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Fast design of centrifugal lab-on-a-chip systems

Von Ingmar Schwarz (05.03.2014)

Today biochemical assays are used for a large number of applications such as the detection of genetically determined illnesses, pathogens, fungicides and insecticides in food, bacterial or viral infections and even chemical weapons. Often it is desirable to be able to perform these assays either fast and/or at a specific place without the detour of shipping a sample to a specialized central laboratory. To allow this, an assay of interest can be fully automated on a so called lab-on-a-chip system (LOAC) [1]. In these systems most or all reagents are present so that only a small number of simple operations needs to be performed by the person that applies the test. A number of labs-on-a-chip that meet the requirements for Point-of-Care (POC) application are widely available such as the paper-based maternity test strips and blood-sugar test strips. These test strips are very cheap in production and simple enough to allow untrained persons to apply the test and interpret the results. Our goal is to extend the range of possible tests also to more complex assays that are hardly or not suitable for the paper based approach while maintaining the simplicity for the end user and the potential of low cost production [2]. Therefore we focus on centrifugal polymer disks with microfluidic structures as basic platform, on which the assays can be performed [3]. 

This approach has several advantages such as the possibility to perform aliquoting without pipetting errors, multiplexed reactions without cross-contamination risks, the actuation of liquids without connections to external pressure sources that might introduce contaminations or the possibility to process an assay on a standard laboratory centrifuge or even a modified CD/DVD player. The most prominent advantage is that by using a common platform – the centrifugal disk – once developed "unit operations" can be reused and combined in the automatization of future LOAC systems. Examples of unit operations are capillary valves, pneumatic pumping capabilities, robust aliquoting structures or structures that allow for mixing of reagents. This modular approach reduces development times and increases robustness. As more and more unit operations are available, dynamic interactions become more common and need to be understood, to be able to design more integrated chips. My thesis is concerned with the development and simulation of new unit operations to solve centrifugal microfluidic problems that arise in the research projects conducted in the LOAC-division of HSG-IMIT. 

Because of the very long computation times for 3d resolved CFD simulations of liquid flow in cases where free interfaces need to be taken into account, these simulations are in general not useful as a practical tool for LOAC system design. For this reason we follow a lumped network model approach in which liquid flow through microfluidic networks is treated analogous to electrical networks. Here pressure differences act as driving forces, viscous dissipation leads to resistances and flow rates as are analogous to electric current [4].

[Bildunterschrift / Subline]: Figure 1: Left: Lumped network model representing a typical unit operation. All blocks represent individual lumped models of element structures of the unit operation. Apart from simulation-environment related blocks, this exemplary model consists of channels with radial orientation on the disk, tangentially oriented channels, a reservoir filled with an ideal gas and a collection reservoir. The channels form a siphon structure to which the ideal gas reservoir is connected. In a potential liquid flow scenario the “Starting channel” and “Siphon base” are filled with liquid in the beginning, the remaining channels/chambers are empty. By heating of the system, the expanding gas in the ideal gas reservoir pushes liquid from the “Starting channel” and “Siphon base” against the centrifugally induced hydrostatic pressure to the radially inward siphon crest. When the liquid passes the siphon crest, the centrifugal pressure on the falling side of the siphon leads to a complete transfer of the liquid to the “Liquid drain”. Right: Example of a centrifugal polymer LOAC system for genotyping assays that determine the presence of methilin-resistant Staphylococcus aureus (MRSA) [5].

As this approximation level reduces the complexity of the calculations to a system of first order differential-algebraic equations, fast and robust numerical solving techniques exist. On the simulation side, my dissertation includes the development of a common framework for the simulation of different lumped unit operation models as well as the development of the lumped models themselves. In cases where no analytical models of the 3d behavior of the unit operations are available, the process of developing a lumped network model includes the experimental or 3d-simulation based determination of characteristic parameters of the unit operation. Examples of such unit operations are the mixing of liquids, such as a lysis buffer with a bacteria containing sample to release the bacteria-DNA, or the mixing of solid particles with liquids, such as silicate beads and bacteria-sample-lysate to capture released DNA from the liquid phase [6]. 

