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Hanke, Maximilian Paul

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Acute myeloid leukaemia is a malicious disease. Although the initial chemotherapeutic treatment often leads to a complete remission (a disappearance of all manifestations of disease), the effective survival rate is only (30-40) % over 4 years due to a high relapse rate. This relapse is attributed to leukaemic stem cells residing in the protective environment of the bone marrow niche. There are two major approaches aiming at achieving better long-term therapeutic results. The first is to make the leukaemic stem cells more susceptible to chemotherapeutic agents and the second is to increase the efficiency of haematopoietic stem cell transplants, which are used to regenerate the haematopoietic system after failure due to chemotherapy. When searching for a receptor-ligand pair suitable as target for therapeutic agents, the prerequisite is that it must exhibit differences between the interaction it mediates in healthy and leukaemic cells. A detailed understanding of the mediated interaction and the differences would then allow exploitation of these to selectively mobilise the leukaemic stem cells increasing their susceptibility for chemotherapeutic drugs. In this work the flow-induced rolling interaction of leukaemic cells with hyaluronic acid was studied in detail using a suspension and an epithelial model cell line. It could be demonstrated, that the flow induced rolling interaction on hyaluronic acid observed for these cells was solely mediated by the cell surface receptor CD44 and that it was independent of the cell type tested. Next to a detailed validation and characterisation of this dependency and the properties of the interaction, the relevance of this interaction for the haematopoietic system and for leukaemic cells was evaluated. Therefore, the CD44 mediated interaction with hyaluronic acid of healthy haematopoietic progenitor cells from umbilical cord blood, mobilised peripheral blood and the bone marrow with that of leukaemic blasts was compared. Throughout the cell types tested two forms of interaction with hyaluronic acid were observed; a flow induced rolling and an immobile adhesion. It could be shown that while the rolling interaction was comparable for all cell types tested, the immobile adhesion to hyaluronic acid and its susceptibility to a monoclonal CD44 antibody (clone BU52) were not. The immobile adhesion was found predominantly in leukaemic cells, only playing a subordinate role in the interaction of healthy cells with hyaluronic acid. It could be demonstrated that a vicinity of the cells to the bone marrow upon isolation was directly correlated to an incomplete suppression of the immobile adhesion by BU52. Furthermore, this incomplete suppression could be linked to a non-response to induction chemotherapy and subsequently to a poor therapeutic outcome. Besides investigating the interaction with surfaces artificially coated with hyaluronic acid, the possibility of using surfaces covered with mesenchymal stromal cells isolated from the bone marrow as more realistic binding partners was explored. Furthermore, the effect of a routinely used mobilisation reagent, namely Plerixafor®, on the migration and cell-surface interaction under flow was investigated. It is not only of great interest to understand the mechanisms of retention in the niche, but also to develop more sophisticated methods of in vitro stem cell expansion. In this context the slow and continuous release of e.g. cytokines or growth factors is of great interest. The cavities in porous materials present the unique opportunity of achieving just that by being pre-loaded with such agents. These can then under the right conditions be released to the cells. Amongst the porous materials the metal-organic frameworks protrude due to their high structural and chemical flexibility. In this work a novel 2-D metal-organic framework structure, namely SURMOF 2, was tested towards its biocompatibility and smart-release properties. It could be shown that SURMOF 2 was highly stable in protein free aqueous media and that its building units did not impair the growth of rat embryonic fibroblasts. Although the stability in cell culture medium is still limited, the water stability and the biocompatibility of the components are the starting point for future SURMOF 2 cell culture applications. A first application of SURMOF 2 as a smart-release matrix was achieved with the marine bacterium Cobetia marina under salt water conditions. The results demonstrated the general applicability of SURMOF 2 as bioactive substrates with responsive properties. For the future, fine-tuning of the stability of SURMOFs will allow to tailor drug release systems for cytokine or growth factor delivery in in vitro stem cell cultures.

Item Type: Dissertation
Supervisor: Rosenhahn, Prof. Dr. Axel
Date of thesis defense: 7 November 2014
Date Deposited: 17 Nov 2014 08:28
Date: 2014
Faculties / Institutes: Fakultät für Chemie und Geowissenschaften > Institute of Physical Chemistry
Subjects: 500 Natural sciences and mathematics
540 Chemistry and allied sciences
610 Medical sciences Medicine
Uncontrolled Keywords: CD44, Acute myeloid leukaemia, AML, Haematopoietic stem cell, HSC, Microfluidics, Metal-organic framework
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