Our current inability to vascularize and perfuse thick cell masses has hindered efforts to engineer many types of functional tissues including, most critically, cardiac muscle. To serve as a graft for myocardial repair, an engineered cardiac construct must be thick and compact, contain physiologic density of differentiated cells, and contract synchronously in response to electrical stimulation. In addition, the graft must have a capability to integrate with the host vasculature in order to maintain the viability and function of transplanted cells. We propose to engineer functional vascularized myocardium by integrating and advancing our ongoing efforts in the areas of cardiac tissue engineering (MIT) and vascular tissue engineering (Duke). We hypothesize that the cultivation of cardiac myocytes and endothelial cells on specialized scaffolds (highly porous, biodegradable, elastic, with an array of channels) in a bioreactor with medium perfusion and electrical stimulation will promote functional assembly of synchronously contractile engineered muscle. We further hypothesize that vascularization in vitro will enhance the graft capacity for survival, integration and function in vivo. In order to test these hypotheses, which have been derived from two lines of our previous investigations, we propose studies with the following Specific Aims: (1) High density culture of cardiac myocytes on channeled scaffolds with medium perfusion and electrical stimulation, (2) Tissue engineering of a vascularized network, and (3) Tissue engineering and functional characterization of a vascularized cardiac muscle. The effects of perfusion and electrical stimulation on the progression of endothelial cell and myocyte assembly into a synchronously contractile myocardium will be studied in vitro and in vivo (implantation onto a left ventricle in an adult rat model of infarction). Tissue structure and function will be characterized at various hierarchical scales (molecular, structural, functional) and the obtained experimental and modeling data will be used to tailor the conditions and duration of cultivation and engineer implantable grafts. As such, the current proposal is a blueprint for the generation of vascularized cardiac muscle suitable for implantation into injured myocardium.
| Ronaldson-Bouchard, Kacey; Ma, Stephen P; Yeager, Keith et al. (2018) Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556:239-243 |
| Savoji, Houman; Mohammadi, Mohammad Hossein; Rafatian, Naimeh et al. (2018) Cardiovascular disease models: A game changing paradigm in drug discovery and screening. Biomaterials : |
| Chen, Timothy; Vunjak-Novakovic, Gordana (2018) In vitro Models of Ischemia-Reperfusion Injury. Regen Eng Transl Med 4:142-153 |
| Liu, Bohao; Lee, Benjamin W; Nakanishi, Koki et al. (2018) Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells. Nat Biomed Eng 2:293-303 |
| Korolj, Anastasia; Laschinger, Carol; James, Chris et al. (2018) Curvature facilitates podocyte culture in a biomimetic platform. Lab Chip 18:3112-3128 |
| Ronaldson-Bouchard, Kacey; Vunjak-Novakovic, Gordana (2018) Organs-on-a-Chip: A Fast Track for Engineered Human Tissues in Drug Development. Cell Stem Cell 22:310-324 |
| Jay, Steven M; Vunjak-Novakovic, Gordana (2017) * Extracellular Vesicles and Their Versatile Roles in Tissue Engineering. Tissue Eng Part A 23:1210-1211 |
| Yuan, Xiaoning; Wei, Yiyong; Villasante, Aránzazu et al. (2017) Stem cell delivery in tissue-specific hydrogel enabled meniscal repair in an orthotopic rat model. Biomaterials 132:59-71 |
| Conant, Genevieve; Ahadian, Samad; Zhao, Yimu et al. (2017) Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires. Sci Rep 7:11807 |
| Lee, Benjamin W; Liu, Bohao; Pluchinsky, Adam et al. (2016) Modular Assembly Approach to Engineer Geometrically Precise Cardiovascular Tissue. Adv Healthc Mater 5:900-6 |
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