Vascular grafts are in great demand because coronary artery diseases cause 12 million deaths in the world each year and account for half of all deaths in the United States. Despite the successful replacement of large-diameter blood vessels with non-biodegradable polymeric materials, critical issues remain in the creation of coronary heart disease-related small vascular grafts. So far no biomaterials and cel-based tissue- engineered blood vessel (TEBV) can meet the urgent needs of patients for coronary artery substitutes. The objective of this project is to develop a cell sheet engineering strategy potentially suitable for the production of a completely biological and mechanically strong off-the-shelf small-diameter vascular graft in large scale by manipulating human stem cells with biomimetic microenvironmental parameters. Our central hypothesis is that the well-defined biomimetic microenvironments composed of physiological-relevant low O2 concentration and hydrodynamic flows would effectively control the fate of human stem cells, enabling the reproducible production of a mechanically strong TEBV. Our goal is to engineer a small-diameter blood vessel that mimics the three-dimensional cellular organization in the natural blood vessel and can be used as allografts by any patient without time concerns.
Aim I : Establish a robust off-the-shelf TEBV manufacturing scheme.
Aim II : Evaluate the regeneration process and long-term patency of the TEBV in a rat abdominal model.
Aim III : Evaluate the immune response of the TEBV as an allograft in an immune competent rat abdominal artery model. This research will establish a robust off-the shelf small-diameter TEBV fabrication strategy using stem cells. Upon completion, this novel cell sheet-based strategy will overcome the limitations of current biomaterial- and cell-based approaches to provide a completely biological small-diameter vascular graft that can sustain the high blood pressure, stimulate the functional vascular tissue regeneration, and induce integration by the host tissue in vivo.

Public Health Relevance

Coronary artery diseases account for half of all deaths in the US and vascular grafts are in great demand. We will develop a completely biological, mechanically strong, and off-the-shelf small-diameter blood vessel by using human mesenchymal stem cell sheets for the enhancement of coronary artery reconstruction and function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15HL115521-01A1
Application #
8497217
Study Section
Special Emphasis Panel (ZRG1-SBIB-L (90))
Program Officer
Lee, Albert
Project Start
2013-07-08
Project End
2016-06-30
Budget Start
2013-07-08
Budget End
2016-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$410,059
Indirect Cost
$124,460
Name
Michigan Technological University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
065453268
City
Houghton
State
MI
Country
United States
Zip Code
49931
Qian, Zichen; Ross, David; Jia, Wenkai et al. (2018) Bioactive polydimethylsiloxane surface for optimal human mesenchymal stem cell sheet culture. Bioact Mater 3:167-173
Zhang, Lijun; Qian, Zichen; Tahtinen, Mitchell et al. (2018) Prevascularization of natural nanofibrous extracellular matrix for engineering completely biological three-dimensional prevascularized tissues for diverse applications. J Tissue Eng Regen Med 12:e1325-e1336
Radke, Daniel; Jia, Wenkai; Sharma, Dhavan et al. (2018) Tissue Engineering at the Blood-Contacting Surface: A Review of Challenges and Strategies in Vascular Graft Development. Adv Healthc Mater 7:e1701461
Chen, Lei; Xing, Qi; Zhai, Qiyi et al. (2017) Pre-vascularization Enhances Therapeutic Effects of Human Mesenchymal Stem Cell Sheets in Full Thickness Skin Wound Repair. Theranostics 7:117-131
Xing, Qi; Qian, Zichen; Tahtinen, Mitchell et al. (2017) Aligned Nanofibrous Cell-Derived Extracellular Matrix for Anisotropic Vascular Graft Construction. Adv Healthc Mater 6:
Liu, Xuan; Zhang, Lijun; Kirby, Mitchell et al. (2016) Iterative l(1)-min algorithm for fixed pattern noise removal in fiber-bundle-based endoscopic imaging. J Opt Soc Am A Opt Image Sci Vis 33:630-6
Shearier, Emily R; Bowen, Patrick K; He, Weilue et al. (2016) In Vitro Cytotoxicity, Adhesion, and Proliferation of Human Vascular Cells Exposed to Zinc. ACS Biomater Sci Eng 2:634-642
Shearier, Emily; Xing, Qi; Qian, Zichen et al. (2016) Physiologically Low Oxygen Enhances Biomolecule Production and Stemness of Mesenchymal Stem Cell Spheroids. Tissue Eng Part C Methods 22:360-9
Zhang, Lijun; Xing, Qi; Qian, Zichen et al. (2016) Hypoxia Created Human Mesenchymal Stem Cell Sheet for Prevascularized 3D Tissue Construction. Adv Healthc Mater 5:342-52
Shearier, Emily; Cheng, Peifu; Bao, Jiming et al. (2016) Surface Defection Reduces Cytotoxicity of Zn(2-methylimidazole)2 (ZIF-8) without Compromising its Drug Delivery Capacity. RSC Adv 6:4128-4135

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