France: PhD student

“A MEMS based flow cytometer, for counting, weighting, density extraction of cells, organic and
synthetized nanoparticles”
. Keywords: MEMS resonators, microfluidic, biosensors, flow cytometry, nanoparticles
· Background:
The advances in micro- and nanofabrication technologies enable the preparation of increasingly smaller mechanical transducers capable of detecting the forces, motion, mechanical properties and masses that emerge in biomolecular interactions and fundamental biological processes ¹. These nanomechanical systems have gained considerable relevance in the last decade, and are a promising technique for medical diagnosis, biological research, functional genomics and pharmacological
research, because of their small size, high sensitivity and suitability for integration into miniaturized analytical systems.

One of the most promising emerging technology is based on nanomechanical NEMS resonators. They enable the measurement of mass with extraordinary sensitivity. Previously, samples as light as 7 zeptograms (1 zg = 10-21 g) have been weighed in vacuum ², and proton level resolution seems to be within reach. Resolving small mass changes requires the resonator to be light and to ring at a very pure tone—that is, with a high quality factor. In solution, viscosity severely degrades both of these characteristics, thus preventing many applications in nanotechnology and the life sciences where fluid
is required. Although the resonant structure can be designed to minimize viscous loss, resolution is still substantially degraded when compared to measurements made in air or vacuum. An entirely different approach eliminates viscous damping by embedding a micro- nanofluidic channel inside a MEMS resonator. This concept has been devised in 2003 in MIT by Scott Manalis’ group ³. In that case, the analyte liquid to be interrogated is confined and flowing through channels buried in the sensor, which is the contrary of the by far way of thinking. Based on that, the cantilever sensor, known as Suspended Microchannel Resonator (SMR), oscillates in dry medium (vacuum packaged
cavity), and thereof features very high quality factor (up to 15000) ⁴.
Recently the hosted team for this thesis topic, developed a MEMS mass sensor based on a high frequency square plate hollow resonator operating in a Lamé-mode ⁵-⁸. Using such strategy, resonance frequency x quality factor product as high as 3.4 × 1E11 could be measured while flowing fluid inside the resonator, which is the state of the art in liquid medium for MEMS /NEMS oscillators and at least one order of magnitude higher than previous structures alike ⁹. These performances provide a mass sensitivity improved by six orders of magnitude over a high-end commercial QCM. It
enabled DNA biomolecules to be weighed in solution in real-time with fg resolution (while the DNA targets continuously accumulate onto the channel inner walls surface coated with complementary DNA probes).

· Thesis objectives and overall ambition
Within the thesis, the student will develop a new generation of cells and nanoparticles counting system, and (state) identification by mass and density extraction, using micro- nanochannel embedded in high frequency MEMS/NEMS resonators. In this thesis, it is proposed to improve the existing system by several aspects
· The MEMS/NEMS sensor will be further miniaturized to improve mass resolution as
compared to existing devices down to a few attograms and be able to track single virus,
nanoparticle. The sensor variants will first be developed as single device designs and scaled
up to sensor arrays with increased throughput in the second phase of the thesis.
· Transduction method will be optimized to boost the signal to noise ratio, and correlative
approach combining either different transduction methods or resonant frequency modes will be carried out to provide extra information on the interrogated particle.
· Experimental test bench automation to allow accurate feedback between the mass sensing
signal and the fluidic pressure controlled sources to transport the cells or nanoparticles through the sensor.

The student task will include the microfluidic sensor chip design (resonators, and transduction scheme) and follow up of their production within the LETI clean room, establish counting protocols with existing lab tools (flow cytometer), adaptation of the existing experimental setup, experiments to validate the counting, and sizing concept of this novel high resolution analysis tool with particle models (cells, both organic and inorganic nanoparticles).

The expected impact of this thesis project will provide researchers in nanotechnology and
nanomedicine with a new tool to better understand and advance a range of fields from nanomaterials and drug delivery to diagnostics. This multidisciplinary project will require skills in MEMS and μfluidic design, micro- and nano- scale flow phenomena, instrumentation, and experimental validation (fluidic and electrical tests)

· Collaboration:
This thesis will entered in the framework of an international collaboration. Some tests will be
performed in the Laboratory of P. Renaud at EPFL to combine a dedicated frond-end μfluidic sample preparation module with the developed mass sensing system.

· Requirements:
Successful candidates will have a master/diploma either in Engineering, Physics, biochemistry, microengineering or related fields. You are highly motivated, have a strong interest in MEMS/NEMS based sensing methods, μfluidics, instrumentation development, as well as complementary simulation and design. Ideally, you have an experience in one or several of the following areas: MEMS/NEMS resonators, μfluidics (micro- and nano- scale flow phenomena), biology, simulation methods (finite elements based or others), labview programming. Applicants need no experience in microfabrication techniques, however a profound understanding of sensors for biological applications is a plus. A target-oriented, structured attitude and team spirit are absolutely necessary. Excellent communication skills and fluency in English are required (working language will be either French or English). We further expect creativity in problem solving and integrative skills.

· We offer Excellent working conditions in a highly interdisciplinary environment (http://www-leti.cea.fr/en ). Further information on the working group can be found at: http://www.nanobio.fr/ (Science Park, campus West), and http://www-liphy.ujf-grenoble.fr/ (group of Elisabeth Charlaix)
The position is limited to a three years contract

Starting date: The intended thesis project should start around October-November 2013
· Thesis host location : CEA/LETI, MINATEC Campus | 17 rue des Martyrs | 38054 Grenoble Cedex 9 France ; www.leti.fr
· Application: Candidate should send CV, Cover Letter and References to: vincent.agache@cea.fr

References:
¹ J.L. Arlett J.L., E.B. Myers, M.L. Roukes, Comparative advantages of mechanical biosensors. Nat Nanotechnol. 6(4), 203-15 (2011)
² Y.T. Yang, C. Callegari, X.L. Feng, K.L. Ekinci, & M.L. Roukes, Zeptogram-scale nanomechanical mass sensing. Nano Letters 6, 583-586 (2006).
³ T. P. Burg and S. R. Manalis, “Suspended microchannel resonators for biomolecular detection,” Appl. Phys. Lett., vol. 83, no. 13, pp.
2698–2700, Sep. 2003.
⁴ T. P. Burg, M. Godin, S. M. Knudsen, W. Shen, G. Carlson, J. S. Foster, K. Babcock, and S. R. Manalis, “Weighing of biomolecules,
single cells and single nanoparticles in fluid,” Nature, vol. 446, no. 26, pp. 1066–1069, Apr. 2007.
⁵ V. Agache, G. Blanco Gomez, et al, Lab On a Chip, Vol. 11, No 15, pp. 2598-2603, June 2011.
⁶ V. Agache et al, Proceedings of IEEE MEMS 2011, pp.157-160, Mexico, January 23-27, 2011.
⁷ G. Blanco-Gomez, and V. Agache, IEEE Journal of Microelectromechanical Systems, Vol. 21, No. 1, pp. 224-234, Feb. 2012.
⁸ G. Blanco-Gomez, E. Trioux, and V. Agache, IEEE Electron Device Letters, Vol. 33, No. 4, pp. 609-611, April 2012
⁹ J. Lee, W. J. Shen, K. Payer, T. P. Burg and S. R. Manalis, Nano Lett., 2010, 10, 2537–2542.

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