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

摘要

ABSTRACT HLS16-07 - 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, 7-10 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 1 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 3 and 6 months to evaluate TEVG growth, patency, remodeling and function. The 6 month time period is equivalent to about 5 human years (sheep lifespan ~ 8 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.