Modeling an Excitable Biosynthetic Tissue with Inherent Variability for Paired Computational-Experimental Studies.
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To understand how excitable tissues give rise to arrhythmias, it is crucially necessary to understand the electrical dynamics of cells in the context of their environment. Multicellular monolayer cultures have proven useful for investigating arrhythmias and other conduction anomalies, and because of their relatively simple structure, these constructs lend themselves to paired computational studies that often help elucidate mechanisms of the observed behavior. However, tissue cultures of cardiomyocyte monolayers currently require the use of neonatal cells with ionic properties that change rapidly during development and have thus been poorly characterized and modeled to date. Recently, Kirkton and Bursac demonstrated the ability to create biosynthetic excitable tissues from genetically engineered and immortalized HEK293 cells with well-characterized electrical properties and the ability to propagate action potentials. In this study, we developed and validated a computational model of these excitable HEK293 cells (called "Ex293" cells) using existing electrophysiological data and a genetic search algorithm. In order to reproduce not only the mean but also the variability of experimental observations, we examined what sources of variation were required in the computational model. Random cell-to-cell and inter-monolayer variation in both ionic conductances and tissue conductivity was necessary to explain the experimentally observed variability in action potential shape and macroscopic conduction, and the spatial organization of cell-to-cell conductance variation was found to not impact macroscopic behavior; the resulting model accurately reproduces both normal and drug-modified conduction behavior. The development of a computational Ex293 cell and tissue model provides a novel framework to perform paired computational-experimental studies to study normal and abnormal conduction in multidimensional excitable tissue, and the methodology of modeling variation can be applied to models of any excitable cell.
Published Version (Please cite this version)10.1371/journal.pcbi.1005342
Publication InfoGokhale, Tanmay; Kim, JM; Kirkton, RD; Bursac, Nenad; & Henriquez, CS (2017). Modeling an Excitable Biosynthetic Tissue with Inherent Variability for Paired Computational-Experimental Studies. PLoS Comput Biol, 13(1). pp. e1005342. 10.1371/journal.pcbi.1005342. Retrieved from https://hdl.handle.net/10161/14219.
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Professor of Biomedical Engineering
Bursac's research interests include: Stem cell, tissue engineering, and gene based therapies for heart and muscle regeneration; Cardiac electrophysiology and arrhythmias; Organ-on-chip and tissue engineering technologies for disease modeling and therapeutic screening; Small and large animal models of heart and muscle injury, disease, and regeneration. The focus of my research is on application of pluripotent stem cells, tissue engineering, and gene therapy technologies for: 1) basic s
MD, Duke University School of Medicine, 2018PhD, Duke University Graduate School / Pratt School of Engineering, 2018Dissertation: Bridging Scales: How Microstructural Features Impact Macroscopic Cardiac PropagationAdvisor: Craig Henriquez, PhD
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