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Toward a better understanding of the microbial growth inhibition by electromagnetic fields

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Start date : 1 September 2017

offer n° IMEPLaHC-01252017-RFM

             Logo_IMEP-LAHC                                                               PhD proposal – sept. 2017 to sept. 2020        

                                     Title : Toward a better understanding of the microbial growth inhibition by electromagnetic fields

 

Keywords :
Electromagnetism, microbial decontamination, growth inhibition mechanisms, numerical modeling

Labs :
– Institut de Microélectronique, Electromagnétisme et Photonique (IMEP-LAHC) http://imep-lahc.grenoble-inp.fr
Minatec – Grenoble  – 3, parvis Louis Néel, BP 257
38 016 GRENOBLE Cedex 1, FRANCE

– Institut des Géosciences de l’Environnement (IGE, UGA-CNRS-IRD-G-INP) http://www.ige-grenoble.fr
70 rue de la Physique, Bâtiment OSUG B , BP 53
38 041 GRENOBLE Cedex 09, FRANCE

PhD Director : XAVIER Pascal, pascal.xavier@univ-grenoble-alpes.fr, +33 (0)4.56.52.95.69,+33(0)4.76.82.53.65
PhD co-director : MARTINS Jean, jean.martins@univ-grenoble-alpes.fr, +33 (0)4.76.63.56.04

Funding : french research ministery doctoral grant (application must be made before march-april 2017)

Required skills and level of the applicant :
Master in biomedical or biophysical engineering. Some work experience in electronics are also desired. The proposed study is very large, from multiphysics modeling to experimental microbiological tests.

The transdisciplinary nature of this thesis provides skills in several domains as the design in analog and digital electronics instrumentation, testing in microbiology, multi-physics numerical finite element modeling. These skills will greatly be valued in a resume.
All necessary means for the progress of the work are already available within the two partner groups. The management team is composed of a university Professor and a CNRS Research Director, accompanied by two more Assistant Professors on instrumental aspects and modeling.

1.     Scientific context and objectives

In the battle against pathogenic microorganisms, in addition to the oldest curative process of pasteurization (heating) requiring large quantities of energy, current methods are mechanical actions (brushing) and the action of chemical products: acetic acid, hydrogen peroxide, chlorine dioxide… For example, the cheese industry is one of the largest users of chlorine. Unfortunately, some strains have become very resistant.
The use of physical means for the decontamination of water has only been explored for less than a century. Low intensity DC or AC current has been proven to be effective. This process was reported more than fifty years ago. Most articles in the literature focus on improving the effectiveness of antibiotics against microorganisms by applying weak currents, a phenomenon called “bioelectric effect” (Blenkinsopp 1992, Costerton 1994, Giladi 2008).
Several mechanisms have been proposed for this inhibition: electrolysis, production of toxic derivatives and free radicals linked to the electrodes, modification of the pH. In addition, the application of a high amplitude pulsed electric field has been used as a non-thermal effect for the inhibition of bacterial growth with the major disadvantage of the phenomenon of electroporation.
High-frequency electromagnetic fields (above MHz) but with small amplitudes (<1 V / cm) have also been reported as a means to improve the susceptibility of bacteria to antibiotics or to decrease their number in the absence of an antibiotic (Asami 2002, Bai 2006, Caubet 2004).
By exploiting this idea between 2011 and 2015, in the framework of the APELBIO project resulting from the ECO-INDUSTRY program of the French Ministry of Industry and carried out by the SME LEAS, in collaboration with SCHNEIDER ELECTRIC and two Grenoble laboratories involved in this project (IMEP-LAHC and IGE), we validated an innovative, non-polluting and energy-saving experimental concept for the prevention of microbial contamination in aqueous media . We noted that the optimal frequency for which this inhibition was maximal appeared to depend on the type of bacterium, which was confirmed by our numerical simulations using the COMSOL Multiphysics software with an original model (Xavier 2017). So we had the idea of using a white noise source (10kHz-10MHz) instead of a CW source. Our results, better than with a fixed frequency source, are in the state of the art and led to a patent in May 2015. Unfortunately, the fine mechanisms leading to the growth inhibition of bacterial cells could not be precisely identified. This is what we intend to do in the framework of this thesis project.

