A pH-triggered antioxidative stem cell spheroid platform restores paracrine signaling to enhance osteoporotic bone regeneration

In osteoporotic bone defects, bone marrow mesenchymal stem cells (BMSCs) play a pivotal role in tissue regeneration by orchestrating the local microenvironment through both differentiation and paracrine signaling. However, persistent pathological stimuli such as oxidative stress significantly impair their functionality, while limited cell survival and homing efficiency at the defect site remain major obstacles hindering therapeutic efficacy. To overcome these issues, we designed a stem cell delivery system using microfluidic techniques, in which microspheres were modified with resveratrol. This system leveraged a sustained-release liposomal formulation of resveratrol to enhance the antioxidant resilience of BMSCs. Simultaneously, the platform created a three-dimensional porous microenvironment using pH-responsive microspheres, which supported the maintenance of paracrine activity and promoted osteogenic differentiation of transplanted cells, thereby accelerating bone regeneration. In vitro experiments demonstrated that this system significantly enhanced mineralized nodule formation, accompanied by marked upregulation of osteogenesis-related genes and proteins including RUNX2, COL-1, and SP7. Furthermore, BMSCs exhibited increased secretion of key paracrine factors such as VEGFA, thereby improving proangiogenic support to endothelial cells. In vivo study, we employed an osteoporotic rat model with femoral bone defects, micro-CT imaging and multimodal histological analyses confirmed that the proposed platform markedly facilitated new bone formation and structural tissue reconstruction. Collectively, this study proposes a synergistic strategy for osteoporotic bone repair, providing a new approach to cell therapy design.