Mechanoregulating HA-integrated anisotropic fibrous vessel promote AKT-sensitive and YAP-associated endothelial responses and improve regional lymphatic drainage in lymphedema.

Abstract

Secondary lymphedema, characterized by localized tissue swelling caused by lymphatic damage or dysfunction, remains a major clinical challenge that compromises quality of life. Current physical therapies provide only temporary relief, underscoring the need for effective regenerative strategies. Here, we report the fabrication of a micropatterned, small-diameter fibrous artificial lymphatic vessel incorporating hyaluronic acid (HA) via electrospinning to enhance lymphatic fluid transport. The engineered scaffold exhibits optimized mechanical properties and elicits favorable cellular responses through HA-mediated biochemical cues. Lymphatic endothelial cells (LEC) cultured on the scaffold show increased expression of lymphangiogenesis-related markers, including Prox1 and LYVE-1, accompanied by AKT activation and increased VEGF-C/VEGFR3-associated marker expression. The topographical features of the scaffold were also associated with altered YAP localization and increased lymphatic endothelial marker expression. In vivo implantation of the scaffold in a rat lymphedema model reduced ankle swelling and lymphatic retention across the surgically disrupted region toward an anatomically preserved drainage basin. Collectively, these findings suggest that HA-integrated fibrous lymphatic scaffolds represent a promising strategy for lymphedema treatment by synergistically engaging biochemical and biomechanical pathways associated with lymphatic repair and functional fluid transport.