[R01] Engineering Self-healing, Cell-free and Regenerating Vascular Grafts
Ente: National Heart Lung and Blood Institute
Scadenza: 2030-04-30
Importo max: 740.447 EUR
Paese: US
Descrizione
ABSTRACT
End-stage renal disease (ESRD) is a major cause of mortality in the United States, affecting more than 800,000
patients, with approximately 570,000 of them undergoing hemodialysis1-3. Of those, only ~15% receive
arteriovenous fistulae (AVF) either because of unsuitable veins associated with comorbidities or the prolonged
maturation time (3–4 months) required to achieve sufficient blood flow for dialysis. Synthetic grafts, such as
expanded polytetrafluoroethylene (ePTFE), are used clinically but often fail over time due to loss of mechanical
integrity with repeated cannulation.4,5 Moreover, early cannulation of arteriovenous (AV) grafts carries a high risk
of bleeding, pseudoaneurysm, intimal hyperplasia, thrombosis, and hematoma6. Tissue engineering offers
promising strategies for creating vascular grafts that may serve as viable alternatives to AVF or synthetic grafts7-
18. Our group developed acellular tissue engineered vessels (ATEVs) by employing a native biomaterial
decorated with multidomain peptides designed to mimic the activated endothelium. These ATEVs demonstrated
excellent patency and seamless integration with native vasculature when implanted into the arterial circulation
of mice and sheep19-24. Patients undergoing hemodialysis require vascular grafts that are robust and capable of
maintaining their mechanical integrity through multiple weekly cannulation sessions over extended periods.
However, most existing vascular grafts lack the self-healing properties necessary to withstand repeated needle
punctures. Therefore, there remains an unmet need for self-healing (SH) tissue-engineered vessels (TEVs)
suitable for use as arteriovenous (AV) shunts.
The overarching goal of the proposed work is to engineer SH-TEVs that heal quickly following
cannulation, while maintaining their mechanical strength and regenerative capacity in vivo. Aim 1 will
systematically design a library of polyurethane (PU) elastomers with multiple dynamic bonds and composition of
soft and hard segments, that will be screened for optimal self-healing performance and mechanical properties
under physiological conditions in vitro. SH-TEVs will be engineered as hybrid, bi-layered grafts composed of a
native biomaterial, small intestinal submucosa (SIS) that is decorated with a bidomain protein to recruit host
cells, endothelialize and regenerate; and a self-healing elastomer (SHE) that endows the grafts with self-healing
properties. Aim 2 will test several SH-TEV designs in a rat animal model to evaluate their self-healing capacity,
endothelialization and patency in vivo. In Aim 3, the SH-TEV with optimal performance in rats will be implanted
into a large pre-clinical ovine animal model to evaluate long-term patency and function under multiple cannulation
sessions, mimicking the clinical setting. This highly innovative proposal aims to engineer an SH-TEV that can
withstand repeated needle-punctures while maintaining patency and regeneration potential in a preclin
Istituzione: STATE UNIVERSITY OF NEW YORK AT BUFFALO
PI: Stelios T. Andreadis
Progetto: 1R01HL184001-01A1
Settori: National Heart Lung and Blood Institute
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.