Functionalized Silk Vascular Grafts with Decellularized Human Wharton's Jelly Improves Remodeling via Immunomodulation in Rabbit Jugular Vein

Abstract Cell‐free polymeric tissue‐engineered vascular grafts (TEVGs) have shown great promise towards clinical translation; however, their limited bioactivity and remodeling ability challenge this cause. Here, a novel cell‐free bioresorbable small diameter silk TEVG system functionalized with decellularized human Wharton's jelly (dWJ) matrix is developed and successfully implanted as interposition grafts into rabbit jugular vein. Implanted TEVGs remain patent for two months and integrate with host tissue, demonstrating neo‐tissue formation and constructive remodeling. Mechanistic analysis reveals that dWJ matrix is a reservoir of various immunomodulatory cytokines (Interleukin‐8, 6, 10, 4 and tumor necrosis factor alpha (TNF‐ α )), which aids in upregulating M2 macrophage‐associated genes facilitating pro‐remodeling behavior. Besides, dWJ treatment to human endothelial cells upregulates the expression of functional genes (cluster of differentiation 31 (CD31), endothelial nitric oxide synthase (eNOS), and vascular endothelial (VE)‐cadherin), enables faster cell migration, and elevates nitric oxide (NO) production leading to the in situ development of endothelium. The dWJ functionalized silk TEVGs support increased host cell recruitment than control, including macrophages and vascular cells. It endows superior graft remodeling in terms of a dense medial layer comprising smooth muscle cells and elevates the production of extracellular matrix proteins (collagen and elastin). Altogether, these findings suggest that dWJ functionalization imitates the usefulness of cell seeding and enables graft remodeling.