The Transformative Journey of Vascularized Composite Allotransplantation: Advances, Challenges, and Future Directions.

Vascularized composite allotransplantation (VCA) has emerged as a groundbreaking technique in reconstructive surgery, offering remarkable restoration of both function and aesthetics after severe tissue loss. However, despite its transformative clinical potential, widespread adoption remains limited because of the risk of rejection, the need for lifelong systemic immunosuppression and its associated risks, and donor-specific constraints unique to VCA, including morphological matching requirements and ethical and psychosocial considerations surrounding composite tissue donation. This review synthesizes findings from both basic research and clinical studies on VCA. We analyzed experimental studies using rodent and large-animal models and reviewed clinical outcomes in uterus, face, upper extremity, and abdominal wall transplants. In rodent models, costimulation blockade and interleukin-2/anti-interleukin-2 complexes significantly prolonged graft survival. Local therapies, such as tacrolimus-containing hydrogels and regulatory T cell-inducing microparticles, demonstrated the ability to extend graft survival beyond 200 d while reducing systemic immunosuppression. Clinically, uterus and face transplants have shown improved graft survival and functional outcomes, with reported live birth rates of 35%-40% in uterus transplantation and 5-y graft survival rates of 85% in face transplantation. Upper extremity transplantation resulted in the restoration of protective sensation in nearly all recipients. This study provides a comprehensive review of VCA, encompassing the foundational basic research underpinning its progress, and the clinical outcomes and challenges associated with the procedure. By examining these aspects, we aim to elucidate the current state of VCA, identify persistent challenges, and explore future directions for advancing its clinical application and optimizing patient outcomes.