Physiological Response of Tissue-Engineered Vascular Grafts to Vasoactive Agents in an Ovine Model

Abstract

Tissue-engineered vascular grafts (TEVGs) are emerging as promising alternatives to synthetic grafts, particularly in pediatric cardiovascular surgery. While TEVGs have demonstrated growth potential, compliance, and resistance to calcification, their functional integration into the circulation, especially their ability to respond to physiological stimuli, remains underexplored. Vasoreactivity, the dynamic contraction or dilation of blood vessels in response to vasoactive agents, is a key property of native vessels that affects systemic hemodynamics and long-term vascular function. This study aimed to develop and validate an in vivo protocol to assess the vasoreactive capacity of TEVGs implanted as inferior vena cava (IVC) interposition grafts in a large animal model. Bone marrow-seeded TEVGs were implanted in the thoracic IVC of Dorset sheep. A combination of intravascular ultrasound (IVUS) imaging and invasive hemodynamic monitoring was used to evaluate vessel response to norepinephrine (NE) and sodium nitroprusside (SNP). Cross-sectional luminal area changes were measured using a custom Python-based software package (VIVUS) that leverages deep learning for IVUS image segmentation. Physiological parameters including blood pressure, heart rate, and cardiac output were continuously recorded. NE injections induced significant, dose-dependent vasoconstriction of TEVGs, with peak reductions in luminal area averaging ∼15% and corresponding increases in heart rate and mean arterial pressure. Conversely, SNP did not elicit measurable vasodilation in TEVGs, likely due to structural differences in venous tissue, the low-pressure environment of the thoracic IVC, and systemic confounders. Overall, the TEVGs demonstrated active, rapid, and reversible vasoconstrictive behavior in response to pharmacologic stimuli. This study presents a novel in vivo method for assessing TEVG vasoreactivity using real-time imaging and hemodynamic data. TEVGs possess functional vasoactivity, suggesting they may play an active role in modulating venous return and systemic hemodynamics. These findings are particularly relevant for Fontan patients and other scenarios where dynamic venous regulation is critical. Future work will compare TEVG vasoreactivity with native veins and synthetic grafts to further characterize their physiological integration and potential clinical benefits.

Keywords: in vivo testing; ovine model; physiological response; tissue-engineered vascular grafts; vasoreactivity.