Representative Publications & Projects

    Representative Publications

    J1. Stab J., Zlatev I., Raudszus B., Meister S., Pietrzik C. U., Langer K., von Briesen H. and Wagner S.: “Flurbiprofen-loaded Nanoparticles Can Cross a Primary Porcine In vitro Blood-brain Barrier Model to Reduce Amyloid-ß42 Burden.” J Nanomedine Biotherapeutic Discov 6:140. doi:10.4172/2155-983X.1000140

    Elevated amyloid-β42 (Aβ42) in the brain is expected to cause Alzheimer’s Disease (AD). Reducing Aβ42 is therefore a cornerstone in causal drug development. Nevertheless, many promising substances failed in clinical trials, because reaching the target organ in vivo is difficult. The brain is protected by the Blood-Brain Barrier (BBB) that shields off most molecules to maintain the brain homeostasis. Brain-targeted nanoparticles are one successful tool to bypass this problem: by acting as Trojan horses they carry embedded drugs across the BBB for brain disorder treatment.

    J2. Linz U., Hupert M., Santiago-Schübel B., Wien S., Stab J., Wagner S.: “ Transport of treosulfan and temozolomide accross an in-vitro blood-brain barrier model” Anti-Cancer Drugs 26, 728-36, 2015 (

    In vitro, treosulfan (TREO) has shown high effectiveness against malignant gliomas. However, a first clinical trial for newly diagnosed glioblastoma did not show any positive effect. Even though dosing and timing might have been the reasons for this failure, it might also be that TREO does not reach the brain in sufficient amount. Surprisingly, there are no published data on TREO uptake into the brain of patients, despite extensive research on this compound. An in-vitro blood–brain barrier (BBB) model consisting of primary porcine brain capillary endothelial cells was used to determine the transport of TREO across the cell monolayer. Temozolomide (TMZ), the most widely used cytotoxic drug for malignant gliomas, served as a reference. An HPLC-ESI-MS/MS procedure was developed to detect TREO and TMZ in cell culture medium. Parallel to the experimental approach, the permeability of TREO and the reference substance across the in-vitro BBB was estimated on the basis of their physicochemical properties. The detection limit was 30 nmol/l for TREO and 10 nmol/l for TMZ. Drug transport was measured in two directions: influx, apical-to-basolateral (A-to-B), and efflux, basolateral-to-apical (B-to-A). For TREO, the A-to-B permeability was lower (1.6%) than the B-to-A permeability (3.0%). This was in contrast to TMZ, which had higher A-to-B (13.1%) than B-to-A (7.2%) permeability values. The in-vitro BBB model applied simulated the human BBB properly for TMZ. It is, therefore, reasonable to assume that the values for TREO are also meaningful. Considering the lack of noninvasive, significant alternative methods to study transport across the BBB, the porcine brain capillary endothelial cell model was efficient to collect first data for TREO that explain the disappointing clinical results for this drug against cerebral tumors.

    J3. Neubauer J. C., Sébastien I., Germann A.,  Müller S. C., Meyerhans A., von Briesen H., Zimmermann H.: “Towards standardized automated immunomonitoring: an automated ELISpot assay for safe and parallelized functionality analysis of immune cellsCytotechnology. 2017 Feb;69(1):57-73. doi: 10.1007/s10616-016-0037-4

    The ELISpot assay is used for the detection of T cell responses in clinical trials and vaccine evaluations. Standardization and reproducibility are necessary to compare the results worldwide, inter- and intra-assay variability being critical factors. To assure operator safety as well as high-quality experiment performance, the ELISpot assay was implemented on an automated liquid handling platform, a Tecan Freedom EVO. After validation of the liquid handling, automated loading of plates with cells and reagents was investigated. With step by step implementation of the manual procedure and liquid dispensing optimization on the robot platform, a fully automated ELISpot assay was accomplished with plates remaining in the system from the plate blocking step to spot development. The mean delta difference amounted to a maximum of 6%, and the mean dispersion was smaller than in the manual assay. Taken together, we achieved with this system not only a lower personnel attendance but also higher throughput and a more precise and parallelized analysis. This platform has the potential to guarantee validated, safe, fast, reproducible and cost-efficient immunological and toxicological assays in the future.

    J4. Neubauer, J.C., Beier, A.F., Stracke, F., Zimmermann, H. (2015) “Vitrification in pluripotent stem cell banking: Requirements & technical solutions for large-scale biobanks.” Chapter 24 in: 2nd Edition of the book Vitrification in Assisted Reproduction: From Basic Science to Clinical Application (Liebermann, J. and Tucker, M.J., eds.). CRC press, 203-224.

    J5. M. Oeri, W. Bost, S. Tretbar, M. Fournelle (2016) Calibrated Linear Array-Driven photoacoustic/Ultrasound tomography. Ultrasound Med Biol. 42(11), 2697-2707.

    The anisotropic resolution of linear arrays, tools that are widely used in diagnostics, can be overcome by compounding approaches. We investigated the ability of a recently developed calibration and a novel algorithm to determine the actual radial transducer array distance and its misalignment (tilt) with respect to the center of rotation in a 2-D and 3-D tomographic setup. By increasing the time-of-flight accuracy, we force in-phase summation during the reconstruction. Our setup is composed of a linear transducer and a rotation and translation axis enabling multidimensional imaging in ultrasound and photoacoustic mode. Our approach is validated on phantoms and young mice ex vivo. The results indicate that application of the proposed analytical calibration algorithms prevents image artifacts. The spatial resolution achieved was 160 and 250 μm in photoacoustic mode of 2-D and 3-D tomography, respectively

    Representative Projects

    P1. EBiSC – European Bank of Pluripotent Stem Cells (Innovative Medicine Initiative IMI 115582-project, 2013-2018, Principal Investigators: H. Zimmermann / J. Neubauer. Project volume: € 36.50.000

    P2. DropTech - Hanging Drop based automated and parallelized cell technology platform for production and testing (EU FP7 601865-project, 2014-2017). Project Coordinator: H. Zimmermann / J. Neubauer. Project volume: € 5.250.000

    P3. Hyperlab-High yield and performance stem cell lab (EU FP7 22301–project, 2009-2012). Project Coordinator: H. Zimmermann / J. Neubauer. Project volume: € 3.950.000

    P4. NanoBrain- Alzheimer drugs incorporated in nanoparticles for specific transport over the blood-brain barrier (ERA-Net NEURON –project, 2010-2013, 01EW1010)

    P5. HISENTS – High level Integrated Sensor for Nano Toxicity Screening (EU H2020, 2016-2019)

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