Reconstructing the ischemic osteogenic microenvironment through hierarchical scaffolds orchestrating Mg2+ signaling and neuropilin-1-mediated angiogenesis

Zijie Pei; Haojing Xu; Piqian Zhao; Ya Wen; Ze Zhang; Liangkun Huang; Mengyu Wang; Bo Peng; Liangyuan Wen; Peng Wen; Fengpo Sun

doi:10.1016/j.bioactmat.2026.02.031

Reconstructing the ischemic osteogenic microenvironment through hierarchical scaffolds orchestrating Mg²⁺ signaling and neuropilin-1-mediated angiogenesis

Bioact Mater. 2026 Mar 26:62:738-758. doi: 10.1016/j.bioactmat.2026.02.031. eCollection 2026 Aug.

Authors

Zijie Pei^{1

2}, Haojing Xu³, Piqian Zhao⁴, Ya Wen⁵, Ze Zhang¹, Liangkun Huang^{1

2}, Mengyu Wang^{1

2}, Bo Peng³, Liangyuan Wen¹, Peng Wen³, Fengpo Sun¹

Affiliations

¹ Department of Orthopedics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, China.
² Peking Union Medical College, China.
³ State Key Laboratory of Clean and Efficient Turbomachinery Power Equipment, Department of Mechanical Engineering, Tsinghua University, China.
⁴ Department of Orthopedics, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, China.
⁵ Capital Medical University School of Biomedical Engineering, China.

Abstract

Ischemic bone defects remain a major challenge in bone tissue engineering, primarily due to insufficient angiogenesis caused by severely compromised local blood supply. Here, we develop a bioactive implant that mechanistically amplifies magnesium-induced angiogenesis by integrating pro-angiogenic liposomes encapsulating neuropilin-1 (NRP-1) with a 3D-printed magnesium (Mg) alloy porous scaffold. The customized Mg scaffold matched defect morphology, provided reliable mechanical support, and featured interconnected micropores to facilitate bone ingrowth and integration. Composite surface coatings simultaneously moderated the rapid degradation of Mg and supplied abundant binding sites for NRP-1-loaded lipos, enabling coordinated regulation of angiogenesis and osteogenesis. In an ischemic bone defect model, the scaffold significantly enhanced neovascularization, bone formation density, and interfacial osseointegration. Mechanistically, the controlled release of Mg²⁺ promoted osteogenic differentiation and upregulated Vascular Endothelial Growth Factor A (VEGFA) expression, establishing a biochemical foundation for angiogenesis. Importantly, the incorporation of NRP-1 further potentiated VEGFA-VEGFR2 signaling, markedly amplifying angiogenic efficacy. Collectively, this work identifies an Mg/NRP-1-mediated coupling axis of osteogenesis and angiogenesis, providing a mechanistically informed strategy for bone regeneration in severely ischemic microenvironments.

Keywords: Angiogenesis; Ischemic bone defect; Magnesium scaffold; Neuropilin-1; Osteogenesis.