Functionality, growth and accelerated aging of tissue engineered living autologous vascular grafts.
Living autologous tissue engineered vascular-grafts (TEVGs) with growth-capacity may overcome the limitations of contemporary artificial-prostheses. However, the multi-step in vitro production of TEVGs requires extensive ex vivo cell-manipulations with unknown effects on functionality and quality of TEVGs due to an accelerated biological age of the cells. Here, the impact of biological cell-age and tissue-remodeling capacity of TEVGs in relation to their clinical long-term functionality are investigated. TEVGs were implanted as pulmonary-artery (PA) replacements in juvenile sheep and followed for up to 240 weeks (∼4.5years). Telomere length and telomerase activity were compared amongst TEVGs and adjacent native tissue. Telomerase-activity of in vitro expanded autologous vascular-cells prior to seeding was <5% as compared to a leukemic cell line, indicating biological-aging associated with decreasing telomere-length with each cellular-doubling. Up to 100 weeks, the cells in the TEVGs had consistently shorter telomeres compared to the native counterpart, whereas no significant differences were detectable at 240 weeks. Computed tomography (CT) analysis demonstrated physiological wall-pressures, shear-stresses, and flow-pattern comparable to the native PA. There were no signs of degeneration detectable and continuous native-analogous growth was confirmed by vessel-volumetry. TEVGs exhibit a higher biological age compared to their native counterparts. However, despite of this tissue engineering technology related accelerated biological-aging, growth-capacity and long-term functionality was not compromised. To the contrary, extensive in-vivo remodeling processes with substantial endogenous cellular turnover appears to result in "TEVG rejuvenation" and excellent clinical performance. As these large-animal results can be extrapolated to approximately 20 human years, this study suggests long-term clinical-safety of cardiovascular in vitro tissue engineering and may contribute to safety-criteria as to first-in-man clinical-trials.
Swiss Centre for Regenerative Medicine, University Hospital and University of Zurich, Zurich, Switzerland.
Jens M
JM
Kelm
Maximilian Y
MY
Emmert
Armin
A
Zürcher
Dörthe
D
Schmidt
Yvonne
Y
Begus Nahrmann
Karl L
KL
Rudolph
Benedikt
B
Weber
Chad E
CE
Brokopp
Thomas
T
Frauenfelder
Sebastian
S
Leschka
Bernhard
B
Odermatt
Rolf
R
Jenni
Volkmar
V
Falk
Gregor
G
Zünd
Simon P
SP
Hoerstrup
D000375:Aging / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005434:Flow Cytometry; D007150:Immunohistochemistry; D011651:Pulmonary Artery / Q000166:cytology; D012756:Sheep; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods*
D019098:Telomerase