2. General issues

This doctoral work aims to contribute to a better understanding of the molecular mechanisms of the interactions between electromagnetic waves and biological cells in a context of microbial decontamination in liquids. The project is based on the recent work carried out within the framework of the APELBIO project cited above and seeks to identify the mechanisms of action of electromagnetic waves limiting the growth of micro-organisms in suspension (bacteria, yeasts and fungi, …). The different stages of doctoral work will therefore be:
1 / Design and realization of a compact instrument covering the 10 Hz – 50 MHz range for pilot experiments. This stand-alone instrument is based on the implementation of a DDS component in conjunction with a microcontroller. It will have the task of generating in a perfectly controlled manner the electromagnetic noise enabling the decontamination and, alternatively, of measuring the impedance detecting the decontaminating effect. A first prototype has already been developed recently and allowed us to carry out preliminary tests with the bacterium Escherichia coli.
The in situ detection of the decontamination efficiency requires a bio-impedance measurement of the solution containing the microorganisms. This last subject has, for many years, given rise to many patents and works: we know what toavoid to build a compact device, insensitive to the effects of electrodes
2 / Decontamination tests carried out following a wide range of physical conditions (amplitude and frequency of electromagnetic waves), chemical (variable geochemical environment, in terms of composition and strength ionic properties of the solution, which have an important effect on the surface properties of living cells, such as their zeta potential or their dispersed or agglomerated state which can potentially modulate electromagnetic effects) and biological (the type of bacterium studied could influence the electromagnetic effects already Observed on E. coli).
During the first year of the thesis, the doctoral student will establish a rigorous and reliable experimental plan which will allow to test all the factors initially identified as preponderant in the process of inhibition of the biological growth. From an experimental point of view, these tests will consist in treating cell cultures obtained under different conditions and culture media and in standardized conditions (same initial cell concentration, temperature, agitation, etc.). For each assay, cell growth and viability rates (flow cytometry, fluorescence microscopy, qPCR) and ATP synthesis (measured by bioluminescence and reflecting the cell physiological state) will be determined. Electromagnetic treatments (far below levels leading to thermal effects) will be carried out on selected bacterial models representative of different media and contexts (Escherichia coli, Pseudomonas sp, Salmonella anatum, Listeria sp., Bacillus subtilis, Listeria innocu … ). Tests with cell mixtures will also be conducted. In this case, molecular biology approaches will be implemented to monitor the effects of electromagnetic waves: genetic fingerprinting and cellular quantification by qPCR.
3 / Comprehension and numerical modeling under COMSOL Multiphysics of the mechanisms involved at the molecular and membrane level during the application of electromagnetic signals of low intensity. In our previous work, the model of the bacterium developed internally was simple. It is now necessary to refine this numerical model without, however, aiming at the complexity of the elaborated models used in synthetic biology, following two parallel paths, namely the modeling of microorganisms on the one hand and their environment on the other. The coupling and comparison of the results of modeling and microbiological follow-up of the decontamination tests should make it possible to identify the main mechanisms of action of the waves on the living cells.
As far as the environmental part is concerned, we wish to model realistically the behavior of the nutrient solutions in which the microorganisms are immersed, taking into account, in terms of electrical conduction and dielectric polarization, the various components of these solutions. Moreover, the modeling of the environment involves the fine study of the interface in the vicinity of the electrode.
The second major part of the proposed modeling work concerns the microorganism itself. We wish to pursue the approach that prevailed in our earlier work. Thus, the study previously carried out on E. coli has used a purely passive and dielectric shell model. This model made it possible to identify the frequency range leading to a maximum current absorbed by the microorganism, when an alternating voltage was applied to the medium loaded by the bacteria. Several improvements are needed today to refine the understanding of the phenomenon. First of all, it is necessary to take into account the presence of the charges (mostly protonic) involved in the bacterium, whether these are at rest or in motion: the bacterium becomes an active system. In the second place, it will be necessary to take into account the phenomena of mechanical vibrations, intervening in particular at the membrane level, since these also contribute to load shifts, the creation of electromagnetic fields or coupling with external fields.
To conclude on the modeling part, it should be noted that all these simulations are likely to lead to the development of an equivalent electrical network. This approach will make it possible, thanks to a systematic upstream study based on COMSOL Multiphysics, to treat general cases more simply by using free tools on the market (for example, SPICE software).

