Advancements and Challenges in Tissue-Engineered Heart Valves: Integrating Biomechanics, Biomaterials, and Biomimetic Design for Functional Maturity.

Valvular heart disease remains a major global health burden, with currently available prosthetic heart valves failing to fully reproduce the adaptive, regenerative, and long-term functional properties of native valves. Tissue-engineered heart valves (TEHVs) have emerged as a promising alternative, aiming to develop living valve replacements capable of growth, remodeling, and physiological integration. However, despite substantial progress, the clinical translation of TEHVs remains limited, indicating the need for design strategies that go beyond material selection toward functionally mature constructs. This review presents recent advances in TEHV development from a biomimetic perspective, using native heart valves as a biological reference characterized by hierarchical structure, anisotropic mechanical behavior, mechanoresponsive cell populations, immune regulation, and temporally coordinated remodeling. We integrate current understanding of valve biology and mechanobiology with advances in scaffold materials and architecture, bioactive functionalization, biomechanical conditioning, and emerging fabrication and monitoring technologies. We discuss how biomimetic scaffold designs aim to replicate native extracellular matrix organization and nonlinear mechanics, how biological cues are used to regulate thrombosis, immune response, and cell recruitment, and how dynamic bioreactor systems support functional tissue maturation through controlled mechanical stimulation. Finally, key challenges for clinical translation are highlighted, and future directions are outlined, emphasizing integrated and biomimetically informed design approaches. Overall, this review aims to define guiding principles that may accelerate the development of durable, regenerative, and clinically translatable tissue-engineered heart valves. We argue that successful TEHV translation requires synchronized control of scaffold anisotropy, immune modulation, and mechanical conditioning rather than incremental material optimization.