Synthetic vascular grafts have been used effectively in clinical settings for large vessel repairs, but there is a limited supply of grafts for small-diameter vessels, which are primarily needed for coronary bypass surgery. The only clinically approved option for small diameter vascular bypass currently involves using a blood vessel from another part of the patient's body. However, this method is invasive and restricted by the availability of suitable vessels. Additionally, the quality of the graft may be compromised if the patient has other health conditions. Alternatively, blood vessels from donors can be used, but these are subject to immune responses that can lead to graft rejection. Previous clinical trials have successfully engineered venous synthetic vascular grafts for peripheral vascular bypass by harvesting patient-specific venous endothelial cells. Now, scientists have developed a universal, small-diameter vascular graft using stem cell-derived arterial endothelial cells (AECs) that could significantly advance vascular bypass surgery.

Researchers at the University of Wisconsin–Madison (Madison, WI, USA) aimed to create an "off-the-shelf" small diameter arterial graft that could be easily utilized in clinical applications. They designed a small graft made from ePTFE, a porous material derived from Teflon. After generating high-quality stem cell-derived AECs, the team developed methods to line these cells onto the ePTFE grafts. One major advantage of using pluripotent stem cells is their ability to self-renew, offering an unlimited cell source and the ability to differentiate into any human cell type. However, the researchers encountered a challenge in that ePTFE is hydrophobic and repels water, making it difficult for the cells to attach to the graft material.

Drawing inspiration from adhesive proteins found in mussels, particularly dopamine, a chemical found in these proteins, the team used a dual-layer coating with dopamine and vitronectin, another cell adhesion protein, to enable the attachment of AECs to the inner surface of the ePTFE grafts. The grafts were tested against physiological flow generated by a pump, and the bioengineered cells remained stable and uniform. The team then implanted the grafts into the femoral arteries of Rhesus macaques, a commonly used non-human primate model due to its biological similarities to humans. For any transplant to succeed, the cells must express the major histocompatibility complex (MHC), which includes proteins involved in immune responses that reject foreign bodies.

In this study, the researchers experimented with various graft compositions—bare ePTFE grafts, grafts lined with AECs expressing MHC (wildtype), and grafts lined with AECs lacking MHC (double knockout)—to assess immune rejection. The grafts were monitored every two weeks using ultrasound imaging to check for signs of failure, such as stenosis, cell wall thickening, or thrombosis (blood clots in the graft). Surprisingly, 50% of the MHC double knockout grafts failed, as reported in the study published in Cell Reports Medicine. The researchers hypothesized that natural killer cells could be involved in mediating immune rejection of these grafts since the knockout of MHC class I and II reduces the T-cell response. In contrast, the MHC wildtype grafts maintained normal function for six months, showing greater success than the other grafts. Additionally, the researchers observed that the graft endothelium was repopulated with host cells, contributing to the long-term success of the grafts. These findings suggest that bioengineered grafts may improve vascular bypass surgery and could pave the way for human clinical trials.

“Stem cell-based, off-the-shelf vascular grafts, have the potential to expand surgical indications, limit morbidity of operations, and give options for surgery that currently don’t exist, impacting subspecialities such as plastic and reconstructive surgery, vascular and cardiac surgery,” said Samuel Poore, chair of the division of plastic surgery at UW–Madison and co-author on the study. 

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