3. References

* IMEP-LAHC and IGE groups
Xavier P., D. Rauly, E. Chamberod and J.M.F. Martins. Theoretical evidence of maximum intracellular currents vs frequency in an Escherichia coli cell submitted to AC voltage. Bioelectromagnet. J. DOI:10.1002/bem.22033.
Archundia D., C. Duwig, L. Spadini, G. Uzu, S. Guédron, M.C. Morel, R. Cortez, Oswaldo Ramos, J. Chincheros, and J.M.F. Martins. How uncontrolled urban expansion increases the contamination of the Titicaca lake basin (El Alto – La Paz, Bolivia). Water, Air and Soil Pollution J. In press. 2017.
Navel A., L. Spadini, J.M.F. Martins, E. Vince and I. Lamy. Soil aggregates as a scale to investigate organic matter versus clay reactivities toward metals and protons. Accepted with revision. Eur. J. Soil Sci. 2017.
Archundia, D., C. Duwig, F. Lehembre, S. Chiron, M-C Morel, B. Prado, M. Bourdat-Deschamps, E. Vince, G. Flores Aviles and J.M.F. Martins. Antibiotic pollution in the Katari subcatchment of the Titicaca Lake: major transformation products and occurrence of resistance genes. Sci. Total Environ. 576 : (15) 671–682. 2017.
Ivankovic T., S. Rolland du Roscoat, C. Geindreau, P. Séchet, Z. Huang and J.M.F. Martins. Development and evaluation of an experimental and protocol for 3D visualization and characterization of bacterial biofilm’s structure in porous media using laboratory X-Ray Tomography. (GBIF-2016-0154). In press Biofouling J.
Simonin M., J.M.F. Martins, G. Uzu, E. Vince and A. Richaume. A combined study of TiO2 nano-particles transport and toxicity on microbial communities under acute and chronic exposures in soil columns. DOI: 10.1021/acs.est.6b02415. Environ. Sci. & Technol. 50: 10693–10699. 2016.
Simonin M., J. P. Guyonnet, J.M.F. Martins, M. Ginot and A. Richaume. Influence of soil properties on the toxicity of TiO2 nanoparticles on carbon mineralization and bacterial abundance. J. Haz. Mat. 283: 529-535. 2015.
D. Rauly, E. Chamberod, P. Xavier, J. M.F. Martins, J. Angelidis, H. Belbachir. First approach toward a modelling of the impedance spectroscopic behavior of microbial living cells, COMSOL Conference, Grenoble, 14-16 Octobre 2015
D. Rauly, E. Chamberod, P. Xavier, J. M.F. Martins, J. Angelidis, H. Belbachir, Stochastic Approach for EM Modelling of Suspended Bacterial Cells with Non-Uniform Geometry & Orientation Distribution, 36ème Progress In Electromagnetics Research Symposium (PIERS 2015), Prague (Rép Tchèque), 06-09/07/2015

* Others
Asami K. 2002. Characterization of biological cells by dielectric spectroscopy. Journal of Non-Crystalline Solids 305(1–3):268–277.
Blenkinsopp, A E Khoury, and J W Costerton. Electrical Enhancement of biocide efficay against Pseudomonas aeruginosa biofilms. Applied and Environmental Microbiology    Appl. Environ. Microbiol. November 1992 ; 58:11 3770-3773
Bai W, Zhao KZ, Asami K. 2006. Dielectric properties of E. coli cell as simulated by the three-shell spheroidal model. Biophysical Chemistry 122 :136–142.
Caubet R, Pedarros-Caubet F, Chu M, Freye E, de Belém Rodrigues M, Moreau JM, Ellison WJ. 2004. A radio frequency electric current enhances antibiotic efficacy against bacterial biofilms. Antimicrobial Agents and Chemotherapy 48(12):4662-4664.
Costerton JW, Ellis B, Lam K, Johnson F, Khoury AE. 1994. Mechanism of electrical enhancement of efficacy of antibiotics in killing biofilm bacteria. Antimicrobial Agents and Chemotherapy 38(12):2803-2809.
Giladi M, Porat Y, Blatt A, Wasserman Y, Kirson ED, Dekel E, Palti Y. 2008. Microbial growth inhibition by alternating electric fields. Antimicrobial Agents Chemotherapy 52(10):3517–3522.
Guiné V, Spadini L, Muris M., Sarret G., Delolme C., Gaudet JP, Martins JMF. 2006, Zinc Sorption to cell wall components of three gram-negative bacteria: a combined titration. Modelling and EXAFS study. Environ. Sci. Technol.  40 :1806-1813.

