Chondrosarcoma and giant cell tumour of bone (GCTB) are bone tumours characterized by recurrent mutations (IDH1/IDH2 and H3F3A, respectively) that induce remodelling of the epigenetic landscape.... Show moreChondrosarcoma and giant cell tumour of bone (GCTB) are bone tumours characterized by recurrent mutations (IDH1/IDH2 and H3F3A, respectively) that induce remodelling of the epigenetic landscape. The standard of care for both of these sarcoma subtypes is surgery and alternative treatment options for patients with inoperable disease are currently lacking (chondrosarcoma) or suboptimal (GCTB). Therefore, the aim of this thesis was to identify novel therapeutic targets for high-grade chondrosarcoma as well as GCTB, with a focus on potential therapies that could counteract the remodelling of the epigenome. PARP and HDAC inhibition, alone or in combination treatment strategies, were identified as promising therapeutic strategies for chondrosarcoma or both of these bone tumours, respectively. Additionally, this thesis describes the development and use of novel 3D cell culture models which can be used to improve the translation of preclinical findings to the clinic. Show less
A new type of tripodal squaramide-based supramolecular hydrogels is developed and studied. The mechanical properties of hydrogel with a wide stiffness range that can be easily modulated and also... Show moreA new type of tripodal squaramide-based supramolecular hydrogels is developed and studied. The mechanical properties of hydrogel with a wide stiffness range that can be easily modulated and also special and temporal controlled either by decorating with the activated group to offer additional chemical crosslinks or using hybrid hydrogel by incorporating the second network through light irradiation to overcome the weakness of traditional self-assembled supramolecular materials. Moreover, the designed synthetic hydrogel systems are biocompatible with several cell lines and have the potential to use as a 3D culture substrate. Show less
Traditional drug discovery approaches have been hampered by (in vitro) cell-culture models that poorly represent the situation in the human body. Principally, cells grow in the body in a three... Show moreTraditional drug discovery approaches have been hampered by (in vitro) cell-culture models that poorly represent the situation in the human body. Principally, cells grow in the body in a three-dimensional (3D) environment that cannot generally be captured using cell culture methods. For this reason, cell-culture models have been developed where cells grow in a 3D-environment, which allows them to form structures that are more comparable to tissue in the body. However, the full complexity of these advanced cell-culture models can only be fully used for routine drug testing if the cell culture model can be used on a large scale (also termed high-throughput screening or HTS), and if the readout can capture all of the biological complexity reflected by the 3D-cultured cells (high-content screening or HCS). Due to these technological limitations, 3D cellular models are not yet routinely applied in drug and drug-target discovery. This thesis describes the development of fully-scalable 3D cell-culture screening platforms in the context of cancer and polycystic kidney disease. Show less
There is an urgent need for more physiologically relevant cell culture methods to guide compound selection in pre-clinical stages of the drug development pipeline. This thesis describes the... Show moreThere is an urgent need for more physiologically relevant cell culture methods to guide compound selection in pre-clinical stages of the drug development pipeline. This thesis describes the development of the OrganoPlate, a microfluidic platform that enables enhanced physiology in cell culture models by combining 3D cell culture, co-culture and perfusion flow, whilst maintaining ease of use, compatibility and throughput. Phaseguides are capillary pressure barriers that enable microfluidic liquid routing and patterning without the use of membrane or other physical barriers. This technology was further developed to enable complex liquid routing using only a standard pipette Phaseguide technology was implemented for gel patterning in a dedicated 3D cell culture device embedded in a standard 384 wells plate. Each plate contains up to 96 microfluidic networks that enable perfusion culture of extracellular matrix embedded tissues and perfused epithelial or endothelial tubules. The standard dimensions and high quality optical readout allows interrogation of these tissues using high content readers as well as other standard readout equipment. The platform has been used for the culture of a variety of tissue types and disease models by the authors, but has also been adopted by expert and non-expert users across the field. Show less
