title: Dynamic metabolic flux analysis using a convex analysis approach: Application to hybridoma cell cultures in perfusion.
abstract: In recent years, dynamic metabolic flux analysis (DMFA) has been developed in order to evaluate the dynamic evolution of the metabolic fluxes. Most of the proposed approaches are dedicated to exactly determined or overdetermined systems. When an underdetermined system is considered, the literature suggests the use of dynamic flux balance analysis (DFBA). However the main challenge of this approach is to determine an appropriate objective function, which remains valid over the whole culture. In this work, we propose an alternative dynamic metabolic flux analysis based on convex analysis, DMFCA, which allows the determination of bounded intervals for the fluxes using the available knowledge of the metabolic network and information provided by the time evolution of extracellular component concentrations. Smoothing splines and mass balance differential equations are used to estimate the time evolution of the uptake and excretion rates from this experimental data. The main advantage of the proposed procedure is that it does not require additional constraints or objective functions, and provides relatively narrow intervals for the intracellular metabolic fluxes. DMFCA is applied to experimental data from hybridoma HB58 cell perfusion cultures, in order to investigate the influence of the operating mode (batch and perfusion) on the metabolic flux distribution.
authors.affiliation: Automatic Control Laboratory, University of Mons, 31 Boulevard Dolez, Mons, 7000, Belgium. sofia.afonsofernandes@umons.ac.be.
authors.forename: Sofia
authors.initials: S
authors.lastname: Fernandes de Sousa
authors.affiliation: Department of Mathematical Engineering, ICTEAM, Catholic University of Louvain, Louvain-La-Neuve, Belgium.
authors.forename: Georges
authors.initials: G
authors.lastname: Bastin
authors.affiliation: Department of Chemical Engineering, Laboratory in Applied Metabolic Engineering, Polytechnic University of Montreal, Montréal, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Jolicoeur
authors.affiliation: Automatic Control Laboratory, University of Mons, 7000 Mons, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Vande Wouwer
mesh_terms: D000465:Algorithms; D000818:Animals; D019149:Bioreactors; D018929:Cell Culture Techniques; D003198:Computer Simulation; D006825:Hybridomas / Q000166:cytology / Q000378:metabolism*; D064688:Metabolic Flux Analysis; D053858:Metabolic Networks and Pathways; D051379:Mice; D008954:Models, Biological; D010477:Perfusion; D051381:Rats
keywords: convex analysis; hybridoma cells; mathematical modeling; metabolic flux analysis; underdetermined system