  • Keywords : Engineering science, Electronics and microelectronics - Optoelectronics, FMNT, IMEP-LaHc
  • Laboratory : FMNT / IMEP-LaHc
  • CEA code : IMEPLaHC-01252017-RFM
  • Contact : pascal.xavier@univ-grenoble-alpes.fr

Advanced X-ray Characterisation for the development of efficient high power transistors

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Start date : 1 October 2017

offer n° SL-DRT-17-0740

One of the objectives of the « Commissariat aux Energies Atomiques et Alternatives » (CEA) is to support scientific and technological research for renewable energies. As part of this objective, CEA-LETI is developing highly efficient power transistors and lighting (with LEDs) with several important industrial partners. These high performance components include thin layers of III-nitride semiconductor materials (GaN, AlGaN, InGaAlN), which are grown by epitaxial deposition on 200 mm diameter silicon wafers. The reliability and performance of these layers is closely linked to their microstructural characteristics, such as their crystalline quality, the strain in the layers and any composition gradients.

Currently, CEA-LETI is studying two different III-N hetero-structures for use in high power components. The first, AlGaN/GaN structures, are already being integrated into industrial devices, while the second, InGaAlN/GaN have the potential to produce even better performance, especially as they are lattice matched on GaN pseudo-substrates. Finally, it has been shown [1] that ultrathin layers of dichalcogenide materials (MoSe2, MoS2, etc) can be integrated into these components to minimize strain during growth, and to improve the performance of the devices.

It is necessary to have a deep understanding of the microstructure of these materials in order to fully master such complex systems. It is therefore the goal of this PhD to develop techniques to measure and analyze these complex hetero-structures using techniques based on X-rays. These developments will both ensure the quality of the GaN based structures currently being used at CEA-LETI, and increase the understanding of the innovative structures described above, leading to their improvement. The work will include:

– The determination of the microstructure of these materials (quaternary alloys of InGaAlN on GaN, interface layers influence on the quality of growth) and especially the measurement of strain fields in the materials with reciprocal space mapping using X-ray diffraction

– Analysis of segregation/diffusion at the interfaces or in the bulk of InGaAlN by combining X-ray diffraction, grazing incidence X-ray fluorescence (GIXRF), and X-ray photoelectron spectroscopy (XPS). In-situ annealing will also be implemented in these experiments.

For these studies, the student will have access to state of the art laboratory equipment (whether for characterization or growth of structures) and will also have the opportunity to work at the synchrotron. The analysis will also be complemented with other advanced characterization tools (Auger spectroscopy, Atom probe tomography, TEM etc) available on the nano-characterisation platform at CEA-LETI.

[1].Gupta, P.; Rahman, A. A.; Subramanian, S.; Gupta, S.; Thamizhavel, A.; Orlova, T.; Rouvimov, S.; Vishwanath, S.; Protasenko, V.; Laskar, M. R.; Xing, H. G.; Jena, D.; Bhattacharya, A. Scientific Reports 2016, 6, 23708.

  • Keywords : Engineering science, Materials and applications, Metrology, DTSI, Leti
  • Laboratory : DTSI / Leti
  • CEA code : SL-DRT-17-0740
  • Contact : emmanuel.nolot@cea.fr

Study of TADF (Thermal Activated Delayed Fluorescence) emissive materials to increase the performance of OLED stacks

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Start date : 1 September 2017

offer n° SL-DRT-17-0728

In the field of micro-displays, achieving high luminance has become essential today in order to meet the needs, the projection and the display systems integrated in helmets or glasses. The performances of the current organic light-emitting diodes (OLEDs), in terms of luminance and lifetime, do not make them possible to meet high luminance requirements. Improving the performances of OLEDs and in particular emissive materials is therefore essential. Recently, a new generation of emissive materials, TADF (Thermal Activated Delayed Fluorescence) can achieve the resquested performances. Delayed fluorescence is a concept for increasing the luminescence efficiency of OLED devices. This involves using the passage through the triplet state followed by the return to the singlet state at the origin of the emission of light. Thanks to this concept, it is theoretically possible to achieve a quantum efficiency of 100%. Currently, in our standard OLED devices, the emitting materials used are phosphorescent (PhOLED) based on heavy metals such as iridium or platinum. They are interesting from the emissive point of view but have disadvantages in terms of cost and availability. The objective of this thesis will be to increase the performance of OLED by integrating these TADF materials into our stacks which use a dopded transport materials and are in Top emission configuration. To do this, the PhD student will have to define, in terms of adjustment of the energy levels and thickness of the different materials, the complete OLED stack based on TADF. In addition, he will be responsible for the elaboration of the OLEDs samples, using an evaporation deposition machine, and the electro-optical characterization of these on existing measuring benches. After defining the optimal stacking, a study on the understanding of the phenomena of “Roll Off” and degradation of materials under voltage will have to be carried out.

