Piezoelectric-IL-4 programmed regulation of immuno-microenvironment-induced mesenchymal stem cell recruitment and differentiation for bone regeneration

In craniomaxillofacial bone defect repair, both classically (M1) and alternatively (M2) activated macrophages coexist and are crucial to the repair process. However, recent studies focus on regulating macrophage M2 repolarization to promote osteogenic differentiation, overlooking the significant role of the M1 phenotype in bone marrow-derived mesenchymal stem cells (BMSCs) recruitment. Consequently, this research reports a programmed macrophage polarization therapy that is based on natural immunoregulatory. First, ultrasound-driven piezoelectric potential from β-phase polyvinylidene fluoride (β-PVDF) film activates M1 polarization. In vitro results show that the M1 phenotype exhibits a remarkable ability to recruit BMSCs and promote osteogenic differentiation. Subsequently, the rapid and potent M2 repolarization was achieved after interleukin-4 (IL-4) treatment, which promoted osteogenic differentiation. In vivo results indicate that the piezo-IL-4 programmed immunomodulatory system effectively facilitated the rapid repair of bone defects. This study first combined ultrasound piezoelectricity with IL-4 to promote programmed regulation of macrophage polarization and promote BMSCs recruitment and differentiation. This approach offers an effective strategy based on natural immunoregulatory for modulating the immune microenvironment, which is essential for the design and development of bone repair materials, provides a significant theoretical foundation for the optimisation of immune regulation strategies in the field of bone tissue engineering.