The evaluation of functional small intestinal submucosa for abdominal wall defect repair in a rat model: Potent effect of sequential release of VEGF and TGF-β1 on host integration

Ineffective vessel penetration and extracellular matrix (ECM) remodeling are responsible for the failure of porcine small intestinal submucosa (SIS)-repaired abdominal wall defects. Combined growth factors could be used as directing signals in a nature-mimicking strategy to improve this repair through mesh functionalization. In this work, vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF-β1) were incorporated into a silk fibroin membrane via coaxial aqueous electrospinning to exploit their benefits of biological interactions. The membrane was sandwiched into the SIS bilayer as a functional mesh to repair partial-thickness defects in a rat model. Membrane characterization demonstrated that the core-shell structure ensured the independent distribution and sequential release of two regulators and protection of their bioactivities, which were confirmed by cell viability and protein expression. The mesh was further assessed to facilitate vasculature formation and collagen secretion in vitro, and exhibited better host integration than VEGF- or TGF-β1-containing mesh and developed reinforced mechanical properties compared with the VEGF-containing mesh after 28 days in vivo. Determination of the underlying biological interactions revealed that rapid VEGF release promotes angiogenesis and collagen secretion but initially potentiates the inflammatory response. Sustained TGF-β1 release at relatively low concentrations promoted VEGF for vessel permeation and maturation and steadily induced ECM remodeling under milder foreign body reactions. The functionalization of SIS improves repair by sufficient integration with timely remodeling and helps elucidate the related regulatory interactions.