Nanopeptides-Loaded Electro-Assembled Oriented Collagen Matrix for the Synergistically Promotes Early Angiogenesis in Tendon Healing

Angiogenesis is a critical process in the early stages of tendon healing but is always limited by its avascular structure, thus impairing effective healing. Nanopeptides targeting endogenous vascular endothelial growth factor (VEGF) presented a promising strategy for promoting early angiogenesis in tendon healing. In this study, we introduced a nanoscale electro-assembly technique to kinetically control the collagen assembling to form VEGF-binding protein (VEGF-BP) and PR1P-loaded oriented collagen matrix (BP/P Col) for tendon healing. The specific binding of VEGF-BP and PR1P to endogenous VEGF mediated the proangiogenic effects during the early stages of repair. In vitro cell experiments showed that BP/P Col could promote human umbilical vein endothelial cell migration and tube formation as well as new vessel formation in chick chorioallantois. In a rabbit model of tendon defect, it increased vascular area and new vessel formation within the first 2 weeks. Additionally, multiomics analysis further revealed the potential mechanism of BP/P Col in promoting early angiogenesis was to modulate the macrophage-regulated VEGF expression, providing positive feedback for early angiogenesis. This process induced the organized collagen structure along the oriented collagen matrix, which ultimately facilitated rapid tendon healing during the early stage. Overall, this study demonstrated that BP/P Col, through the efficient loading of VEGF-BP and PR1P, exerted a synergistic enhancement effect on endogenous VEGF. It could not only accelerate early angiogenesis but also promote subsequent rapid and functional tendon healing, offering a promising treatment strategy for tendon injuries.