This work will be in collaboration with one or several partners who manufacture these TADF materials. In this context, the doctoral student will have to manage a collaboration with the partners in the form of regular exchange in order to enter to a loop of continuous improvement of TADF materials.

  • Keywords : Engineering science, Materials and applications, DOPT, Leti
  • Laboratory : DOPT / Leti
  • CEA code : SL-DRT-17-0728
  • Contact : benoit.racine@cea.fr

High-performance TeraHertz detectors for passive imaging

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Start date : 1 October 2017

offer n° SL-DRT-17-0722

The Terahertz (THz, 300 GHz-3 THz) frequency band triggers a high interest in numerous application domains (imaging, spectrometry, industrial inspection and test, surveillance, instrumentation) thanks to the good propagation properties through non-conductive materials, the presence of resonance frequencies typical of numerous molecules, the potential for high spatial resolution, and their non-ionizing properties. CEA-LETI is a world-leading research laboratory in THz technologies and developed several THz detectors and imaging circuits, both cooled and uncooled, for imaging applications. Recently, a THz imager was demonstrated and is in industrialization stage.

The objective of this PhD thesis is to investigate and develop a new THz detector technology with a significant breakthrough in terms of sensitivity enabling passive imaging applications. The PhD student will work in a team gathering all the expertise, instrumentation and facilities required in this project (system studies, design and simulation, fabrication, characterization) and will tackle all these activities in order to design new detectors, supervise their fabrication in CEA-LETI clean rooms and characterize them.

  • Keywords : Engineering science, Electromagnetism - Electrical engineering, Electronics and microelectronics - Optoelectronics, DOPT, Leti
  • Laboratory : DOPT / Leti
  • CEA code : SL-DRT-17-0722
  • Contact : jerome.meilhan@cea.fr

SystemC Acceleration for multi-physics co-simulation and heterogeneous model complexity

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Start date : 1 October 2017

offer n° SL-DRT-17-0315

The increase in System-on-Chip (SoC) complexity, driven by the reduction in transistor size, called for a design flow integrating validation as early as possible in the design phases. The SystemC hardware description language, is widespread to model and simulate SoCs in this flow. It provides Virtual Prototypes (VP) that ease the development and validation of hardware/software integration in the earliest design phases.

The advent of Internet of Things (IoT) and more generally of autonomous systems requires simulation solution integrating at the same time processing elements but also external actioners and sensors. This calls for SystemC co-simulation with Multiphysics tools. As simulation speed is key to reduce design time and time to market, fast simulation solutions are needed.

CEA and Verimag have both developed state-of-the-art solutions for the acceleration of SystemC simulation. These approaches provide significant acceleration (more than one order of magnitude) to parallel models whose computing complexity is homogeneous. However, they fail to provide significant acceleration when heterogeneous model complexity is encountered. Such heterogeneity historically stemmed from various abstraction levels (CABA, TLM). But Multiphysics simulation will also exhibit strong variation in complexity due to the diversity of physical phenomena.

This thesis will target the definition of a novel parallel SystemC simulation kernel able to accelerate simulations in the context of Multiphysics co-simulation and heterogeneous complexity. To achieve this, the student will leverage the joint usage of state-of-art solutions. The work will take into account models’ synchronization frequencies so as to maximize their parallelism. The thesis will also target the identification of relevant hardware execution support for every SystemC model types, and use this knowledge to define adaptive scheduling of SystemC threads on heterogeneous computing architecture (CPU/GPU/FPGA).

  • Keywords : Engineering science, Computer science and software, Electronics and microelectronics - Optoelectronics, DACLE, Leti
  • Laboratory : DACLE / Leti
  • CEA code : SL-DRT-17-0315
  • Contact : tanguy.sassolas@cea.fr
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