Preclinical Safety and Toxicology


In regards to the fast growing social and clinical importance of stem cell research and regenerative medicine, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) aims to become a competent partner for non-clinical safety and toxicology research of Advanced Therapy Medicinal Products (ATMPs) in particular for cell –based therapeutics. Therefore, we will expand our services in stem cell toxicology according to the authority guidelines, in order to enable cell-based therapeutics to reach the clinical phase.

Research Focus

Service Unit:
The Fraunhofer ITEM in Hannover is specialized in developing product-specific testing strategies for pre-clinical testing of non-biologics and biologics, including ATMPs. The basic requirements for the registration of biopharmaceuticals including human cell-based medical products, such as iPSCs, for the European market are regulated by the European Medicines Agency (EMA) Commission Directive 2001/83/EC. With their “guideline on human cell-based medicinal products” EMA takes into account that these human cell-based products are heterogeneous regarding origin, type of cells and complexity and that conventional non-clinical pharmacology and toxicology studies may not be appropriate. Therefore, for every new, innovative human cell-based medicinal products, a specific strategy for pre-clinical testing has to be developed and should be presented to and discussed with the drug registration authorities at an early time point.
Fraunhofer ITEM provides support in each aspect of pre-clinical testing, from consulting up to set-up, validation and performance of complex assays, all the way ensuring regulatory acceptance of the development strategy. Further effort has to be made to get into regenerative science. Fraunhofer ITEM has a long-standing tradition in pre-clinical testing of new drugs including safety-relevant studies according to the principles of GLP. Fraunhofer ITEM holds a respective GLP certificate.

Transplantation of multipotent hematopoietic stem cells is successfully supplied for treatment of blood derived diseases, like leukemia or sickle cell anemia. However, the number of compatible donors is limited and complications with graft-versus-host (GvHD) or host-versus-graft disease (HvGD) is still an unresolved issue. To overcome these hurdles, researchers are investigating protocols for efficient expansion of isolated hematopoietic stem cells (HSC) as well as for de novo generation of HSC in vitro since decades.

Positioned within the REBIRTH network, the Institute of Experimental Hematology (MHH), Institute for Laboratory Animal Science (MHH) and Fraunhofer ITEM, started a collaborative project investigating teratoma formation with pluripotent stem cells, their potential to differentiate into hematopoietic cells and resulting effects on the host organism. This model will help to identify responsible key players for early human hematopoiesis regarding cell environment of hematopoiesis including cellular components and cell interactions. Mediated insights offer opportunity to improve and establish in vitro protocols for generation and proliferation of human HSC. Valid protocols perspectively enable the installation of stem cell banks, covering most immunotypes, which can be used for transplantation needs.

A core area of our research is the detection and the immunohistochemical demonstration of HSC and iPSC in tissues and whole organ slices of laboratory animals, also if the number of cells distributed throughout the body is low. For this issue a broad spectrum of antibodies could be established at Fraunhofer ITEM. For safety toxicology and in regard of registration purposes, histopathology and immunohistochemistry were performed under GLP-conditions.


Further Research Projects

  • EU-CELL-PID: Advanced Cell-based Therapies for the treatment of Primary ImmunoDeficiency, MHH-Institute of Experimental Hematology; Fraunhofer-ITEM
  • German Centre for Lung Research (DZL): Fraunhofer ITEM is also a member of the DZL and A. Braun and K. Sewald are also PIs of DZL
  • iCARE: induced pluripotent stem cells for Clinically Applicable heart REpair, MHH Clinic of Cardiothoracic, Transplantation and Vascular Surgery; Leibniz Research Laboratories for Biotechnology and Artificial Organs; Institute of Cellular Therapeutics, Cellular Therapy Centre; CELLS, Leibniz University Hannover; German Primate Center (DPZ)


  • Seminars entitled »Basics of pathology in laboratory rodents I« for PhD-students of the programme PhD Reg Sci (REBIRTH/HBRS) were performed in November 2014 and 2015. Additionally, we participate in the training of students from MHH, TiHo (PhD students of the HGNI) and Leibniz University and further supervise and co-supervise several internships, diploma theses and Ph.D. theses.


2013 - ongoing


Neehus AL, Lam J, Haake K, Merkert S, Schmidt N, Mucci A, Ackermann M, Schubert M, Happle C, Kuhnel MP, Blank P, Philipp F, Goethe R, Jonigk D, Martin U, Kalinke U, Baumann U, Schambach A, Roesler J, Lachmann N. Impaired IFN gamma-Signaling and Mycobacterial Clearance in IFN gamma R1-Deficient Human iPSC-Derived Macrophages. Stem Cell Reports. 2018;10(1):7-16.


Granitzny A, Knebel J, Muller M, Braun A, Steinberg P, Dasenbrock C, Hansen T. Evaluation of a human in vitro hepatocyte-NPC co-culture model for the prediction of idiosyncratic drug-induced liver injury: A pilot study. Toxicol Rep. 2017;4:89-103.

Granitzny A, Knebel J, Schaudien D, Braun A, Steinberg P, Dasenbrock C, Hansen T. Maintenance of high quality rat precision cut liver slices during culture to study hepatotoxic responses: Acetaminophen as a model compound. Toxicology in Vitro. 2017;42:200-13.

