The Role of Collagen Cross-Links in Biomechanical Behavior of Human Aortic Heart Valve Leaflets—Relevance for Tissue Engineering

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Abstract
A major challenge in tissue engineering of functional heart valves is to determine and mimic the dominant tissue structures that regulate heart valve function and in vivo survival. In native heart valves, the anisotropic matrix architecture assures sustained and adequate functioning under high-pressure conditions. Collagen, being the main load-bearing matrix component, contributes significantly to the biomechanical strength of the tissue. This study investigates the relationship between collagen content, collagen cross-links, and biomechanical behavior in human aortic heart valve leaflets and in tissue-engineered constructs. In the main loading direction (circumferential) of native valve leaflets, a significant positive linear correlation between modulus of elasticity and collagen cross-link concentration was found, whereas no correlation between modulus of elasticity and collagen content was found. Similar findings were observed in tissue-engineered constructs, where cross-link concentration was higher for dynamically strained constructs then for statically cultured controls. These findings suggest a dominant role for collagen cross-links over collagen content with respect to biomechanical tissue behavior in human heart valve leaflets. They further suggest that dynamic tissue straining in tissue engineering protocols can enhance cross-link concentration and biomechanical function.