We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)–approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.
Accelerated atherosclerosis is the critical manifestation of macrovascular disease in both type 1 and 2 diabetics and the major etiology of morbidity and mortality in these individuals ( 1, 2 ). In 2000, the global excess mortality attributable to diabetes mellitus was estimated at 2.9 million deaths ( 3 ), with 80% the result of major cardiovascular events ( 4 ). Clinical studies of diabetic cardiovascular disease have mainly focused on type 2 diabetes. However, despite its younger age of onset, type 1 diabetes is also associated with a signifi cantly increased risk of cardiovascular diseases, with an age-adjusted risk greater than 10 times the general population, which even exceeds that of type 2 diabetes ( 2, 5-8 ). The mechanism of type 1 diabetesaccelerated atherosclerosis is not well studied, and a major reason has been the lack of a good animal model ( 9 ). The most commonly used animal model of type 1 diabetes is the streptozotocin (STZ)-treated mouse. In this model, injection of STZ ablates pancreatic  -cells. Deficiencies of this model include considerable mouse-tomouse variation; age dependency of pancreatic  -cell destruction; toxicity to other cells and tissues, including DNA damage and induction of carcinogenesis; instability of the diabetes phenotype due to pancreatic islet  -cell regeneration; and the diffi culty of inducing diabetes in females ( 10-12 ). The variability and instability of STZ-treated mouse model make it especially diffi cult to perform the long-term experiments required for atherosclerosis studies.Abstract Accelerated atherosclerosis is the leading cause of death in type 1 diabetes, but the mechanism of type 1 diabetes-accelerated atherosclerosis is not well understood, in part due to the lack of a good animal model for the longterm studies required. In an attempt to create a model for studying diabetic macrovascular disease, we have generated type 1 diabetic Akita mice lacking the low density lipoprotein receptor (
Objective Recent efforts to tissue engineer long-segment tracheal grafts have been complicated by stenosis and malacia. It has been proposed that both the mechanical characteristics and cell seeding capacity of TETG scaffolds are integral to graft performance. Our aim was to design a tracheal construct that approximates the biomechanical properties of native sheep trachea and optimizes seeding with bone marrow derived mononuclear cells prior to preclinical evaluation in an ovine model. Methods A solution of 8% polyethylene terephthalate (PET) and 3% polyurethane (PU) was prepared at a ratio of either 8:2 or 2:8 and electrospun onto a custom stainless steel mandrel designed to match the dimensional measurements of the juvenile sheep trachea. 3D-printed porous or solid polycarbonate C-shaped rings were embedded within the scaffolds during electrospinning. The scaffolds underwent compression testing in the anterior-posterior and lateral-medial axes and the biomechanical profiles compared to that of a juvenile ovine trachea. The most biomimetic constructs then underwent vacuum seeding with ovine bone marrow derived mononuclear cells. Fluorometric DNA assay was used to quantify scaffold seeding. Results Both porous and solid rings approximated the biomechanics of the native ovine trachea, but the porous rings were most biomimetic. The load-displacement curve of scaffolds fabricated from a ratio of 2:8 PET:PU most closely mimicked that of native trachea in the anterior-posterior and medial-lateral axes. Solid C-ringed scaffolds had a greater cell seeding efficiency when compared to porous ringed scaffolds (Solid: 19 × 104 vs. Porous: 9.6 × 104 cells/mm3, p = 0.0098). Conclusion A long segment tracheal graft composed of 2:8 PET:PU with solid C-rings approximates the biomechanics of the native ovine trachea and demonstrates superior cell seeding capacity of the two prototypes tested. Further preclinical studies using this graft design in vivo would inform the rational design of an optimal TETG scaffold.
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