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Tissue Engineered Vascular Grafts in Humans: Correlating Clinical Outcomes to Vascular Neotissue Formation in Mice
Narutoshi Hibino1, Edward McGillicuddy1, Tai Yi1, Goki Matsumura2, Uji Naito2, Hiromi Kurosawa2, Christopher Breuer1, Toshiharu Shinoka1; 1Yale University School of Medicine, New Haven, CT; 2Tokyo Women’s Medical University, Tokyo, Japan
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Objective: The development of a tissue engineered vascular graft (TEVG) that possesses the ability to grow holds great promise for advancing the field of cardiac surgery. In 2001, we initiated a human trial evaluating the use of TEVGs as conduits in patients with single ventricle physiology. Concurrently, we developed and optimized a murine model to investigate the mechanisms underlying vascular neotissue formation. This study correlates the clinical feasibility and long term outcomes of TEVGs in humans with the basic biology of vascular neotissue formation in mice.
Methods: Human Trial: Autologous bone marrow (BM) mononuclear cells were seeded onto a biodegradable tubular scaffold fabricated from a polyglycolic acid (PGA) mesh coated with a co-polymer of l-lactide and ε-caprolactone (P(LA/CL)). Twenty-five TEVGs were implanted as extracardiac total cavopulmonary connections (EC TCPCs) in patients with single ventricle abnormalities. Patient age ranged from 1 to 24 years (median: 5.5 years). Post-operatively, patients were followed by serial angiography and/or CT. Mouse Model: Biodegradable PGA-P(LA/CL) scaffolds, 0.6mm in diameter, were implanted into the IVC in mice (N=12). Six scaffolds were seeded with murine BM prior to implantation and six scaffolds were implanted unseeded. Following implantation, grafts were followed with serial ultrasonography. All mice were sacrificed 14 days following implantation for histological analysis of the grafts.
Results: Human Trial: There was no graft-related mortality during the follow-up period (mean 4.2 years). There was no evidence of aneurysm formation, graft rupture, or ectopic calcification. Five patients (20%) developed silent graft stenoses which did not require intervention. Two conduits (8%) developed critical graft stenoses that were successfully treated with balloon angioplasty. Mouse Model: All seeded grafts remained patent, while 5 unseeded grafts (83%) developed significant stenoses. Seeded grafts expressed von Willebrand factor on the luminal aspect, consistent with early endotheliazation. Unseeded grafts, however, demonstrated dense populations of cells expressing smooth muscle actin, transforming growth factor-beta, and macrophage-3 antigen consistent with macrophage-driven inflammation.
Conclusion: In humans undergoing EC TCPC, use of TEVGs is associated with acceptable morbidity and mortality. In mice, BM seeded grafts demonstrate increased patency, early endotheliazation, and an attenuated inflammatory response compared to unseeded grafts.
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