Decellularized scaffolds and heart valve treatment: present techniques, long-standing hurdles and the challenging future

Decellularized scaffolds represent a promising frontier in heart valve therapy, offering potential advantages over traditional mechanical and bioprosthetic alternatives. However, significant challenges persist in their clinical implementation. We try to review the critical factors affecting decellularized valve performance, focusing on the interplay between physical, chemical, and enzymatic decellularization methods and their impact on extracellular matrix (ECM) integrity. Our comprehensive analysis reveals that while these scaffolds can support cellular repopulation and demonstrate growth potential- particularly beneficial for pediatric applications- they face substantial limitations including thrombogenicity, calcification, immunogenicity, and leaflet retraction. The balance between effective cellular removal and ECM preservation emerges as a central challenge, with evidence suggesting that optimization of decellularization protocols may mitigate calcification risks. The development of standardized processing parameters across various tissue sources remains challenging, as source-dependent variations significantly influence functional outcomes. Xenogeneic tissues, while more readily available, demonstrate heightened immunogenicity and thrombogenic potential compared to allogeneic alternatives. Recent advancements in antigen removal techniques, particularly targeting the α-Gal epitope, show promise in reducing xenogeneic scaffold immunogenicity. Novel approaches incorporating surface modifications and crosslinking agents demonstrate significant potential in enhancing scaffold durability and cellular integration. Recellularization strategies, including pre-implantation endothelialization and the use of mesenchymal stem cells, may further improve scaffold functionality and reduce thrombogenic risk. Here, we examine advanced methodological developments in the field of heart valve decellularization, while identifying critical technical barriers that currently limit broad clinical translation. The ongoing refinement of decellularization technologies represents significant progress toward a fundamental objective in cardiovascular medicine: creating functional valve replacements with capacity for growth, regeneration, and hemodynamic adaptation throughout the patient's lifespan.