Bio-Boosting Transplants: A Systematic Review on Biopolymers in Vascular Composite Allotransplantation

Leonard Knoedler^1,2*Tobias Niederegger³Thomas Schaschinger³Jakob Fenske¹Varun P. A. Murugan^2,4Samuel Knoedler⁵Max Heiland¹Adriana C. Panayi^1,6Gabriel Hundeshagen⁶Alexandre G. Lellouch^2,7,8,9*

• ¹Charité University Medicine Berlin, Berlin, Germany
• ²Cedars-Sinai Medical Center, Los Angeles, United States
• ³Universitat Heidelberg, Heidelberg, Germany
• ⁴Amrita Vishwa Vidyapeetham Amrita School of Engineering Bengaluru, Bengaluru, India
• ⁵Yale School of Medicine Division of Plastic & Reconstructive Surgery, New Haven, United States
• ⁶BG Klinik Ludwigshafen, Ludwigshafen, Germany
• ⁷Innovative Therapies in Haemostasis, INSERM UMR-S 1140, University of Paris, 75006 Paris, France, Paris, France
• ⁸Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, Boston, United States
• ⁹Hopital Europeen Georges Pompidou, Paris, France

Background Vascularized composite allotransplantation (VCA) joins skin, muscle, bone, nerve, and vessels into a single graft that is both highly immunogenic and mechanically complex. Biopolymers, natural or synthetic, can provide structural scaffolding, localized drug release, and immune modulation. Although widely explored in solid-organ transplantation, their utility in VCA is poorly defined. We therefore conducted a systematic review to consolidate current evidence and map translational priorities. Methods Adhering to PRISMA 2020 and registered in PROSPERO (CRD420251039845), we searched PubMed, Web of Science, EMBASE, Cochrane Library, and Google Scholar through April 2025. Original studies evaluating biopolymers in any VCA-relevant setting (in vitro, animal, or clinical) were eligible. Clinical quality was judged with the Newcastle-Ottawa Scale and pre-clinical studies with the SYRCLE tool. Given methodological heterogeneity, findings were narratively synthesized. Results Eleven studies published between 2014 and 2024 fulfilled inclusion criteria. Collectively, they demonstrate that biopolymers, ranging from decellularized limb and auricular scaffolds to collagen-hydroxyapatite or polycaprolactone bone substitutes, hyaluronic-acid–functionalized vascular grafts, chitosan-or alginate-based drug-eluting coatings, and extracellular-matrix (ECM) sheets delivering cytotoxic T-lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) with or without rapamycin, consistently enhance vascularization, support multi-tissue regeneration, and preserve mechanical integrity across diverse VCA models. Immunologically, polymer platforms bias host responses toward tolerance: in a murine hind-limb model, ECM combined with CTLA4-Ig and rapamycin extended graft survival to 72 days while promoting pro-regenerative macrophage polarization. Drug-delivery applications also proved effective; calcium-alginate coatings prolonged vancomycin release for up to 50 days in vitro, highlighting the potential for infection control during graft integration. Notwithstanding these benefits, chitosan scaffolds displayed inadequate load-bearing capacity, and heterogeneity in species, graft types, follow-up intervals, and outcome metrics limited direct comparison and impeded meta-analysis. Conclusion Biopolymers emerge as potential adaptable platforms that merge mechanical support with finely tuned immune regulation in VCA. Successful translation will depend on tissue-specific material optimization, standardized immunological endpoints, and multicenter studies that replicate clinical complexity. Drawing on lessons from solid-organ transplantation and fostering collaboration among immunologists, biomaterial scientists, and surgeons will be pivotal to moving these technologies from bench to bedside in VCA.