Synergistic Effect of Topographical Cue and Local Drug Delivery: An Axially-Aligned AM80-Loaded Graft for Preventing Intimal Hyperplasia in Small-Diameter Vascular Grafts

Small-diameter vascular grafts (SDVGs) continue to present significant clinical challenges due to their poor long-term patency, which primarily results from incomplete endothelialization and intimal hyperplasia (IH). Inspired by the structure of natural blood vessels, this study developed a bilayered electrospun vascular graft. The inner layer consisted of axially aligned poly(L-lactide-co-ε-caprolactone) (PLCL)/silk fibroin (SF) nanofibers designed to guide the alignment and elongation of endothelial cells (ECs), thereby mimicking the natural endothelial architecture. The outer layer was composed of non-aligned PLCL/SF fibers incorporating mesoporous silica nanoparticles (MSNs) loaded with tamibarotene (AM80), a selective retinoic acid receptor α (RARα) agonist. The graft exhibited an aligned microstructure, excellent mechanical properties, and favorable compliance. In vitro studies demonstrated that AM80, at certain concentrations, selectively inhibited the proliferation and migration of vascular smooth muscle cells (VSMCs). Transcriptomic analysis further revealed that AM80 exerted its inhibitory effect on VSMCs by regulating the cell cycle. In vivo evaluation in a rat abdominal aorta implantation model confirmed that, compared to the control group, the graft showed superior patency at 1 and 3 months, accompanied by functional maturation of ECs, absence of significant intimal thickening, and favorable vascular remodeling. In summary, this bilayered graft integrates biomimetic structural design with sustained drug release to achieve long-term patency and offers a promising strategy for next-generation SDVG development.