Four-Synergy Piezoelectric Microspheres Based on Bone Self-Mineralization for Enhanced Bone Regeneration

The clinical treatment of irregular bone defects resulting from trauma, tumor resection, and infection remains a significant challenge. To address this issue while enhancing material applicability and bioactivity, this study pioneers the development of injectable piezoelectric bioactive poly(l-lactic acid) (PLLA) microspheres with time-controlled release functionality. These microspheres possess a unique internal three-dimensional network structure, are surface-modified with carboxymethyl cellulose (CMC), and are loaded with geniposide (GEN), achieving a quadruple synergistic effect encompassing structural support, biomimetic mineralization, electrical stimulation, and drug release. Specifically, the negatively charged CMC coating chelates Mg²⁺/Ca²⁺ ions in body fluids, significantly enhancing osseointegration through a biomimetic mineralization process. Following CMC modification, the zeta potential of the microspheres shifted from -9.9 mV to -32.27 mV, and the water contact angle decreased from 116° to 56°, markedly improving their stability and hydrophilicity. The 3D network scaffold generates rhythmic electrical stimulation via the piezoelectric effect, effectively promoting directed migration and differentiation of osteoblasts. Under ultrasonic activation, the peak cumulative drug release rate increased from 68.17% to 73.12%, while the 36 h closure rate in a cell scratch assay rose from 84.9% to 98.8%. The PLLA microspheres employ a piezoelectric-chemically coupled bioactive regulation model, offering an innovative solution to treating traumatic bone injuries.