Engineering a novel, bio-inspired, mechanically robust pancreatic cancer model.

Pancreatic ductal adenocarcinoma is an aggressive disease with an extremely low survival rate. This is due to the (i) poor prognosis and (ii) high resistance of the disease to current treatment options. The latter is partly due to the very complex and dense tissue/tumour microenvironment of pancreatic cancer, which contributes to the disease's progression and the inhibition of apoptotic pathways. Over the last years, advances in tissue engineering and the development of three-dimensional culture systems have shed more light into cancer research by enabling a more realistic recapitulation of the niches and structure of the tumour microenvironment. Herein, for the first time, 3D porous mechanically robust polyurethane scaffolds were fabricated and surface modified with different extracellular matrix proteins to mimic features of the structure and extracellular matrix present in the pancreatic cancer tumour microenvironment. The developed 3D scaffold could support the proliferation of the pancreatic tumour cells, which was enhanced with the presence of fibronectin, for 68 days, which is a significantly prolonged in vitro culturing duration. Furthermore, in situ imaging of cellular and biomarker distribution showed the formation of dense cellular masses, the production of collagen-I by the cells and the expression of environmental stress gradients (e.g. HIF-1a) with similar heterogeneity trends to the ones reported in in vivo studies. The 3D pancreatic cancer model enabled long-term chemotherapy, radiotherapy and chemoradiation screening. The 3D tumours were monitored up to 17 days post treatment, which is the longest in vitro reported time period, and demonstrated dose dependent cell inactivation and apoptosis, with similar trends to in vivo. The results obtained in this thesis suggest that the bioinspired, mechanically robust, highly porous scaffold has great potential for in vitro high throughput studies of pancreatic cancer including drug and treatment screening