There is a significant need for a successful vascular graft for the nearly one million aortocoronary bypass, peripheral arterial bypass, and arterio-venous access graft procedures performed each year in the US, as current clinical options are unreliable. The overall goal of this R21 proposal is to begin the process of clinical translation o our novel, autologous, stem cell-based tissue engineered vascular graft (TEVG) by addressing critical issues of practical implementation and rate-limiting barriers that have prevented current paradigms from being successful. This proposal will focus on use of adipose-derived stem cells (ADSCs), given the relative ease of isolation and availability of fat in the patient population in need. The following important issues/questions will be addressed in this proposal: A) Autologous adult ADSCs isolated in a typical single harvest from a patient are limited in number. What is the lower bound of ADSC seeding density necessary to yield a successful TEVG? B) Age and sex have both been shown to influence cardiovascular disease development and treatment efficacy. Will a stem cell-based TEVG using ADSCs from all patients be feasible, or will certain factors (e.g., male or female sex, patients beyond a certain age) preclude this therapy? Accordingly, the two specific aims of this 2-year proposal are: 1) Assess the effect of ADSC seeding density on the performance of TEVG constructs tested in a rat model;and 2) Assess the effect of donor age and sex in a rat model of the same sex on in-vivo performance of human cell-based TEVG constructs. The expected outcome of this work is an important step toward the successful development of a human stem cell-based TEVG, moving it significantly closer to clinical translation. No other study, to our knowledge, has addressed critical issues of clinical practicality, such as those to be addressed here, for the development of a human, stem cell-based TEVG.
Nearly one million vascular bypass grafts are placed in patients in the US each year. A significant number of these grafts fail, and many more patients in need do not receive bypass grafts due to limitations of current clinical options. A tissue engineered vascular graft, constructed by incorporating the patient's own stem cells into a biodegradable vessel-shaped scaffold, is a promising solution to this challenge. The proposed work will address critical issues of practicality and existing rate-limiting barriers that must be overcome for this technology to move closer to clinical translation.
|Krawiec, Jeffrey T; Weinbaum, Justin S; St Croix, Claudette M et al. (2015) A cautionary tale for autologous vascular tissue engineering: impact of human demographics on the ability of adipose-derived mesenchymal stem cells to recruit and differentiate into smooth muscle cells. Tissue Eng Part A 21:426-37|