These symposia explore the interface between macroscale function and microscale physiology with the perspective from the macroscale to the microscale. This theme includes the modulation and control of macroscale whole-organ-level function from its interactions with microscale muscle and neurophysiological processes, and the corresponding diseases associated with disruption between the micro and micro scale dynamics. It also includes systems level function from the integration of multiple microscale components. Modeling is from the macroscale to the microscale: macroscale function from microscale physiology. Modeling complexity involves both numerical and mathematical issues, and often the modeling integrates with data from imaging modalities.

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ABSTRACTS

• Roy Kerckhoffs: Modeling the Cardiovascular Closed-Loop Baro-Reflex

Roy C.P. Kerckhoffs (1), Lawrence J. Mulligan (2), Jeffrey H. Omens (3), Andrew D. McCulloch (1)

(1) Department of Bioengineering and (3) Department of Medicine, University of California San Diego; (2) Therapy Delivery Systems/Leads Research, Medtronic Inc.

In cardiac physiology, a strong interconnection exists between all scales: normal function at a given level (e.g. tissue) depends on the underlying synergy of sublevels (myocytes) – but also on higher levels, when considering feedback mechanisms. Hence, we propose a comprehensive model of the cardiovascular system that includes a finite element model of ventricular mechanics with passive and active material properties, the circulation, and the baro-reflex which feeds back to heart rate and beta-adrenergic stimulation of the cardiac myocytes

• Marco Cabrera:Intracellular Mechanisms of Regulation of Muscle Metabolism During Exercise

Yanjun Li, Ranjan K. Dash, Asit K. Saha, Jaeyeon Kim, Gerald M. Saidel, Marco E. Cabrera

Departments of Biomedical Engineering and Pediatrics, Case Western Reserve University, Cleveland, OH Department of Physiology, Medical College of Wisconsin, Milwaukee, WI

ABSTRACT Skeletal muscle can maintain intracellular [ATP] constant during the transition from rest to exercise, while reaction rates may increase significantly. Among the key regulatory factors, the dynamics of cytosolic and mitochondrial NADH and NAD+ during exercise have not been characterized. To determine the extent of regulation exerted by these intracellular metabolic signals on skeletal muscle metabolism at the onset of exercise, a computational model was developed. In this model, transport and metabolic fluxes in distinct capillary, cytosolic, and mitochondrial domains are integrated. We hypothesized that during the transition from rest to exercise (60% VO2max), the dynamics of lactate concentration [Lac] in exercising muscle is independent of mitochondrial redox state. We tested this hypothesis by simulating the metabolic responses of skeletal muscle to exercise, while altering the transport rate of reducing equivalents from cytosol to mitochondria and muscle glycogen content. Simulation with optimal parameter estimates showed good agreement with experimental data from muscle biopsies in human subjects. Compared with the optimal values, a 20% increase (decrease) in NADH transport coefficient led to an 85% decrease (7-fold increase) in cytosolic redox state, and ~50% decrease (~85% increase) in muscle [Lac]. Doubling (halving) glycogen concentration resulted in a 30% increase (20% decrease) in cytosolic redox state, and ~10% increase (~25% decrease) in [Lac]. In both cases, mitochondrial redox states had minor changes. In conclusion, simulations suggest that the regulation of lactate production at the onset of exercise (~60% VO2max) is primarily dependent on the dynamics of cytosolic redox state and independent of mitochondrial redox state.

• Robert F. Kunz: Geometric and Fluid Flow Coupling Between Macro and Micro Scales in Respiration Simulation

Robert F. Kunz (1,2), Daniel C. Haworth (3), Andres Kriete (4), Gulkiz Dogan (2), David P. Porzio (5)

(1) Applied Research Laboratory,(2) Department of Aerospace Engineering, (3) Department of Mechanical and Nuclear Engineering, and (5) Department of Bioengineering, Pennsylvania State University; (4) Department of Bioengineering, Drexel University.

We present several components of a semi-automated subject-specific end-to-end medical image through CFD analysis capability for the human respiratory system. The particular model components emphasized here are related to the macro-through-micro scale coupling of geometry and flow physics. Specifically, in the area of geometric modeling, four elements are summarized: i) semi-automated processing of medical image data to derive upper airway and lobe geometries, ii) partitioning and truncation algorithms, iii) automated unstructured 3D gridding of the trachea through generation 5-8, and iv) interfacing this upper bronchi and lobe geometry with a volume filling algorithm for the subresolved bronchi. In the area of flow modeling, algorithm components related to 3D through quasi-1D transition, loss modeling, and boundary conditions are presented. Particular emphasis here is placed on the issues and models related to interfacing the macro and micro scales. The overall model is demonstrated through application to unsteady respiration simulation of a live subject.

• Ching-Long Lin: Multiscale Simulation of Gas Flow in Subject-Specific Models of the Human Lung

Ching-Long Lin (1,2), Merryn H. Tawhai (6), Geoffrey McLennan (3,4,5), and Eric A. Hoffman (3,4,5)

(1) Department of Mechanical and Industrial Engineering, (2) IIHR-Hydroscience & Engineering, (3) Biomedical Engineering, (4) Medicine and (5) Radiology, The University of Iowa; (6) Bioengineering Institute, The University of Auckland, New Zealand.

This presentation describes a comprehensive computational fluid dynamics (CFD) framework for pulmonary gas flow that utilizes multidetector-row computed tomography (MDCT)-based subject-specific airway geometries, spans multiple scales, and employs a data-driven approach to simulate flow in a breathing lung. The framework is based upon MDCT imaging, geometric modeling of airway trees, three-dimensional (3D) and one-dimensional (1D) coupled mesh generation, 3D and 1D CFD methods, image-based physiological boundary conditions, and a novel moving mesh technique. At a local level, the fluid-structure interaction and acinar flow simulations are employed for regional wall-shear stress in compliant airways and mixing in alveolar sacs. Some applications of the multiscale technique will be presented

Media: CLLin_MSM_080708.ppt