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Engineering extracellular vesicles for cellular delivery

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Title: Engineering extracellular vesicles for cellular delivery
Authors: Winter, Charles W.
Item Type: Thesis or dissertation
Abstract: Extracellular Vesicles (EV) are a complex collection of cell derived particles which efficiently transport functionally active bio-molecules over large inter-cellular distances and across biological barriers. To realise the potential of EV to act as next-generation personalised drug delivery vectors novel methods are needed to engineer EV contents and to characterise the interactions of EV with various cellular targets. The rapid pace of development of EV for therapeutic delivery means that the need for robust and sensitive methods which accurately elucidate EV-cell interactions are ever increasingly required. In this work, EV are engineered to carry a small molecule transgene activator called doxycycline (DXC). Dosing of DXC-sensitive reporter cells with loaded DXC-EV was used to trigger red fluorescent protein (RFP) expression in recipient cells. This response was spatiotemporally monitored and the dynamics and penetration of DXC-EV delivery within reporter cell systems cultured as mono-layers, as well as, more advanced 3D multi-cellular spheroid models overtime was tracked overtime. In addition, this reporter system was applied to investigate to study whether EV interactions with target cells could be modulated through the application of ultrasound to release EV from microbubble-EV complexes. Ultrasound was applied in this context to gain remote physical control over EV delivery and overcome diffusional barriers faced when EV need to signal to cell culture systems embedded within 3D collagen micro-environments. Overall, this thesis will examine cell engineering and post-harvest EV modification in order to engineer EV for enhanced therapeutic loading, and, will devise novel biomaterial inspired approaches to manipulate and gain physical control over EV to cell communication within tissue engineering scaffolds. Overall, these advances could be applied in subsequent studies to enhance the therapeutic properties of EV in the context of regenerative medicine.
Content Version: Open Access
Issue Date: Oct-2019
Date Awarded: Mar-2020
URI: http://hdl.handle.net/10044/1/96498
DOI: https://doi.org/10.25560/96498
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Stevens, Molly
Coombes, Raoul
Sponsor/Funder: Biotechnology and Biological Sciences Research Council (Great Britain)
GlaxoSmithKline
Department: Materials
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Materials PhD theses



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