Hendow, Eseelle Kathreen; (2019) A biomaterials approach for therapeutic angiogenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Peripheral arterial disease (PAD) affects over 200 million people worldwide and can lead to limb ischaemia, amputation and death. Therapeutic angiogenesis aims to promote the formation of new blood vessels in order to treat ischaemia. The programming inherent within cells can be utilised to treat diseases at the cellular level. Adipose derived mesenchymal stem cells (ADMSCs) have been shown to secrete pro-angiogenic proteins, thus could have great potential as a therapy for ischemic disease. In addition, biomaterials can effectively deliver therapeutics to a target site and utilise physical characteristics to influence cell behaviour. Surface topography is known to influence cell alignment, morphology and affect cellular expression of growth factors. This work investigated the effect of surface topography on the secretion of angiogenic growth factors from ADMSCs. Hierarchically structured substrate materials were prepared from poly-DL-lactide-co-glycolide (PLGA) using a thermally induced phase separation (TIPS) process. TIPS materials were characterised using atomic force microscopy to quantify roughness and stiffness, as well as scanning electron microscopy techniques where PLGA processed with TIPS were shown to have higher surface roughness and porosity values. ADMSC proliferation increased on the TIPS-processed substrates compared with the control substrates and the effect of surface topography on the angiogenic secretome of ADMSCs was measured using an in vitro model of angiogenesis, proteomic analysis and measurement of vascular endothelial growth factor (VEGF165). VEGF165 was significantly increased in the supernatants collected from ADMSCs cultured on the TIPS substrate compared with control substrates when normalised for the number of cells. The collected supernatants resulted in increased capillary tubule length, number of capillary junctions and capillary branches in the in vitro angiogenesis assay compared with supernatants collected from control substrates. 5 This work also investigated the effects of TIPS-processed materials implanted in a pre-clinical model of PAD. Laser Doppler imaging revealed an increase in revascularisation in the ischeamic limbs treated TIPS processed materials compared with control materials. Histology and von Willebrand factor staining revealed evidence of blood vessel formation around the implanted TIPS processed materials. This study has shown that ADMSCs seeded onto 2D and 3D TIPS-processed PLGA secreted increased quantities of pro-angiogenic factors in vitro, and when implanted in vivo, TIPS-processed biomaterials improved reperfusion in a pre-clinical model of PAD. These findings open up the opportunity for utilising a unique biomaterial for the treatment of ischemic disease through the promotion of angiogenesis.

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