Induced Pluripotent Stem Cell‐Derived Small‐Diameter Vascular Grafts: Scaffold Design, Immune Engineering, and Clinical Translation

Abstract

Small‐diameter vascular grafts (≤ 6 mm) remain a critical unmet need in cardiovascular surgery, as autologous vessels are unavailable in up to 30% of patients requiring coronary or peripheral bypass. Induced pluripotent stem cells (iPSCs) have emerged as a transformative cell source for tissue‐engineered vascular grafts (TEVGs), offering unlimited self‐renewal, patient‐specific or universal donor potential, and the capacity to generate all vascular cell lineages. Recent breakthroughs—including iPSC‐derived grafts achieving 100% patency in allogeneic primate models and the first United States Food and Drug Administration (FDA) approval of an acellular tissue‐engineered vessel (SYMVESS, December 2024)—signal that clinical translation is accelerating. This review provides a comprehensive synthesis of the iPSC‐to‐graft pipeline, encompassing vascular cell differentiation protocols, biomaterial scaffold design, immune engineering strategies for universal grafts, bioreactor maturation, preclinical evaluation, and the evolving clinical‐regulatory landscape. We critically evaluate how the convergence of clustered regularly interspaced short palindromic repeats (CRISPR)‐based immune editing, advanced biomaterials, and scalable manufacturing is reshaping the field toward off‐the‐shelf vascular grafts. Finally, we identify remaining challenges in long‐term patency, thrombogenicity, and manufacturing scalability, and propose a translational roadmap for the next decade.