This project's objective is to create an implantable cardiac patch which functions to replace damaged tissue after a myocardial infarction, commonly referred to as a """"""""heart attack"""""""". Regenerative medicine strategies for repair of the heart are hampered particularly by the inability to recreate the cardiac architecture. Specifically, cells must be properly aligned in order to propagate the electrical signals of the heart. Misaligned cells can lead to arrhythmias. Furthermore, implanted cells need a permissive environment (proper cell matrix, soluble signals, and supporting cells) for integration into the host tissue. Our proposed plan is to use natural occurring matrices and engineering to produce aligned cells for the purpose of implantation. The three primary aims of this project are as follows: (1) Characterize three candidate biomaterials alone and in combination for inherent physical properties that support cell viability and tissue remodeling. These matrices will be explored individually and combined into layers for optimization of;1.1) maintenance of high populations of viable cardiomyocytes and endothelial cells, 1.2) mechanical properties that possess strength and stiffness for manual manipulation and implantation, and 1.3) materials that allow for cellular remodeling and vessel formation. (2) To develop an optimal architectural design for the proposed 3-D patch which incorporates appropriate porosity for each gel working towards seeding at high cell densities and integration of layers of different materials. The incorporation of topological channels allows alignment of cardiomyocytes and endothelial cells. Sequenced patterning of channels in materials will be accomplished using laser etching and/or thin layer printing. Successful designs will allow for maximum delivery of cell combinations (seeding density) and integration of various cell-matrix layers. Because nutritional gradients wane with both increased cell density and increased distance from a nutrient source, cell viability will also be assessed. The analysis of architecture will be done with scanning electron microscopy (SEM), and confocal microscopy. Analysis of proper electrical alignment of the cardiomyocytes will be analyzed using dye exchange and electrical conduction studies. (3) To compare 3-D scaffolding modes of delivery with direct injection of cells, and a myogeneic strategy of repair (cardiac cells only in the cardiac patch) with a combined myogenic and angiogenic strategy (cardiac and endothelial cells in the cardiac patch). A pre-clinical large animal (swine) myocardial infarction model will be used in collaboration with Dr. Ronald Li, UC, Davis. Outcomes will focus on the evaluation of cell viability and retention, blood vessel formation, wall thinning, and functional performance of the heart.
Over 8 million Americans live with damaged heart tissue, due to the inability of the adult hearts to produce new cardiomyocytes after damage, and could benefit from innovations in regenerative medicine. Successful replacement of scar tissue in the heart with cardiac cells leads to proper cardiac function and alleviates physical strain that is a precursor to heart failure and death. This proposal will focus on the development of a patch as a cell delivery vehicle for these cardiac cells, providing an environment which is nourishing and time permissive for integration into the heart.
| Turner, William S; Sandhu, Nabjot; McCloskey, Kara E (2014) Tissue engineering: construction of a multicellular 3D scaffold for the delivery of layered cell sheets. J Vis Exp :e51044 |
| Turner, William S; McCloskey, Kara E (2012) Rapid fibroblast removal from high density human embryonic stem cell cultures. J Vis Exp :e3951 |
| Turner, William S; Wang, Xiaoling; Johnson, Scott et al. (2012) Cardiac tissue development for delivery of embryonic stem cell-derived endothelial and cardiac cells in natural matrices. J Biomed Mater Res B Appl Biomater 100:2060-72 |