Neuhaus V, Schaudien D, Golovina T, Temann UA, Thompson C, Lippmann T, Bersch C, Pfennig O, Jonigk D, Braubach P, Fieguth HG, Warnecke G, Yusibov V, Sewald K, Braun A. Assessment of long-term cultivated human precision-cut lung slices as an ex vivo system for evaluation of chronic cytotoxicity and functionality. Journal of Occupational Medicine and Toxicology. 2017;12.

Niehof M, Hildebrandt T, Danov O, Arndt K, Koschmann J, Dahlmann F, Hansen T, Sewald K. RNA isolation from precision-cut lung slices (PCLS) from different species. BMC Res Notes. 2017;10(1):121.

Wujak L, Hesse C, Sewald K, Jonigk D, Braubach P, Warnecke G, Fieguth HG, Braun A, Lochnit G, Markart P, Schaefer L, Wygrecka M. FXII promotes proteolytic processing of the LRP1 ectodomain. Biochimica Et Biophysica Acta-General Subjects. 2017;1861(8):2088-98.


Bleyer M, Curths C, Dahlmann F, Wichmann J, Bauer N, Moritz A, Braun A, Knauf S, Kaup FJ, Gruber-Dujardin E. Morphology and staining behavior of neutrophilic and eosinophilic granulocytes of the common marmoset (Callithrix jacchus). Exp Toxicol Pathol. 2016;68(6):335-43.

Selich A, Daudert J, Hass R, Philipp F, von Kaisenberg C, Paul G, Cornils K, Fehse B, Rittinghausen S, Schambach A, Rothe M. Massive Clonal Selection and Transiently Contributing Clones During Expansion of Mesenchymal Stem Cell Cultures Revealed by Lentiviral RGB-Barcode Technology. Stem cells translational medicine. 2016;5(5):591-601.


Pohler P, Muller M, Winkler C, Schaudien D, Sewald K, Muller TH, Seltsam A. Pathogen Reduction by Ultraviolet C Light Effectively Inactivates Human White Blood Cells in Platelet Products. Transfusion. 2015;55(2):337-47.


Le DD, Rochlitzer S, Fischer A, Heck S, Tschernig T, Sester M, Bals R, Welte T, Braun A, Dinh QT. Allergic Airway Inflammation Induces the Migration of Dendritic Cells into Airway Sensory Ganglia. Respir Res. 2014;15:73.

Lauenstein L, Switalla S, Prenzler F, Seehase S, Pfennig O, Forster C, Fieguth H, Braun A, Sewald K. Assessment of Immunotoxicity Induced by Chemicals in Human Precision-Cut Lung Slices (Pcls). Toxicol In Vitro. 2014;28(4):588-99.


Switalla S, Knebel J, Ritter D, Dasenbrock C, Krug N, Braun A, Sewald K. Determination of Genotoxicity by the Comet Assay Applied to Murine Precision-Cut Lung Slices. Toxicol In Vitro. 2013;27(2):798-803.

Rittinghausen S, Bellmann B, Creutzenberg O, Ernst H, Kolling A, Mangelsdorf I, Kellner R, Beneke S, Ziemann C. Evaluation of Immunohistochemical Markers to Detect the Genotoxic Mode of Action of Fine and Ultrafine Dusts in Rat Lungs. Toxicology. 2013;303:177-86.

Paranjpe M, Neuhaus V, Finke JH, Richter C, Gothsch T, Kwade A, Buttgenbach S, Braun A, Muller-Goymann CC. In Vitro and Ex Vivo Toxicological Testing of Sildenafil-Loaded Solid Lipid Nanoparticles. Inhal Toxicol. 2013;25(9):536-43.

Neuhaus V, Schwarz K, Klee A, Seehase S, Forster C, Pfennig O, Jonigk D, Fieguth HG, Koch W, Warnecke G, Yusibov V, Sewald K, Braun A. Functional Testing of an Inhalable Nanoparticle Based Influenza Vaccine Using a Human Precision Cut Lung Slice Technique. PLoS One. 2013;8(8):e71728.

Greaves P, Chouinard L, Ernst H, Mecklenburg L, Pruimboom-Brees IM, Rinke M, Rittinghausen S, Thibault S, Von Erichsen J, Yoshida T. Proliferative and Non-Proliferative Lesions of the Rat and Mouse Soft Tissue, Skeletal Muscle and Mesothelium. J Toxicol Pathol. 2013;26(3 Suppl):1S-26S.

Fuhst R, Runge F, Buschmann J, Ernst H, Praechter C, Hansen T, von Erichsen J, Turowska A, Hoymann HG, Muller M, Pohlmann G, Sewald K, Ziemann C, Schluter G, Garn H. Toxicity Profile of the Gata-3-Specific Dnazyme Hgd40 after Inhalation Exposure. Pulm Pharmacol Ther. 2013;26(2):281-9.

2006 - 2012


Rodt T, von Falck C, Dettmer S, Hueper K, Halter R, Hoy L, Luepke M, Borlak J, Wacker F. Lung Tumour Growth Kinetics in Spc-C-Raf-1-Bb Transgenic Mice Assessed by Longitudinal in-Vivo Micro-Ct Quantification. J Exp Clin Cancer Res. 2012;31:15.

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