Biomedical subjects

Michael A Henson

Publications and source records attributed to Michael A Henson.

7 recordsLinked to original sources

PubMed2006

Incorporating energy metabolism into a growth model of multicellular tumor spheroids.

Diffusion limitations in tumors create regions that are deficient in essential nutrients and contain a large number of quiescent and dying cells. Chemotherapeutic compounds are not effective against quiescent cells and therefore have reduced efficacy against tumors with extensive quiescence. We have formulated a mathematical model that predicts the extent and location of quiescence in multicellular spheroids. Multicellular spheroids are in vitro models of in vivo tumor growth that have proven to be useful experimental systems for studying radiation therapy, drug penetration, and novel chemotherapeutic strategies. Our model incorporates a realistic description of primary energy metabolism within reaction-diffusion equations to predict local glucose, oxygen, and lactate concentrations and an overall spheroid growth rate. The model development is based on the assumption that local cellular growth and death rates are determined by local ATP production generated by intracellular energy metabolism. Dynamic simulation and parametric sensitivity studies are used to evaluate model behavior, including the spatial distribution of proliferating, quiescent, and dead cells for different cellular characteristics. Using this model we have determined the critical cell survival parameters that have the greatest impact on overall spheroid physiology, and we have found that oxygen transport has a greater effect than glucose transport on the distribution of quiescent cells. By predicting the extent of quiescence based on individual cellular characteristic alone this model has the potential to predict therapeutic efficiency and can be used to design effective chemotherapeutic strategies.

Biological Transport↗

PubMed2004

Modeling the synchronization of yeast respiratory oscillations.

The budding yeast Saccharomyces cerevisiae exhibits autonomous oscillations when grown aerobically in continuous culture with ethanol as the primary carbon source. A single cell model that includes the sulfate assimilation and ethanol degradation pathways recently has been developed to study these respiratory oscillations. We utilize an extended version of this single cell model to construct large cell ensembles for investigation of a proposed synchronization mechanism involving hydrogen sulfide. Ensembles with as many as 10,000 cells are used to simulate population synchronization and to compute transient number distributions from asynchronous initial cell states. Random perturbations in intracellular kinetic parameters are introduced to study the synchronization of single cells with small variations in their unsynchronized oscillation periods. The cell population model is shown to be consistent with available experimental data and to provide insights into the regulatory mechanisms responsible for the synchronization of yeast metabolic oscillations.

Cell Culture Techniques↗

PubMed2003

Dynamic modeling of microbial cell populations.

Microbial cultures are comprised of heterogeneous cells that differ according to their size and intracellular concentrations of DNA, proteins and other constituents. Recent advances have been made in cell population modeling, which allow the effects of cell heterogeneity on culture dynamics and metabolite production to be predicted. If the intracellular state can be captured with a few variables, the population balance equation framework is a viable modeling approach. The cell ensemble modeling technique is better suited for the development of population models that include more detailed descriptions of cellular metabolism and/or cell-cycle progression.

Bacterial Physiological Phenomena↗

PubMed2003

Nonlinear parameter estimation for solution-diffusion models of membrane pervaporation.

An optimization-based procedure for estimating unknown parameters in solution-diffusion models of membrane pervaporation is presented. Permeation of two components through a polymer membrane is described by distinct solution and diffusion models. The solution model is based on a modified form of Flory-Huggins theory that accounts for interactions between the two penetrants. The diffusion model is derived from Fick's law, where the diffusion coefficients are allowed to depend on the local concentration of each component in the membrane. A phenomenologic relation is used to account for the effect of temperature on the component fluxes. The solution and diffusion models, as well as the temperature-flux relation, contain parameters that are not directly measurable. It is shown that these parameters can be estimated effectively from sorption and flux data by the solution of suitably formulated nonlinear optimization problems. The separation of styrene and ethylbenzene with a polyurethane membrane is used to illustrate the parameter estimation procedure.

Chemistry↗

PubMed2002

Cell population modelling of yeast glycolytic oscillations.

We investigated a cell-population modelling technique in which the population is constructed from an ensemble of individual cell models. The average value or the number distribution of any intracellular property captured by the individual cell model can be calculated by simulation of a sufficient number of individual cells. The proposed method is applied to a simple model of yeast glycolytic oscillations where synchronization of the cell population is mediated by the action of an excreted metabolite. We show that smooth one-dimensional distributions can be obtained with ensembles comprising 1000 individual cells. Random variations in the state and/or structure of individual cells are shown to produce complex dynamic behaviours which cannot be adequately captured by small ensembles.

Glycolysis↗

PubMedDate not supplied

Cell population modeling and parameter estimation for continuous cultures of Saccharomyces cerevisiae.

Saccharomyces cerevisiae is known to exhibit sustained oscillations in chemostats operated under aerobic and glucose-limited growth conditions. The oscillations are reflected both in intracellular and extracellular measurements. Our recent work has shown that unstructured cell population balance models are capable of generating sustained oscillations over an experimentally meaningful range of dilution rates. A disadvantage of such unstructured models is that they lack variables that can be compared directly to easily measured extracellular variables. Thus far, most of our work in model development has been aimed at achieving qualitative agreement with experimental data. In this paper, a segregated model with a simple structured description of the extracellular environment is developed and evaluated. The model accounts for the three most important metabolic pathways involved in cell growth with glucose substrate. As compared to completely unstructured models, the major advantage of the proposed model is that predictions of extracellular variables can be compared directly to experimental data. Consequently, the model structure is well suited for the application of estimation techniques aimed at determining unknown model parameters from available extracellular measurements. A steady-state parameter selection method developed in our group is extended to oscillatory dynamics to determine the parameters that can be estimated most reliably. The chosen parameters are estimated by solving a nonlinear programming problem formulated to minimize the difference between predictions and measurements of the extracellular variables. The efficiency of the parameter estimation scheme is demonstrated using simulated and experimental data.

Cell Count↗

PubMedDate not supplied

Optimization of fed-batch Saccharomyces cerevisiae fermentation using dynamic flux balance models.

We developed a dynamic flux balance model for fed-batch Saccharomyces cerevisiae fermentation that couples a detailed steady-state description of primary carbon metabolism with dynamic mass balances on key extracellular species. Model-based dynamic optimization is performed to determine fed-batch operating policies that maximize ethanol productivity and/or ethanol yield on glucose. The initial volume and glucose concentrations, the feed flow rate and dissolved oxygen concentration profiles, and the final batch time are treated as decision variables in the dynamic optimization problem. Optimal solutions are generated to analyze the tradeoff between maximal productivity and yield objectives. We find that for both cases the prediction of a microaerobic region is significant. The optimization results are sensitive to network model parameters for the growth associated maintenance and P/O ratio. The results of our computational study motivate continued development of dynamic flux balance models and further exploration of their application to productivity optimization in biochemical reactors.

Amino Acids↗