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Background <p>Osteoinductive biomaterials hold promise for repairing critical-size bone defects, yet the mechanisms underlying materials-instructed osteoinduction (MIOI) remain unclear. Macrophages are central, and local liposomal clodronate (LipClod) typically suppresses osteogenesis. Whether systemic LipClod modulates MIOI is unknown. We investigated the effect of intraperitoneal (i.p.) LipClod on ectopic osteoinduction.</p> Methods <p>Male FVB mice received subcutaneous β-tricalcium phosphate (TCPs) scaffolds and a single i.p. LipClod dose 1&#xa0;day after implantation; vehicle liposomes served as controls (<i>n</i> = 5 per group; 10 µL/g). Recombinant macrophage colony-stimulating factor (M-CSF; 0.5–2&#xa0;µg/mL; 100 µL per pocket) was injected locally, with contralateral pockets receiving PBS. Outcomes were assessed by histology, immunohistochemistry, RT-qPCR, flow cytometry.</p> Results <p>Intraperitoneal LipClod paradoxically enhanced TCPs-induced ectopic osteogenesis at 8 weeks. Following i.p. LipClod administration, the number of circulating monocytes in peripheral blood was increased. Concurrently, expansion of the monocyte–macrophage population at the implantation site was observed, accompanied by increased recruitment of mesenchymal stem cells (MSCs). In addition, local application of M-CSF further enhanced macrophage infiltration and significantly augmented osteogenesis.</p> Conclusions <p>Collectively, these findings demonstrate that i.p. LipClod alters the osteogenic outcome of TCPs-induced ectopic bone formation. Systemic immune modulation is associated with changes in monocyte–macrophage dynamics and mesenchymal stem cell recruitment at the implantation site. These observations underscore the importance of immune regulation in materials-instructed osteoinduction and suggest that immune-targeted strategies may be considered to enhance the performance of osteoinductive biomaterials.</p>

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Intraperitoneal clodronate liposomes remodel the local macrophage niche and potentiate biomaterial-induced osteoinduction

  • 期刊论文

  • 发表日期：

    2026年2月9日

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  • Wei Cao,
  • Zhiqiao Hu,
  • Xiaodong Guo,
  • Mingzheng Li,
  • Zhangling Nie,
  • Yue Wang,
  • Chengen Li,
  • Wenting Qi,
  • Yu Xiao,
  • Chongyun Bao

摘要

Background

Osteoinductive biomaterials hold promise for repairing critical-size bone defects, yet the mechanisms underlying materials-instructed osteoinduction (MIOI) remain unclear. Macrophages are central, and local liposomal clodronate (LipClod) typically suppresses osteogenesis. Whether systemic LipClod modulates MIOI is unknown. We investigated the effect of intraperitoneal (i.p.) LipClod on ectopic osteoinduction.

Methods

Male FVB mice received subcutaneous β-tricalcium phosphate (TCPs) scaffolds and a single i.p. LipClod dose 1 day after implantation; vehicle liposomes served as controls (n = 5 per group; 10 µL/g). Recombinant macrophage colony-stimulating factor (M-CSF; 0.5–2 µg/mL; 100 µL per pocket) was injected locally, with contralateral pockets receiving PBS. Outcomes were assessed by histology, immunohistochemistry, RT-qPCR, flow cytometry.

Results

Intraperitoneal LipClod paradoxically enhanced TCPs-induced ectopic osteogenesis at 8 weeks. Following i.p. LipClod administration, the number of circulating monocytes in peripheral blood was increased. Concurrently, expansion of the monocyte–macrophage population at the implantation site was observed, accompanied by increased recruitment of mesenchymal stem cells (MSCs). In addition, local application of M-CSF further enhanced macrophage infiltration and significantly augmented osteogenesis.

Conclusions

Collectively, these findings demonstrate that i.p. LipClod alters the osteogenic outcome of TCPs-induced ectopic bone formation. Systemic immune modulation is associated with changes in monocyte–macrophage dynamics and mesenchymal stem cell recruitment at the implantation site. These observations underscore the importance of immune regulation in materials-instructed osteoinduction and suggest that immune-targeted strategies may be considered to enhance the performance of osteoinductive biomaterials.