The goal of this research plan is to translate the progress made with prior NIH funding into a completely biological tissue-engineered pulmonary valve replacement, made of tissue grown in vitro from fibroblast remodeled fibrin. This will be accomplished using (1) advances in heart valve bioreactor design and operation to strengthen the root segment and the root-leaflet attachment line, and (2) a new decellularization and optional recellularization strategy using mesenchymal stem cells to obviate the leaflet contraction that occurred post-implantation due to the transplanted fibroblasts, which are used to grow the tissue valve in vitro. This tissue-engineered heart valve (TEHV), both decellularized (relying on host cell invasion) and recellularized (with mesenchymal stem cells pre-implantation) will be validated in a lamb model to demonstrate growth capacity and sustained function of the engineered valve. Success will ultimately benefit approximately 10,000 pediatric patients in the U.S. annually and ultimately 100,000 patients in the U.S. annually if this TEHV can subsequently be improved to withstand forces associated with the aortic valve position. Enabling technologies relevant to other cardiovascular tissue engineering applications will be generated as a by-product of this research.

Public Health Relevance

In the United States alone, over 95,000 valve replacement surgeries are now performed annually according to the AHA. While mechanical and bioprosthetic heart valves have made a dramatic impact since their introduction in the 1960's, the 10-year mortality after replacement is still 30-55%. The need is particularly great for pediatric patients, since these valves do not have the capacity to grow. Thus, there is great interest in developing a new generation of tissue-engineered heart valves and this research is aimed at the design and testing of a completely biological living valve replacement.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107572-03
Application #
8449249
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Blaisdell, Carol J
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$662,291
Indirect Cost
$220,176
Name
University of Minnesota Twin Cities
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Syedain, Zeeshan; Reimer, Jay; Lahti, Matthew et al. (2016) Tissue engineering of acellular vascular grafts capable of somatic growth in young lambs. Nat Commun 7:12951
Reimer, Jay; Syedain, Zeeshan; Haynie, Bee et al. (2016) Implantation of a Tissue-Engineered Tubular Heart Valve in Growing Lambs. Ann Biomed Eng :
Schmidt, Jillian B; Chen, Kelley; Tranquillo, Robert T (2016) Effects of Intermittent and Incremental Cyclic Stretch on ERK Signaling and Collagen Production in Engineered Tissue. Cell Mol Bioeng 9:55-64
Schmidt, Jillian B; Tranquillo, Robert T (2016) Cyclic Stretch and Perfusion Bioreactor for Conditioning Large Diameter Engineered Tissue Tubes. Ann Biomed Eng 44:1785-97
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Syedain, Zeeshan H; Meier, Lee A; Reimer, Jay M et al. (2013) Tubular heart valves from decellularized engineered tissue. Ann Biomed Eng 41:2645-54