Abstracts From the Emerging Science Series, April 24, 2013
Human Acellular Vascular Grafts: Preclinical Dataset Supports Bench-to-Bedside Transition of Tissue-Engineered Grafts for Hemodialysis Vascular Access
Shannon L Dahl, Humacyte, Inc., Durham, NC; Jeffrey H Lawson, Duke Univ, Durham, NC; Heather L Prichard, Humacyte, Inc., Durham, NC; Roberto J Manson, Duke Univ, Durham, NC; William E Tente, Alan P Kypson, Juliana L Blum, Humacyte, Inc., Durham, NC; Laura E Niklason, Yale Univ, New Haven, CT
Introduction: End stage renal disease patients who require hemodialysis access would benefit from an alternative to synthetic grafts, which have high rates of thrombosis and intimal hyperplasia. A graft with success rates that are similar to those of fistulas would be clinically advantageous. Our tissue-engineered vascular graft is comprised of human extracellular matrix and is similar in strength to native human vein and artery. This acellular graft may be stored in a regular refrigerator, making it readily available for off-the-shelf surgical use. This graft is currently in clinical studies for evaluation of safety and efficacy in hemodialysis vascular access in patients with end stage renal disease. Methods: Banked human aortic smooth muscle cells were cultured in bioreactors in vitro to produce vascular tissue grafts, and a decellularization process was subsequently employed to remove cellular antigens and render grafts non-immunogenic. Arteriovenous grafts were implanted into non-human primates for up to 6 months, and were evaluated for patency, durability, cannulation, rejection, and cellular repopulation. Directional guidance for the definitive primate study was provided by implantation of canine-derived grafts into canines. Results: Graft mechanical integrity was retained throughout 1-year of refrigeration in these acellular grafts. In all studies, implanted grafts were safe, well tolerated, and functioned as intended. No significant intimal hyperplasia was observed in any graft. Histologic analysis demonstrated evidence of host vascular cell migration into the graft. Canine studies demonstrated safety and function of engineered tissues in long-term (1-year) studies. These preclinical studies supported initiation of clinical trials. Conclusions: These novel non-immunogenic grafts demonstrated excellent patency, tolerance of cannulation, absence of infection, absence of significant intimal hyperplasia, and low rates of intervention. Based on these successful pre-clinical studies, a Phase I clinical study of the safety and efficacy of Humacyte’s human acellular vascular grafts in patients with end stage renal disease is currently underway.
S.L.M. Dahl: Employment; Significant; Humacyte, Inc.. Ownership Interest; Modest; Humacyte, Inc. J.H. Lawson: Research Grant; Modest; Department of Defense via Humacyte. Consultant/Advisory Board; Significant; Humacyte, Inc. H.L. Prichard: Employment; Significant; Humacyte, Inc.. Ownership Interest; Modest; Humacyte, Inc. R.J. Manson: Research Grant; Significant; Department of Defense via Humacyte. Consultant/Advisory Board; Modest; Humacyte, Inc. W.E. Tente: Employment; Significant; Humacyte, Inc.. Ownership Interest; Modest; Humacyte, Inc. A.P. Kypson: Consultant/Advisory Board; Modest; Humacyte, Inc. J.L. Blum: Employment; Significant; Humacyte, Inc. Ownership Interest; Modest; Humacyte, Inc. L.E. Niklason: Ownership Interest; Significant; Humacyte, Inc.
Bringing Tissue Engineered Technologies to Clinical and Commercial Relevance in Cardiovascular Medicine
Nicolas L’Heureux, Cytograft Tissue Engineering, Novato CA, Nathalie Dusserre, Cytograft Tissue Engineering, Novato CA, Wojciech Wystrychowski, Stanford University School of Medicine, Palo Alto, CA, Sergio Garrido, Buenos Aires, Argentina, Ronald MacKenzie, Buenos Aires, Argentina, Jaime Velez, Cali, Colombia, and Todd McAllister, Cytograft Tissue Engineering, Novato CA
Cell-based cardiovascular therapies have made steady clinical progress since Zilla’s work in the 1990’s with cell-seeded PTFE conduits.In 2001, the field of cardiovascular medicine was revolutionized by landmark studies describing cell-seeded bioresorbable scaffolds to repair congenital defects (Shinoka) and direct cell injections to regenerate myocardium (Menasche). In 2007, we reported the first clinical use of tissue-engineered blood vessels (TEBV) in the high-pressure arterial circulation. This scaffold-free TEBV was used for hemodialysis access, demonstrating a 4-fold reduction in graft-related hospitalizations. The autologous, sheet-based approach, however, is difficult to translate to widespread use because of challenges in manufacturing time, cost, scale-up logistics, and onerous regulatory hurdles.
In order to achieve widespread clinical use, we have recently focused on new manufacturing strategies. In 2011 we reported the first human use of an allogeneic, off-the-shelf, TEBV. This second-generation graft exhibited a lack of immunogenicity, similarly reduced complication rates, and is transitioning to Phase IIb/III clinical use. We now report a third-generation TEBV based on a cell-synthesized thread. Using medical textile technologies, a woven human TEBV can be produced with burst pressures in excess of 10,000 mmHg and improved compliance relative to ePTFE or sheet-based TEBV.This manufacturing approach dramatically reduces manufacturing time and cost. Importantly, hundreds of thousands of grafts can be manufactured from a single master donor.
Combining thread and sheet technologies, we have also built tissue-engineered valve leaflets for Transcatheter Aortic Valve Implantation (TAVI). These manufactured human tissues are thinner than bovine pericardium and can be engineered to match many of the mechanical properties of native valve tissue. This suggests not only a smaller crossing profile, but a reduced quality assurance burden in manufacturing. The leaflets can be mounted to a stent, and deployed without perforation. Hemodynamic testing demonstrates coaptation similar to native tissues. These new cost effective approaches mark an important evolution toward the widespread clinical use of engineered tissues.
T. McAllister: Employment; Significant; Employee of Cytograft Tissue Engineering, the sponsor of the studies presented. Ownership Interest; Significant; Significant stockholder in Cytograft Tissue Engineering, the sponsor of the studies presented. N. L’Heureux: Employment; Significant; Employee of Cytograft Tissue Engineering, the sponsor of the studies presented. Ownership Interest; Significant; Significant stockholder in Cytograft Tissue Engineering, the sponsor of the studies presented. N. Dusserre: Employment; Significant; Employee of Cytograft Tissue Engineering. W. Wystrychowski: None. S. Garrido: None. R. MacKenzie: None. J. Velez: None
- © 2013 American Heart Association, Inc.