The goal of this project is to develop artificial blood vessels based on stem cell and nano-matrix technologies. Cardiovascular disease is a leading cause of death in California and United States. The narrowing and clogging of blood vessels can result in heart failure, stroke, peripheral vascular diseases and disability. To restore tissue and organ functions and ensure the survival of transplanted cells and tissue, vascular therapy to re-establish the blood circulation is the first priority. While transcatheter therapeutics have made a significant impact on the management of coronary and lower extremity arterial occlusive disease, surgical bypass grafting remains the mainstay of arterial reconstructive surgery, especially when a large segment of blood vessel has clogging problem. In the United States, there are over 400,000 coronary and 100,000 lower extremity bypass surgeries performed annually. The use of autologous artery and vein for bypassing offer the best long-term patency in revascularizing the heart and lower extremity. Yet recent large randomized controlled trials have demonstrated that failure rates are a common occurrence (~35%) that incurs significant morbidity and mortality. Further, the arterial or venous conduit is often unavailable due to previous bypass surgery or unsuitable for bypass due to pre-existing disease within the vein necessitating the use of synthetic conduits which have inferior patency rates. In addition to coronary and peripheral arterial diseases, cerebrovascular disease treatment (e.g., extracranial-to-intracranial bypass) could benefit greatly from suitable synthetic grafts, and hemodialysis for the patients with kidney failure needs non-thrombogenic grafts as arterio-venous fistulae. Therefore, the present gulf between available autologous conduit and individual patient’s need for bypass surgery represents one of the most significant unmet clinical needs in cardiovascular medicine. Currently, synthetic vascular grafts made of biomaterials are not suitable for bypass surgery if the inner-diameter of the artery is less than 6 mm. Tissue engineering of small-diameter blood vessels is a promising approach, but there is no appropriate cell source. Here we propose to use bone marrow mesenchymal stem cells (MSCs) and biomimetic nano-matrix to construct the new generation of vascular grafts that can be made available off-the-shelf and can maintain long-term patency. The potential of human embryonic stem cell- and induced pluripotent stem cell-derived endothelial cells as cell sources will also be explored. If the grafts are successfully developed and commercialized, it will advance stem cell-derived therapy towards the clinic, and benefit hundreds of thousands of patients with cardiovascular diseases and kidney failure that needs hemodialysis.
This project will establish the feasibility of using adult bone marrow stem cells for cardiovascular therapy, and explore the potential of human embryonic stem cells- and induced pluripotent stem cell-derived endothelial cells as cell sources for vascular graft construction. The combination of stem cells and novel materials represents a significant progress towards the next generation of tissue engineering products for regenerative medicine applications. With the establishment of a working cell bank and the fabrication of allogeneic grafts, the products will be available off-the-shelf for surgical use. If the grafts are successfully developed and commercialized, it will advance stem cell-derived therapy towards the clinic, and benefit hundreds of thousands of patients with cardiovascular diseases and kidney failure that needs hemodialysis.