[Bildunterschrift / Subline]: Figure 2: Experimental picture taken via a stroboscopic setup from a polymer disk under rotation. In the depicted chamber, silica beads with magnetic core are mixed via two complementary processes: The disk is stopped periodically to allow a magnet to collect the beads in the upper part of the chamber. At subsequent acceleration the beads are pushed to the bottom and are thereby mixed with the liquid. The second mixing process is induced by the fast changes of the rotation frequency which add a circular liquid flow due to the euler force – gradient in radial direction.

Another example is the surface flow dependent enzymatic reaction of a substrate on a functionalized surface during an ELISA assay. An example for a dynamic unit operation exploiting the interaction of several microfluidic elements is the so called "pneumatic inward pumping" which allows to pump liquid from chambers that are located radially outward on the disk to chambers that are located radially inward [7]. With this unit operation, the centrifugal actuation force in radial direction can be used several times instead of only once by simply pumping the liquid back to the center, once a liquid has reached a radial outward chamber on its way through the different assay-reaction stages.

The goal of this thesis is to increase the spectrum of tools for the fast simulation based design of highly integrated LOAC systems. With more and more unit operations available and precise lumped network models, this goal comes into reach. 

Reference List

[1] Mark, D., Haeberle, S., Roth, G., von Stetten, F., and Zengerle, R., Microfluidic Lab-on-a-Chip Platforms: Requirements, Characteristics and Applications,pp. 1153-1182,2010

[2] Focke, M., Kosse, D., Müller, C., Reinecke, H., Zengerle, R., and von Stetten, F., Lab-on-a-Foil: microfluidics on thin and flexible films,pp. 1365-1386,2010

[3] Ducrée, J., Haeberle, S., Lutz, S., Pausch, S., von Stetten, F., and Zengerle, R., The centrifugal microfluidic Bio-Disk platform,pp. S103-S115,2007

[4] M.Sesterhenn, J.Mellmann, M.Löhr, B.Stierle, T.Strobelt, and H.Sandmaier, Simulation of (Self-)Priming in Capillary Systems Using Lumped Models,pp. 538-541,1999

[5] Focke, M., Stumpf, F., Faltin, B., Reith, P., Bamarni, D., Wadle, S., Müller, C., Reinecke, H., Schrenzel, J., Francois, P., Mark, D., Roth, G., Zengerle, R., and von Stetten, F., Microstructuring of polymer films for highly sensitive genotyping by real-time PCR on a centrifugal microfluidic platform,pp. 2519-2526,2010

[6] Grumann, M., Geipel, A., Riegger, L., Zengerle, R., and Ducrée, J., Batch-mode mixing on centrifugal microfluidic platforms,pp. 560-565,2005

[7] Zehnle, Steffen, Schwemmer, Frank, Roth, Gunter, von Stetten, Felix, Zengerle, Roland, and Paust, Nils, Centrifugo-dynamic inward pumping of liquids on a centrifugal microfluidic platform,pp. 5142-5145,2012

Scientific career
  • 2004-2010
  • Diplom Studies in Biophysics, University of Bayreuth
  • 2011-2012
  • Member of research staff at the German Primate Center, Göttingen
  • since 2012
  • PhD under supervision of Prof. Dr. Roland Zengerle in the Lab-on-a-Chip Division of the IMTEK Institute for Application Development, Freiburg.

Awards and scholarships
  • * Erasmus exchange Program, Université 7 Denis Diderot, Paris

  • * I. Schwarz, A. Fortini, C. S. Wagner, A. Wittemann, M. Schmidt. Monte Carlo computer simulations and electron microscopy of colloidal cluster formation via emulsion droplet evaporation. J. Chem. Phys. 135, 244501 (2011).