HLS-Self-endothelializing off-the-shelf vascular grafts

ABSTRACT HLS We propose to develop completely acellular off the shelf tissue engineered vascular grafts TEVG for the treatment of cardiovascular disease As base scaffold biomaterial we will use small intestinal submucosa SIS FDA approved for other medical indications Cook Biotech These acellular tissue engineered grafts will be functionalized to be anti thrombotic utilizing heparin bound to the SIS and self endothelializing with vascular endothelial growth factor VEGF bound to the heparin binding domain The current state of the art for TEVG involves pre cellularization in a lengthy manufacturing process which is limiting due to long culture times involved in cell expansion and bioreactor pre conditioning Further cell harvest and subsequent culturing from patients with comorbidities adds time and risk to TEVG manufacture Some existing technologies partially address this problem by utilizing bioreactor culture to develop grafts from allogeneic cell sources and then decellularizing them before storage and implantation However weeks of culture time are still required and smaller diameter grafts also require the lumen to be endothelialized with the patients own cells prior to implantation a significant limitation In contrast our technology overcomes these major limitations by using heparin VEGF immobilized in the graft lumen to impart anti thrombogenic properties as well as to attract the patients own cells to populate the graft thereby eliminating the need for cells In our preliminary studies these grafts were tested in an ovine carotid model where they demonstrated excellent patency and developed a completely confluent endothelial layer in the lumen within month post implantation In the current proposal we aim to develop these acellular grafts for pediatric surgical applications by evaluating them in an adolescent ovine growth model for and months to evaluate TEVG growth patency remodeling and function The month time period is equivalent to about human years sheep lifespan years during which the size and weight of the animals double and therefore it is an appropriate time to evaluate graft growth long term remodeling and function Further testing of acellular grafts for specific pediatric applications will be performed in Phase II as well storage stability and sterility which will provide a off the shelf product for clinical trials Narrative Development of a completely acellular vascular graft available on demand for surgical application should have a major impact on current treatment of cardiovascular disease To achieve this goal we propose to develop off the shelf acellular vascular grafts assessed long term in a pediatric preclinical setting capable of resisting occlusion and developing endothelial monolayer within the host with optimized surgical placement technique