IMS > Research > Current Projects > Lifelines measured with Lagrangian Sensor Particles (DFG)

CHOlife+ a subproject of SPP 2170 "InterZell"

Novel Production Processes and Multi-Scale Analysis, Modelling and Design of Cell-Cell and Cell-Bioreactor Interactions (SPP2170)

Motivation

Reliable production of new biological agents and efficient strategies to scale-up the processes to industrial sizes are of particular importance. This is a major challenge because industrial scale bioreactors are often subjected to transient cultivation conditions caused by spatial and temporal gradients, which often diminish the cellular performance and cell viability of microorganisms (Lara et al., 2006; Paul and Herwig, 2020). Particularly modern local probes, which are usually located near the reactor wall (Busse et al., 2017) lack the ability to spatiotemporally quantify these heterogeneities in mixing and cellular performance throughout the reactor. Hence, the residence times of cells in prevailing compartments (Kuschel and Takors, 2020) and their turbulent pathways, also called lifelines (Lapin et al., 2004), cannot be mapped, which emphasizes the necessity for a transfer technology between laboratory and industrial scale.

Goals

Lagrangian Sensor Particles (LSPs) provide experimentally accessible trajectories and spatiotemporal information that represent characteristic lifelines inside stirred tank reactors (STRs). Their aim is to mimic cellular exposure to gradients such as pH, dissolved oxygen, or substrate concentration. However, LSP behaviour is influenced by constraints in miniaturisation, sensor design, and inertial flow-following capabilities, especially in turbulent regimes, making systematic validation essential.

To address this, the project combines experiments and numerical simulations across laboratory-, pilot-, and production-scale reactors. High-resolution 4D-PTV measurements in a 3 L STR deliver detailed inertial particle trajectories for benchmarking Lattice-Boltzmann Large Eddy Simulations (LBM-LES). In parallel, multiple LSP designs are investigated in 200 L and 15,000 L transparent reactors to assess how geometry, hardware, buoyancy, and shell properties affect axial distribution, residence times, and trajectory fidelity.

A key objective is to use LSP data to validate and improve the numerical framework, ensuring reproducibility and reliable prediction of particle flow-following behaviour across scales. This includes assessing particle Reynolds and Stokes numbers, comparing experimental and simulated lifelines, and quantifying compartment transitions and mixing phenomena.

Building on this foundation, the project shifts from traditional single-metric scale-up and scale-down approaches (e.g., using only mixing time) toward a Lagrangian, experience-based scaling strategy. By integrating multiphase LBM-LES, mixing-time experiments, and LSP-derived lifelines across all scales, the goal is to capture the actual hydrodynamic environments that cells experience during industrial cultivation and to replicate these conditions reliably at laboratory scale.

The overarching aim is to establish a validated, multiphase Lagrangian characterisation framework that enables more realistic and predictive scale-down bioreactor development.

We gratefully acknowledge the funding by the German Research Foundation (DFG) within the Priority Program “InterZell” (SPP2170, project number 427899833).

Person to contact: M.Sc. Ryan Rautenbach

Financing: German Research Foundation (Deutsche Forschungsgemeinschaft - DFG)

Duration:

December 2019 - November 2022 (first funding period)

June 2023 - May 2026 (second funding period)

Partners:

Prof. Dr.-Ing. Ralf Takors, US, Institute of Biochemical Engineering (IBVT);

Prof. Dr. Georg Sprenger, US, Institute of Microbiology (IMB);

Prof. Dr. rer. nat. Miriam Agler-Rosenbaum, Leibniz-HKI;

Prof. Dr.-Ing. Jochen Büchs, RWTH, Biochemical Engineering (AVT);

Dr. Meike Baumgart, FZ Jülich, Institute of Bio- and Geosciences (IBG);

Prof. Dr. Dietrich Kohlheyer, FZ Jülich, Institute of Bio- and Geosciences (IBG);

Dr.-Ing. Christian Dusny , Helmholtz UFZ;

Dr.-Ing. Stephan Noack, FZ Jülich, Institute of Bio- and Geosciences (IBG);

Prof. Dr.-Ing. Alexander Grünberger, UB, Multiscale Bioengineering;

Prof. Dr.-Ing. Heiko Briesen, TUM, Process Systems Engineering (SVT);

Dr. Anna-Lena Heins, TUM, Biochemical Engineering (BioVT);

Prof. Dr.-Ing. Andreas Kremling, TUM, Systems Biotechnology (SBT);

Dr. Katharina Pflüger-Grau, TUM, Systems Biotechnology (SBT);

Prof. Dr.-Ing. Dirk Weuster-Botz, TUM, Biochemical Engineering (BioVT);

Literature

Bisgaard, J., Muldbak, M., Cornelissen, S., Tajsoleiman, T., Huusom, J.K., Rasmussen, T., Gernaey, K.V., 2020. Computational and Structural Biotechnology Journal 18, 2908–2919. doi:10.1016/j.csbj.2020.10.004

Bisgaard, J., Muldbak, M., Tajsoleiman, T., Rydal, T., Rasmussen, T., Huusom, J.K., Gernaey, K.V., 2021. Chemical Engineering Research and Design 174, 471–485. doi:10.1016/j.cherd.2021.08.008

Buntkiel, L., Reinecke, S., Heller, A., Budelmann, C., Hampel, U., 2021. Dresdner Sensor-Symposium 2021, AMA Service GmbH, Von-Münchhausen-Str. 49, 31515 Wunstorf, Germany, Online, pp. 22–27. doi:10.5162/15dss2021/2.2

Busse, C., Biechele, P., de Vries, I., Reardon, K.F., Solle, D., Scheper, T., 2017. Eng. Life Sci. 17, 940–952. doi:10.1002/elsc.201700049

Kuschel, M., Takors, R., 2020. Biotechnology and Bioengineering 117, 2760–2770. doi:10.1002/bit.27457

Lapin, A., Müller, D., Reuss, M., 2004. Ind. Eng. Chem. Res. 43, 4647–4656. doi:10.1021/ie030786k

Lara, A.R., Galindo, E., Ramírez, O.T., Palomares, L.A., 2006. MB 34, 355–382. doi:10.1385/MB:34:3:355

Lauterbach, T., Lüke, T., Büker, M.-J., Hedayat, C., Gernandt, T., Moll, R., Grösel, M., Lenk, S., Seidel, F., Brunner, D., Bley, T., Walther, T., Lenk, F., 2019. Sensors and Actuators A: Physical 287, 29–38. doi:10.1016/j.sna.2019.01.003

Ouellette, N.T., O’Malley, P.J.J., Gollub, J.P., 2008. Phys. Rev. Lett. 101, 174504. doi:10.1103/PhysRevLett.101.174504

Paul, K., Herwig, C., 2020. Eng. Life Sci. elsc.201900162. doi:10.1002/elsc.201900162

Schanz, D., Gesemann, S., Schröder, A., 2016. Exp Fluids 57, 70. doi:10.1007/s00348-016-2157-1

Stine, J.M., Beardslee, L.A., Sathyam, R.M., Bentley, W.E., Ghodssi, R., 2020. Sensors and Actuators B: Chemical 320, 128381. doi:10.1016/j.snb.2020.128381

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