. In this study, it is aimed to design and prepare hierarchically porous poly(methylmethacrylate)/polyethyleneimine/poly(vinylidenefluoride) composite implants presenting a similar viscoelastic and piezoelectric microenvironment to bone tissue via anti-solvent vapor-induced phase separation. The viscoelastic and piezoelectric cues of the composite implants for human bone marrow mesenchymal stem cell line stimulate and activate Piezo1 proteins associated with mechanotransduction signaling pathways. Cortical and spongy bone exhibit excellent regeneration and integration in models of critical-size bone defects on the knee joint and femur in vivo. This study demonstrates that implants with integrated physiological cues are promising artificial bone substitute materials for regenerating critical-size bone defects.