Electrohydrodynamically printed microfibrous scaffolds with different pore sizes modulate macrophage polarization and foreign body reaction to enhance bone regeneration

Abstract

Foreign body reaction (FBR) is a major obstacle to effective osseointegration in bone defect repair. The pore size of scaffolds is a key determinant of FBR; however, its impact on FBR remains controversial, with limited in vivo evidence available. In this study, electrohydrodynamically printed polycaprolactone scaffolds with pore sizes of 100 μm, 200 μm, and 300 μm were fabricated to investigate their effects on macrophage polarization, FBR, and bone regeneration. In vitro experiments showed that the 300 μm group promoted M2 polarization of macrophages, reduced tumor necrosis factor-alpha expression (0.71-fold and 0.81-fold relative to the 100 μm and 200 μm groups, respectively), and increased transforming growth factor-beta 1 expression (1.39-fold and 1.19-fold, respectively), thereby enhancing osteogenic gene expression in MC3T3-E1 cells (Runx2, Col1, and Ocn). Finite element analysis and transcriptomics sequencing revealed that pore size-dependent changes in scaffold stiffness modulate Piezo1 activation, influencing macrophage polarization. In vivo experiments showed that the 300 μm group exhibited the thinnest fibrous capsule (0.78-fold and 0.79-fold relative to the 100 μm and 200 μm groups, respectively), demonstrated enhanced angiogenesis, and achieved better bone regeneration, with increased bone volume/total volume and bone mineral density. These findings indicate that 300 μm pore-sized scaffolds promote bone regeneration by modulating macrophage polarization and attenuating FBR, providing a basis for optimized scaffold design and clinical translation in bone defect repair.

 

Keywords

Bone regeneration / Electrohydrodynamic printing / Foreign body reaction / Polarization / Pore size

Funding

This work was financially supported by the National Key R&D Program of China (No. 2024YFB4607800), the National Natural Science Foundation of China (52125501, 52405325, 82072522), the Cross training Support Project for Doctoral Students at Xi’an Jiaotong University (IDT2315), the Key Research Project of Shaanxi Province (2021LLRH- 08), the Program for Innovation Team of Shaanxi Province (2023-CX-TD-17), the Postdoctoral Fellowship Program of CPSF (GZB20230573), the Postdoctoral Project of Shaanxi Province (2023BSHYDZZ30), and the Fundamental Research Funds for the Central Universities (xzy012023022).

Conflict of Interest

Jiankang He serves as the Editorial Board Member of the journal, but did not in any way involve in the editorial and peer-review process conducted for this paper, directly or indirectly. Other authors declare they have no competing interests.

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