Elevator‐Like Hollow Channels in Porous Scaffolds Accelerate Vascularized Bone Regeneration via NETs‐Fibrin‐Mediated Macrophage Recruitment

TL;DR

Hollow channels in bone scaffolds speed up blood vessel and bone growth by guiding immune cells and proteins to form a supportive network.

Contribution

The study reveals a novel immunomodulatory mechanism of hollow-channel scaffolds in vascularized bone regeneration.

Findings

Hollow channels enable rapid infiltration of fibrinogen and platelets, initiating a biological cascade involving neutrophils and macrophages.

The NETs-fibrin matrix promotes directional vascular invasion and enhances angiogenic-osteogenic coupling.

The strategy significantly improves bone regeneration and offers a clinically translatable solution.

Abstract

Developing viable tissue‐engineered constructs for large‐scale bone defects remains a fundamental challenge due to the difficulty of establishing adequate vascular networks. Channel structures act as biological elevators, rapidly promoting vascularization in scaffold materials. However, the underlying mechanisms driving this accelerated process remain unclear. In this study, porous silk fibroin (SF) scaffolds with hollow channels are engineered to investigate their vascularization‐accelerating mechanisms. It is demonstrated that the channels enable the rapid infiltration of fibrinogen and platelets. This initiates a sequential biological cascade involving neutrophil recruitment, the formation of neutrophil extracellular traps (NETs), and subsequent macrophage migration. This coordinated process generates a provisional yet bioactive matrix that promotes directional vascular invasion. Leveraging the architecture of the hollow channels, a biomimetic system is developed that rapidly establishes provascular microenvironments featuring macrophage‐populated NETs‐fibrin networks through blood clot preloading. This combined structural and biological strategy enhances angiogenic–osteogenic coupling through spatially controlled bone morphogenetic protein‐2 (BMP‐2) presentation, significantly improving bone regeneration and providing a clinically translatable solution for vascularized bone regeneration. This study not only elucidates the mechanistic link between scaffold architecture and host immune response, but also establishes a novel paradigm for biomaterial design in hard tissue engineering.

This study demonstrates that how hollow‐channel scaffolds promote vascularized bone regeneration via an immunomodulatory mechanism. The channel structures facilitate the formation of a neutrophil extracellular traps‐fibrin scaffold that recruits vascular endothelial growth factor A (VEGF‐A)‐secreting M2 macrophages to drive angiogenesis. Combining this approach with autologous blood clot and localized BMP‐2 release, the strategy significantly enhances angiogenic–osteogenic coupling, improving bone regeneration.

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