Bridging Decellularization and Recellularization: A Systematic Review of the Unmet Challenge in Whole-Heart Bioengineering

(1) Background: Whole-heart tissue engineering through decellularization and recellularization offers a potential alternative to transplantation. However, these two strategies remain major challenges. This systematic review evaluates whole-heart decellularization protocols and recellularization strategies. (2) Materials and Methods: Following PRISMA guidelines, PubMed, Embase, and Scopus were searched. Of 1981 records identified, 28 studies reporting whole-heart decellularization protocols were included. Two reviewers independently performed study selection and data extraction using Covidence, followed by narrative synthesis. (3) Results: Coronary perfusion was the predominant decellularization method, commonly using sodium dodecyl sulfate (SDS), alone or combined with Triton X-100. Protocols varied in detergent concentrations, exposure times, perfusion conditions, and washing procedures. Decellularization was reported in all included studies, although assessment methods and reporting of residual cellular material and extracellular matrix preservation lacked standardization. Recellularization was less consistently investigated: 12 studies attempted whole-heart recellularization, describing broader cell-seeding procedures. Cell sources included endothelial cells, mesenchymal stem cells, and induced pluripotent stem cell-derived cardiovascular lineages. Delivery methods included vascular perfusion and intramyocardial injection. Outcomes varied, and no study demonstrated a fully functional, transplantable whole heart. (4) Conclusions: Decellularization protocols are relatively established, whereas recellularization remains inconsistent and experimental. Standardized assessment, optimized multicellular seeding strategies, and improved bioreactor systems are essential for advancing functional whole-heart regeneration.