Jürgen Hubbuch

Karlsruhe Institute of Technology

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Florian Dismer

Karlsruhe Institute of Technology

Gang Wang

Boehringer Ingelheim (Germany)

Stefan A. Oelmeier

Boehringer Ingelheim (Germany)

Tobias Hahn

University of Rostock

Matthias Rüdt

Karlsruhe Institute of Technology

David Saleh

Boehringer Ingelheim (Germany)

Till Briskot

Boehringer Ingelheim (Germany)

Anna Osberghaus

Karlsruhe Institute of Technology

Pascal Baumann

Max Planck Institute for Software Systems

Eric von Lieres

Forschungszentrum Jülich

Cooperative Institutions

John Wiley & Sons (United States)

458

Hudson Institute

346

Bioengineering Center

296

National Center for Genetic Engineering and Biotechnology

284

Karlsruhe Institute of Technology

216

Biocat

112

Forschungszentrum Jülich

Boehringer Ingelheim (Germany)

Harvard University

Technical University of Munich

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Implementation of an analytical microfluidic device for the quantification of protein concentrations in high-throughput format

Engineering in Life Sciences (2016)

Carsten P. Radtke Marie‐Therese Schermeyer Yün Claudia Zhai Jacqueline Göpper Jürgen Hubbuch

10.1002/elsc.201500185

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Citations (1)

Detection, Quantification, and Propagation of Uncertainty in High-Throughput Experimentation by Monte Carlo Methods

Chemical Engineering & Technology (2012)

Anna Osberghaus Pascal Baumann Stefan Hepbildikler S. Nath Markus Haindl

Abstract Since the efficiency and speed of computing has increased significantly in the last decades, in silico‐approaches, e.g., quasi‐experimental analyses based on mechanistic simulations combined with Monte Carlo (MC) methods, are on the rise for uncertainty analyses and estimation of uncertainty propagation. The power and convenience of these approaches for high‐throughput processes will be demonstrated with a case study including miniaturized screenings on robotic platforms: a binding study for lysozyme on the adsorbent SP Sepharose FF in 96‐well format. All relevant uncertainties during the experimental preparations and automated high‐throughput experimentation were identified, quantified, and then embedded in a simulation algorithm for the calculation of uncertainty propagation based on MC sampling. A proof‐of‐concept for this approach is then followed by the simulation‐based analysis of various case scenarios. The MC‐based approach can easily be transferred to uncertainty analyses in other high‐throughput processes.

Propagation of uncertainty

Uncertainty Quantification

10.1002/ceat.201100610

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Citations (9)

Model-integrated process development demonstrated on the optimization of a robotic cation exchange step

Chemical Engineering Science (2012)

Anna Osberghaus K. Drechsel Sigrid K. Hansen Stefan Hepbildikler S. Nath

Robustness

10.1016/j.ces.2012.04.004

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Citations (52)

Mechanism and kinetics of protein transport in chromatographic media studied by confocal laser scanning microscopy

Journal of Chromatography A (2003)

Jürgen Hubbuch Thomas Linden Esther Knieps Anders Ljunglöf Jörg Thömmes

Sepharose

Bovine serum albumin

Protein Adsorption

10.1016/j.chroma.2003.08.112

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Citations (102)

Experimental characterisation of piezoelectric silicon micropump for drug delivery applications

Agnes Bußmann Henry Leistner Doris Zhou M. Wackerle Yücel Congar

10.24406/fordatis/143

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Citations (0)

Impact of Polymer Bioconjugation on Protein Stability and Activity Investigated with Discrete Conjugates: Alternatives to PEGylation

Biomacromolecules (2018)

Josefine Morgenstern Gabriela Gil Alvaradejo Nicolai Bluthardt Ana Beloqui Guillaume Delaittre

Covalent attachment of synthetic polymers to proteins, known as protein–polymer conjugation, is currently one of the main approaches for improving the physicochemical properties of these biomolecules. The most commonly employed polymer is polyethylene glycol (PEG), as evidenced by extensive research and clinical track records for its use in biopharmaceuticals. However, the occurrence of allergic reactions or hypersensitivity and the discovery of PEG antibodies, on the one hand, and the rise of controlled polymerization techniques and novel monomers, on the other hand, have been driving the search for alternative polymers for bioconjugation. The present study describes the synthesis, purification, and properties of conjugates of lysozyme with poly(N-acryloylmorpholine) (PNAM) and poly(oligoethylene glycol methyl ether methacrylate) (POEGMA). Particularly, conjugate species with distinct conjugation degrees are investigated for their residual activity, aggregation behavior, and solubility, by using a high-throughput screening approach. Our study showcases the importance of evaluating conjugates obtained by nonsite-specific modification through isolated species with discrete degrees of conjugation rather than on the batch level. Monovalent conjugates with relatively low molar mass polymers displayed equal or even higher activity than the native protein, while all conjugates showed an improved protein solubility. To achieve a comparable effect on solubility as with PEG, PNAM and POEGMA of higher molar masses were required.

