Vascularized composite xenotransplantation: Where we have been and where we could go?

Abstract

Vascularized composite allotransplantation (VCA) enables functional and aesthetic reconstruction after complex tissue loss but remains limited by donor scarcity and immunosuppression. Xenotransplantation, using tissues from other species, offers a potential solution. While progress in solid organ xenografts has accelerated, vascularized composite xenotransplantation (VCX) remains largely experimental. This study presents the first systematic review of VCX, tracing its development over the past century and preclinical efforts to overcome immunologic and technical barriers. A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines searched PubMed, EMBASE, Cochrane, Web of Science, and Google Scholar for English-language VCX studies. Methodological quality was assessed using the Newcastle-Ottawa Scale, SYRCLE Risk of Bias tool, and Oxford Levels of Evidence. Of 257 records, six preclinical studies (1885-2023) met inclusion criteria. Donor species included pigs, rabbits, dogs, and humans; recipients were rodents or nonhuman primates. Most used heterotopic grafts (e.g., limbs, groin flaps, thymosternal blocks) combining skin, muscle, bone, and nerves. Techniques included cryopreservation, microsurgical anastomosis, and genetically modified pig grafts (e.g., GalTKO.hCD46). All demonstrated short-term survival without long-term function. Despite technical feasibility, VCX remains experimental. Advances in gene editing, immune modulation, and tissue engineering are essential for clinical translation and may ultimately redefine reconstructive transplantation.