Model-based design and analysis of a reconfigurable continuous-culture bioreactor

In this paper, we present a model-based design and analysis of prototype laboratory equipment used for growing bacteria under precisely controlled conditions for systems biology experiments. Continuous-culture bioreactors grow microorganisms continuously over periods as long as several months. Depending on the particular experiment, the reconfigurable continuous-culture bioreactor we model and analyze may operate as: (a) a chemostat with constant volume, (b) a turbidostat with constant bacterial concentration as observed through turbidity (optical density), or (c) a morbidostat with constant death-rate of bacteria. Such systems have interesting safety specifications such as not overflowing beakers, maintaining bacterial concentrations within ranges, etc., that must be maintained over long experimental periods. We develop preliminary controller and plant models and analyze them through simulation in Simulink/Stateflow (SLSF), and using reachability analysis in SpaceEx by translating the SLSF models to hybrid automata. The analysis indicates that the proposed design satisfies its regulation specifications for microorganism concentration may avoid error scenarios encountered in experiments with a prior design.

[1]  Remy Chait,et al.  Evolutionary paths to antibiotic resistance under dynamically sustained drug selection , 2011, Nature Genetics.

[2]  S. Solomon,et al.  Antibiotic resistance threats in the United States: stepping back from the brink. , 2014, American family physician.

[3]  Thomas A. Henzinger,et al.  The Algorithmic Analysis of Hybrid Systems , 1995, Theor. Comput. Sci..

[4]  Hermann Kopetz,et al.  Real-time systems , 2018, CSC '73.

[5]  Remy Chait,et al.  Building a morbidostat: an automated continuous-culture device for studying bacterial drug resistance under dynamically sustained drug inhibition. , 2013, Nature protocols.

[6]  A. Novick,et al.  Description of the chemostat. , 1950, Science.

[7]  David Botstein,et al.  Nutritional homeostasis in batch and steady-state culture of yeast. , 2004, Molecular biology of the cell.

[8]  Antoine Girard,et al.  SpaceEx: Scalable Verification of Hybrid Systems , 2011, CAV.

[9]  Marco Caccamo,et al.  A step towards verification and synthesis from simulink/stateflow models , 2011, HSCC '11.

[10]  D. Bhattacharya,et al.  Faculty Opinions recommendation of Genomic analysis of a key innovation in an experimental Escherichia coli population. , 2012 .

[11]  Taylor T. Johnson.  Uniform verification of safety for parameterized networks of hybrid automata , 2013 .

[12]  Paul A Hoskisson,et al.  Continuous culture--making a comeback? , 2005, Microbiology.

[13]  G. Wolkowicz.  The theory of the chemostat: Dynamics of microbial competition , 1996 .