Barriers to clinical translation of small-diameter tissue-engineered vascular grafts in peripheral reconstruction.

Objective: To provide a comprehensive review of small-diameter (<6 mm) tissue-engineered vascular grafts for peripheral vascular applications, examining mechanisms of graft failure, emerging biomaterial and fabrication strategies, and key considerations for clinical translation. Methods: A comprehensive literature review was performed using PubMed, Scopus, and Web of Science through January 2026. Studies were selected on the basis of relevance to peripheral vascular surgery, with emphasis on preclinical and clinical outcomes, biomaterial performance, fabrication approaches, and translational considerations, prioritizing recent studies while including seminal work. Results: Despite over four decades of research, small-diameter synthetic grafts continue to demonstrate poor patency in infrainguinal bypass, with expanded polytetrafluoroethylene and Dacron achieving 25% to 50% patency at 5 years compared with 60% to 80% for autologous saphenous vein in below-the-knee applications. Up to 20% of patients experience graft thrombosis within 6 months, with early failure associated with increased amputation rates. Graft failure is driven by acute thrombosis, intimal hyperplasia related to compliance mismatch and chronic inflammation, and incomplete endothelialization. Emerging strategies include multilayered scaffold architectures, hybrid biomaterials incorporating extracellular matrix components and bioactive molecules, advanced manufacturing techniques such as melt electrowriting, and immunomodulatory approaches promoting constructive remodeling. Recent preclinical studies report high patency rates approaching 100%, with complete endothelialization and minimal intimal hyperplasia in animal models. However, translation remains limited by inadequate study design, with median graft lengths of ∼5 cm and follow-up periods of ∼56 days, which do not reflect clinical scenarios where grafts often exceed 30 cm. Conclusions: Clinically viable small-diameter tissue-engineered vascular grafts for peripheral vascular reconstruction will require integrated optimization of hemocompatibility, endothelialization, biomechanical properties, and inflammatory response. Advances in biomaterials, manufacturing technologies, and mechanistic understanding suggest that grafts meeting clinical benchmarks may be achievable, but progress will depend on rigorous preclinical evaluation using clinically relevant models and end points.