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Modeling an Excitable Biosynthetic Tissue with Inherent Variability for Paired Computational-Experimental Studies.

ABSTRACT: 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.

SUBMITTER: Gokhale TA

PROVIDER: S-EPMC5291544 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Modeling an Excitable Biosynthetic Tissue with Inherent Variability for Paired Computational-Experimental Studies.

Gokhale Tanmay A TA Kim Jong M JM Kirkton Robert D RD Bursac Nenad N Henriquez Craig S CS

PLoS computational biology 20170120 1

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 cardiomy ...[more]

PMID: 28107358

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Project description:Trauma/hemorrhagic shock followed by resuscitation (T/HS-R) results in multi-system inflammation and organ dysfunction, in part driven by binding of damage-associated molecular pattern molecules to Toll-like Receptor 4 (TLR4). We carried out experimental T/HS-R (pseudo-fracture plus 2 h of shock followed by 0-22 h of resuscitation) in C57BL/6 (wild type [WT]) and TLR4-null (TLR4-/-) mice, and then defined the dynamics of 20 protein-level inflammatory mediators in the heart, gut, lung, liver, spleen, kidney, and systemic circulation. Cross-correlation and Principal Component Analysis (PCA) on data from the 7 tissues sampled suggested that TLR4-/- samples express multiple inflammatory mediators in a small subset of tissue compartments as compared to the WT samples, in which many inflammatory mediators were localized non-specifically to nearly all compartments. We and others have previously defined a central role for type 17 immune cells in human trauma. Accordingly, correlations between IL-17A and GM-CSF (indicative of pathogenic Th17 cells); between IL-17A and IL-10 (indicative of non-pathogenic Th17 cells); and IL-17A and TNF (indicative of memory/effector T cells) were assessed across all tissues studied. In both WT and TLR4-/- mice, positive correlations were observed between IL-17A and GM-CSF, IL-10, and TNF in the kidney and gut. In contrast, the variable and dynamic presence of both pathogenic and non-pathogenic Th17 cells was inferred in the systemic circulation of TLR4-/- mice over time, suggesting a role for TLR4 in efflux of these cells into peripheral tissues. Hypergraph analysis - used to define dynamic, cross compartment networks - in concert with PCA-suggested that IL-17A was present persistently in all tissues at all sampled time points except for its absence in the plasma at 0.5h in the WT group, supporting the hypothesis that T/HS-R induces efflux of Th17 cells from the circulation and into specific tissues. These analyses suggest a complex, context-specific role for TLR4 and type 17 immunity following T/HS-R.

Project description:PurposeComputational models are widely used during the design and characterization of microwave ablation (MWA) devices, and have been proposed for pretreatment planning. Our objective was to assess three-dimensional (3D) transient temperature and ablation profiles predicted by MWA computational models with temperature profiles measured experimentally using magnetic resonance (MR) thermometry in ex vivo bovine liver.Materials and methodsWe performed MWA in ex vivo tissue under MR guidance using a custom, 2.45 GHz water-cooled applicator. MR thermometry data were acquired for 2 min prior to heating, during 5-10 min microwave exposures, and for 3 min following heating. Fiber-optic temperature sensors were used to validate the accuracy of MR temperature measurements. A total of 13 ablation experiments were conducted using 30-50 W applied power at the applicator input. MWA computational models were implemented using the finite element method, and incorporated temperature-dependent changes in tissue physical properties. Model-predicted ablation zone extents were compared against MRI-derived Arrhenius thermal damage maps using the Dice similarity coefficient (DSC).ResultsPrior to heating, the observed standard deviation of MR temperature data was in the range of 0.3-0.7°C. Mean absolute error between MR temperature measurements and fiber-optic temperature probes during heating was in the range of 0.5-2.8°C. The mean DSC between model-predicted ablation zones and MRI-derived Arrhenius thermal damage maps for 13 experimental set-ups was 0.95. When comparing simulated and experimentally (i.e. using MRI) measured temperatures, the mean absolute error (MAE %) relative to maximum temperature change was in the range 5%-8.5%.ConclusionWe developed a system for characterizing 3D transient temperature and ablation profiles with MR thermometry during MWA in ex vivo liver tissue, and applied the system for experimental validation of MWA computational models.

Dataset Information

Modeling an Excitable Biosynthetic Tissue with Inherent Variability for Paired Computational-Experimental Studies.

Publications

Modeling an Excitable Biosynthetic Tissue with Inherent Variability for Paired Computational-Experimental Studies.

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