Development of an Improved Vascular Graft for Use in Children

Despite significant advances in the care of infants and children born with congenital heart disease, congenital cardiac anomalies represent a leading cause of death in the newborn period. One significant source of morbidity and mortality arises from the use of man-made synthetic materials in the form of vascular patches, grafts, and replacement heart valves in most operations. Use of synthetic materials are associated with an increased risk of thromboembolic complications, increased susceptibility to infection, and perhaps most importantly lack of growth potential. We developed a tissue engineered vascular graft created by seeding an individual’s own cells onto a biodegradable tubular scaffold in order to create an autologous, living vascular conduit with the ability to grow, repair, and remodel. We subsequently translated this technology from the bench to the clinic performing the first clinical trial evaluating the use of tissue engineered vascular grafts in humans. Results of this trial confirmed the growth capacity of the tissue engineered vascular graft making it uniquely suited for use in children but also revealed that stenosis was the primary graft related complication effecting over 25% of graft recipients. We subsequently performed a series of investigations in order to elucidate the molecular mechanisms underlying neotissue formation and the stenosis. Based on our studies we discovered that the seeded cells do not directly contribute to vascular neotissue but instead modulate neotissue formation via a paracrine mechanism. We also discovered that vascular neotissue arises from the neighboring vascular tissue through an immune mediated regenerative process and that excessive inflammation causes stenosis. Next based on our mechanistic discoveries we rationally designed strategies for inhibiting the formation of tissue engineered vascular graft stenosis by altering the foreign body reaction caused by the tissue engineering scaffold. Most recently we are working translate our most recent work to the clinic through the development of the second generation tissue engineered vascular graft.