Bioconjugation

PEGylation

Conjugate

Biomolecule

10.1021/acs.biomac.8b01020

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Citations (40)

Biomass/adsorbent electrostatic interactions in expanded bed adsorption: A zeta potential study

Biotechnology and Bioengineering (2003)

Dong‐Qiang Lin Peter J. Brixius Jürgen Hubbuch Jörg Thömmes Maria‐Regina Kula

Abstract Expanded bed adsorption is an integrated technology that allows the introduction of particle‐containing feedstock without the risk of blocking the bed. The biomass particles contained in the feedstock have to be treated as an integral part of the process and potential interactions between suspended biomass and the adsorbent must be excluded during process design. Because the electrostatic forces dominate the interactions between the biomass and adsorbent, the zeta potential has been studied as a tool to characterize biomass/adsorbent electrostatic interactions. The zeta potentials of four types of biomass (yeast intact cells, yeast homogenate, Escherichia coli intact cells, and E. coli homogenate) and two types of ion exchanger were measured systematically at varying process conditions. Using the cell transmission index from biomass pulse‐response experiments as a parameter, the relations between zeta potential and the biomass/adsorbent interaction were evaluated. Combining the influences from zeta potential of adsorbent (ζ a ), zeta potential of biomass (ζ b ), and biomass size (d), parameter (−ζ a ζ b d) was found to be an appropriate indicator of the biomass/adsorbent interactions in expanded beds under various liquid‐phase conditions for different types of biomass. The threshold value of parameter (−ζ a ζ b d) can be defined as 120 mV 2 μm for cell transmission of >90%, which means that systems with (−ζ a ζ b d) < 120 may have a considerable probability of forming stable expanded beds in a biomass suspension under the particular experimental conditions. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 83: 149–157, 2003.

Zeta potential

Particle (ecology)

Suspension

10.1002/bit.10654

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Citations (90)

Prediction and characterization of the stability enhancing effect of the Cherry-Tag™ in highly concentrated protein solutions by complex rheological measurements and MD simulations

International Journal of Pharmaceutics (2017)

Pascal Baumann Marie‐Therese Schermeyer Hannah Burghardt Cathrin Dürr Jonas Gärtner

Biopharmaceutical

Protein Stability

Pea protein

10.1016/j.ijpharm.2017.08.068

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Citations (6)

Self-interaction chromatography in pre-packed columns: A critical evaluation of self-interaction chromatography methodology to determine the second virial coefficient

Journal of Chromatography A (2013)

Natalie Rakel Kristina Schleining Florian Dismer Jürgen Hubbuch

10.1016/j.chroma.2013.03.077

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Citations (11)

Cell Separation in Aqueous Two‐Phase Systems − Influence of Polymer Molecular Weight and Tie‐Line Length on the Resolution of Five Model Cell Lines

Biotechnology Journal (2017)

Sarah C. Zimmermann Sarah Gretzinger Philipp K. Zimmermann Are Bogsnes Mattias Hansson

The availability of clinical-scale downstream processing strategies for cell-based products presents a critical juncture between basic research and clinical development. Aqueous two-phase systems (ATPS) facilitate the label-free, scalable, and cost-effective separation of cells, and are a versatile tool for downstream processing of cell-based therapeutics. Here, we report the application of a previously developed robotic screening platform, here extended to enable a multiplexed high-throughput cell partitioning analysis in ATPS. We investigated the influence of polymer molecular weight and tie-line length on the resolution of five model cell lines in "charge-sensitive" polyethylene-glycol (PEG)-dextran ATPS. We show, how these factors influence cell partitioning, and that the combination of low molecular weight PEGs and high molecular weight dextrans enable the highest resolution of the five cell lines. Furthermore, we demonstrate that the separability of each cell line from the mixture is highly dependent on the polymer molecular weight composition and tie-line length. Using a countercurrent distribution model we demonstrate that our screenings yielded conditions that theoretically enable the isolation of four of the five cell lines with high purity (>99.9%) and yield.

Downstream processing

10.1002/biot.201700250

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Citations (5)