Niklason, Laura E - Yale University - Biomedical Engineering

研究领域

Vascular and Lung Engineering Cardiovascular regenerative medicine has taken many avenues over the past three decades. One approach currently in clinical trials does not require any cells from the patient, and is an engineered tissue that is available "off-the-shelf". Studies in vascular tissue mechanics showed several decades ago that the bulk of the mechanical properties of arteries derived not from the cellular components, but from the collagen- and elastin-based extracellular matrix. Using this principle, we have utilized banked human vascular smooth muscle cells to engineer implantable arteries. Our approach to vascular engineering involves seeding allogeneic vascular cells onto a degradable substrate to culture vascular tissues in a biomimetic bioreactor. After a period of 8-10 weeks, engineered tissues are then decellularized to produce an engineered extracellular matrix-based graft. The advantage of using allogeneic cells for graft production is that no biopsy need be harvested from the patient, and no patient-specific culture time is required. The acellular grafts can be stored for 6 months and are available at time of patient need. These grafts are being tested in 3, Phase I clinical trials in Europe and in the US. These tissue engineered vascular grafts have been tested most extensively as hemodialysis access in patients who are not candidates for autogenous arteriovenous fistula creation, with the first patient being implanted in December 2012 in Poland. Since that time, a total of 60 patients have been implanted with engineered, acellular grafts for dialysis access, 40 patients in Europe and 20 in the US. Patients utilize the grafts for dialysis access as soon as 4-8 weeks after graft implantation. This early experience supports the potential utility of this novel tissue engineered vascular graft to provide vascular access for hemodialysis. The decellularization approach has also allowed us to generate scaffolds to support whole lung regeneration. Using rat, porcine and human sources of organs, lungs have been subjected to a range of decellularization procedures, with the goal of removing a maximal amount of cellular material while retaining matrix constituents. Next-generation proteomics approaches have shown that gentle decellularization protocols result in near-native retention of key matrix molecules involved in cell adhesion, including proteoglycans and glycoproteins. Repopulation of the acellular lung matrix with mixed populations of neonatal lung epithelial cells results in regio-specific epithelial seeding in correct anatomic locations. Survival and differentiation of lung epithelium is enhanced by culture in a biomimetic bioreactor that is designed to mimic some aspects of the fetal lung environment, including vascular perfusion and liquid ventilation. Current challenges involve the production of a uniformly recellularized scaffold within the vasculature, in order to shield blood elements from the collagenous matrix which can stimulate clot formation. In addition, we have developed methods to quantify barrier function of acellular and repopulated matrix, in order to predict functional gas exchange in vivo.

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A Call to Craft, M.S. Raredon, L.E. Niklason, Science Translational Medicine, 2014, 6(218):218fs1. Mesenchymal Stromal Cells form Vascular Tubes When Placed in Fibrin Sealant and Accelerate Wound Healing In Vivo, J.J. Mendez, M. Ghaedi, A. Sivarapatna, S. Dimitrievska, Z. Shao, C.O. Osuji, D.M. Steinbacher, D.J. Leffell, L.E. Niklason, Biomaterials, 2014. Human iPS Cell-Derived Alveolar Epithelium Repopulates Lung Extracellular Matrix, M. Ghaedi, E.A. Calle, J.J. Mendez, A.L. Gard, J. Balestrini, A. Booth, P.F. Bove, L. Gui, E.S. White, L.E. Niklason, The Journal of Clinical Investigation, 2013, 123, 11; 4950-62. Microfluidic Artificial "Vessels" for Dynamic Mechanical Stimulation of Mesenchymal Stem Cells, J. Zhou, L.E. Niklason, Integrative biology : quantitative biosciences from nano to macro, 2012, 4, 12; 1487-97. Decellularized Tissue-Engineered Blood Vessel as an Arterial Conduit, C. Quint, Y. Kondo, R.J. Manson, J.H. Lawson, A. Dardik, L.E. Niklason, Proceedings of the National Academy of Sciences of the United States of America, 2011, 108, 22; 9214-9. Readily Available Tissue-Engineered Vascular Grafts, S.L. Dahl, A.P. Kypson, J.H. Lawson, J.L. Blum, J.T. Strader, Y. Li, R.J. Manson, W.E. Tente, L. DiBernardo, M.T. Hensley, R. Carter, T.P. Williams, H.L. Prichard, M.S. Dey, K.G. Begelman, L.E. Niklason, Science Translational Medicine. 2011, 3, 68;68ra9. Tissue-Engineered Lungs for In Vivo Implantation, T.H. Petersen, E.A. Calle, L. Zhao, E.J. Lee, L. Gui, M.B. Raredon, K. Gavrilov, T. Yi, Z.W. Zhuang, C. Breuer, E. Herzog, L.E. Niklason, Science, 2010, 329, 5991; 538-41. Small-Diameter Human Vessel Wall Engineered From Bone Marrow-Derived Mesenchymal Stem Cells (hMSCs), Z. Gong, L. Niklason, The FASEB Journal, 2008, 22:1635-1648. Blood Vessels Engineered From Human Cells, M. Poh, M. Boyer, S. Dahl, D. Pedrotty, S. Banik, J. McKee, R. Klinger, C. Counter, L. Niklason, The Lancet, 2005; 366, 9489; 891-892. Possible Role for Vascular Cell Prolieration in Cerebral Vasospasm After Subarachnoid Hemorrage, C. Borel, A. McKee, A. Parra, M. Haglund, A. Solan, V. Prabhakar, H. Sheng, D. Warner, L. Niklason, Stroke, 2003; 34:427-433. Functional Arteries Grown in Vitro, L. Niklason, J. Gao, W.M. Abbott, K.K. Hirschi, S. Houser, R. Marini, R. Langer, Science, 1999, 5413, 489 - 493.