Despite significant advances in the surgical and medical management of congenital heart disease, congenital cardiac anomalies remain a leading cause of death in the newborn period. Most severe forms of congenital heart disease require surgical intervention. Complications arising from the use of currently available prosthetic materials in the form of vascular grafts, patches, or replacement heart valves are a leading source of morbidity and mortality after congenital heart surgery. Currently available prosthetic materials such as polytetrafluoroethylene are a significant source of thromboembolism, have poor durability due to neointimal hyperplasia, are susceptible to infection, and perhaps most importantly lack growth capacity, which results in the need for additional operations as children outgrow their prosthetics. The development of better biomaterials with growth potential could substantially improve the outcomes of children requiring congenital heart surgery by reducing the number of graft-related complications and enabling earlier definitive surgical repair without risk of serial re-operations. Tissue engineering offers a potential solution to this vexing problem. Using tissue engineering methods, bioprosthetics can be made from an individuals own cells creating a living material with excellent biocompatibility and the ability to grow, repair, and remodel. The goal of this application is to optimize the design of an improved vascular graft for use in congenital heart surgery. Using the tissue engineered vascular graft (TEVG) as a model for bioprosthetics specifically developed for use in congenital heart surgery, we will rationally design an improved TEVG based on the mechanisms underlying vascular neotissue formation. We will focus our work on developing strategies for inhibiting TEVG stenosis by anti-LYST immunomodulation. The successful development of therapeutic strategies for inhibiting TEVG stenosis would overcome a critical barrier preventing the widespread use of this promising technology.
Public Health Relevance Statement: Public Health Relevance Statement Congenital cardiac anomalies are the most common birth defect and a leading cause of death in the newborn period. The most effective treatment for congenital cardiac anomalies is reconstructive surgery. Unfortunately, complications arising from the use of currently available vascular conduits are a significant cause of postoperative morbidity and mortality. The development and translation of an improved vascular graft, created from an individuals own cells, with the ability to grow and remodel, holds great promise for advancing the field of congenital heart surgery and improving outcomes of infants requiring surgical intervention.
Project Terms: Affect; Antibodies; Antibody Therapy; Autologous; base; bench to bedside; Binding; Biocompatible Materials; biomaterial compatibility; Bioprosthesis device; Blood Platelets; Blood Vessels; Bone Marrow; Businesses; Cardiac Surgery procedures; Cardiovascular system; Cause of Death; Cells; Cessation of life; Child; CHS protein; CHS1 gene; Clinical; Collaborations; Complication; Congenital Abnormality; Congenital Heart Defects; congenital heart disorder; Defect; design; Development; Devices; Dose; Drug Delivery Systems; Drug Targeting; effective therapy; Endosomes; Endothelial Cells; Equilibrium; FDA approved; Fibroblasts; Genes; Genetic Transcription; Goals; graft failure; Growth; Heart; heart valve replacement; Human; Hyperplasia; Immunologics; Immunomodulators; immunoregulation; implantation; improved; improved outcome; Incidence; Individual; infant outcome; Infection; Infiltration; inhibiting antibody; Investigation; Liposomes; Lysosomes; macrophage; Medical; Methods; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Morbidity - disease rate; mortality; mouse model; Mus; Mutation; Natural Killer Cells; Newborn Infant; novel; novel therapeutics; Ohio; operation; Operative Surgical Procedures; Pediatric Hospitals; Performance; Phase; Pilot Projects; Polytetrafluoroethylene; Population; Postoperative Period; prevent; Prevention; prophylactic; Prosthesis; protein function; Proteins; public health relevance; Publishing; Reconstructive Surgical Procedures; recruit; Regulator Genes; repaired; Risk; Running; Safety; scaffold; Smooth Muscle Myocytes; Source; Stenosis; success; surgery outcome; Technology; Therapeutic; therapeutic development; Thromboembolism; Time; Tissue Engineering; trafficking; Translations; Tubular formation; United States; Universities; Vascular Graft; vascular tissue engineering; Vesicle; Work
