The development of improved biological vascular graft materials is a significant medical need that has under development since the 1980's. We have developed a tissue-engineered, cellular vascular graft that is currently being evaluated in two, Phase I/II clinical trials. Human vascular smooth muscle cells are seeded onto a degradable polymer in a bioreactor, and cultured to produce an engineered vascular smooth muscle-based artery. After quantitative decellularization, an arterial graft is produced which lacks cellular antigens, is composed primarily of collagens, and which retains the mechanical properties of the original, cellular graft. Using this technology, human, engineered grafts have been implanted as arteriovenous (AV) grafts into a total of 60 hemodialysis patients. Interim analysis of ongoing clinical trials has shown primary patency at 6 and 12 months is 64% and 30%, while secondary patency at 6 and 12 months is 97% and 89%, respectively. Secondary patencies of 97% and 89% are substantially better than historical values for PTFE grafts, implying that the acellular grafts are resistant both to infection and to intimal hyperplasia. However, acellular grafts are subject to thrombosis and require thrombectomy interventions, and their primary patency is similar to that reported for PTFE. These results imply that exposed collagen on the graft lumen triggers platelet activation, leading to episodes of acute thrombosis. Collagen-triggered platelet activation may also hamper graft function if they are used for small-diameter (< 6mm) peripheral or coronary artery bypass. To address this issue of exposed collagen and platelet activation, we have developed a novel and innovative covalent surface modification using cross-linked hyaluronan (HA). The HA coating shields platelets from the collagenous graft surface in vitro, and our pilot data show decreased thrombosis in vivo. We hypothesize that coating of acellular, engineered grafts with cross-linked HA will shield collagen from platelets, decrease thrombosis, and allow endothelial repopulation of the graft lumen. To test this hypothesis, we will perform a rational set of in vitro and in vivo studies, using a porcie model of arteriovenous grafting to establish biological efficacy. The impact of this coating could be to improve the function of arteriovenous and small- caliber vascular grafting materials, as well as other types of blood-contacting surfaces, in the future. The expertise that we have brought to bear on this project includes a leader in vascular tissue engineering (Niklason), a surgeon who is an expert in vascular graft remodeling (Dardik), and a leader in biomaterials who has pioneered the development of functionalized HA molecules (Prestwich, consultant).

Public Health Relevance

To address the problem of platelet activation and coagulation of blood-contacting surfaces such as biological vascular grafts, we have developed a novel and innovative covalent surface modification using cross-linked hyaluronan (HA). The HA coating shields platelets from the graft surface in vitro, and our pilot data show decreased thrombosis in vivo. We hypothesize that coating of engineered grafts with cross-linked HA will shield collagen from platelets, decrease thrombosis, and allow endothelial repopulation of the graft lumen.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL127386-03
Application #
9403220
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lee, Albert
Project Start
2016-02-22
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Kristofik, Nina; Calabro, Nicole E; Tian, Weiming et al. (2016) Impaired von Willebrand factor adhesion and platelet response in thrombospondin-2 knockout mice. Blood 128:1642-50
Huang, Angela H; Balestrini, Jenna L; Udelsman, Brooks V et al. (2016) Biaxial Stretch Improves Elastic Fiber Maturation, Collagen Arrangement, and Mechanical Properties in Engineered Arteries. Tissue Eng Part C Methods 22:524-33

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