Foundations for Extended Life Cycle Biological Models

Introduction: To expand our ability to test current concepts about system and organ function within organisms in normal and disease states we need a new class of discrete, event-driven simulation models that achieve a higher level of biological realism across multiple scales, while being sufficiently flexible to represent different aspects of the biology. Here we provide the first description of such models, one that is focused on the rat liver. We use a middle-out design strategy that begins with primary parenchymal units. The models are sufficiently flexible to represent different aspects of hepatic biology, including heterogeneous microenvironments. Model components are designed to be easily joined and disconnected, and to be replaceable and reusable. The models function within a multitier, in silico apparatus designed to support iterative experimentation on models that will have extended life cycles. Results: Validation uses two sets of solute outflow profile data from experiments on isolated perfused rat livers (IPRL). One set, providing a measure of intrasubject variability, consists of four repeat experiments on the same perfused rat liver. The other set consists of one solute outflow profile from each of six different livers under identical experimental conditions. In both cases the solute is C-sucrose. The in silico system contains the functional unit model (ArtModel), along with an accepted mathematical reference model (to help account for the in vitro data), and the experimental data model. The reference model—the two compartment, extended convectiondispersion model—represents the current state of the science in traditional mathematical modeling of in vitro IPRL solute outflow data. In establishing fine-grained control over the vascular geometry, the ArtModel makes four primary assumptions. 1. Physiologically accurate models are necessary to begin fully exploring the liver behavior space as reflected in solute outflow profiles. 2. Between terminal portal and hepatic veins, vascular structure can be represented by a directed graph. A multi-layered, fine-grained sinusoidal unit model is placed on each graph node. 3. The primary functional unit is the acinus or composites thereof. 4. The sucrose outflow profile is solely a function of the extracellular space and its geometry. We define and use a similarity measure to identify regions of parameter space that generate in silico results that are acceptably similar to the in vitro results, even though the model specification used here does not take advantage of interconnections between sinusoids. The results indicate that, although we do cover the behavior of the models’ parameter space, a sinusoidal parameterization that targets the behavior space of the in vitro experiments with high specificity is difficult because the behavior space of the ArtModel is