Nanofiber, Microfiber, or Hybrid: Which Architecture Excels in Soft Tissue Reinforcement and Constructive Regeneration?

Despite extensive efforts, existing scaffolds for soft tissue reconstruction fail to simultaneously provide durable mechanical reinforcement and prevent fibrotic encapsulation while preserving endogenous tissue regeneration, as current antifibrotic strategies rely on solid or coated architectures that hinder tissue integration and compromise long-term performance. Here, we engineer three meshes composed of poly(ε-caprolactone)/polylactic acid nanofibers, microfibers, or their hybrid and evaluate their performance in vitro and in vivo using a subcutaneous implantation model in Sprague–Dawley rats to identify the fiber architecture that best resolves the fibrosis–regeneration trade-off. The hybrid meshes dissipate stress, reduce crack propagation, and enhance tensile strength (up to 38.2 ± 4.5 N) and tear resistance beyond current commercial products through microfiber reinforcement and a dual-network architecture, while recapitulating extracellular matrix-relevant structural cues. In vitro and in vivo studies revealed that the microfiber and hybrid meshes support deep, three-dimensional cell infiltration (>60% vs ∼5% in the nanofiber mesh), neovascularization, and uniform collagen deposition, achieving antifibrotic performance without compromising structural integrity. Our study suggests that increasing the fiber diameter enlarges the pore area and reveals a pore size threshold, where larger, interconnected pores (>100 μm2) enable robust early cellular infiltration and vascularization, promoting regenerative integration, whereas smaller pore architectures (<50 μm2) are associated with limited infiltration and increased fibrotic responses. Together, these results demonstrate that hybrid fiber meshes best balance mechanical reinforcement and regenerative integration, providing structural support while reducing fibrotic encapsulation and promoting constructive tissue remodeling.