Scaffold-free cell sheet therapies: clinical advances, global approval landscapes, and strategic directions to address regenerative medicine barriers.
Lin An A, Yuan Shengmeng S, Liang Cheng C, Huo Fangjun F et al.
Cell sheet therapy has emerged as a transformative technology in regenerative medicine, providing scaffold-free constructs that preserve cell-cell junctions and extracellular matrix components. Compared with traditional cell delivery methods, cell sheets enable improved engraftment, survival, and integration after transplantation. Recent years have witnessed remarkable progress in clinical translation, with several products approved in Japan, the United States, and South Korea. This review summarizes the current landscape of cell sheet therapies approved worldwide, focusing on their fabrication technologies, cell sources, and clinical indications. We highlight representative products such as JACE®, Nepic®, Ocural®, JACEMIN®, HeartSheet®, Epicel®, Holoderm®, Kaloderm®, and ZEVASKYN™, emphasizing their technological foundations and regulatory trajectories. Advances in temperature-responsive culture surfaces, closed culture devices, and automated sheet manipulation have facilitated large-scale and standardized manufacturing. Furthermore, the establishment of cell banks, donor eligibility screening, and Good Manufacturing Practice (GMP)-compliant processes ensure product consistency and safety. In parallel, regulatory frameworks in Japan, the United States, and South Korea have shaped the development paths of autologous and allogeneic products, with different strategies for approval, reimbursement, and long-term monitoring. Cell sheet-based regenerative therapies have already demonstrated clinical and commercial viability, offering novel treatment options for burns, ocular diseases, vitiligo, and cardiac conditions. Despite encouraging outcomes, challenges remain in vascularization, large-scale production, cost-effectiveness, and equitable patient access. Continued progress will depend on addressing biological limitations, optimizing manufacturing logistics, and harmonizing international regulations. Collectively, cell sheet therapies represent a pivotal step toward broader adoption of regenerative medicine in routine clinical practice.