The Structural Biodegradation of Graphene Oxide In Vivo

Abstract

In the field of biomedicine, the oxidised derivative of graphene, graphene oxide (GO), has been intensively researched for applications such as drug delivery, tissue engineering as well as medical imaging. GO has also shown applicability to areas of material science including in the design of anticorrosion coatings and desalinisation membranes. Consequently, there is a risk of the intended or unintended exposures of humans. It is crucial that the biological interactions and fate of GO are revealed. The aim of this thesis is to help in the revealing of this information. Herein, the in vivo biodegradability or susceptibility of GO sheets to be structurally destroyed is explored. Currently, research examining the biodegradability of GO sheets is limited to a few studies. This thesis starts with an in vitro study to characterise the degradative changes that occur in GO sheets under a defined oxidative influence. The author then describes the interrogation of the biodegradability of GO sheets in the spleen and the brain following intravenous and intranasal exposures respectively, in C57BL/6 mice. In order to reach conclusions, various analytical techniques were used, including microscopic (transmission electron microscopy, atomic force microscopy, light microscopy), spectroscopic (Raman spectroscopy), spectrometric (inductively coupled plasma mass spectrometry) and histological techniques (immunostaining and standard hematoxylin and eosin staining) as well as correlative techniques (immunostaining followed by Raman spectroscopy on the stained cells or tissue sections). The data indicate that under in vivo conditions in the C57BL/6 mice strain, GO nanosheets undergo biodegradative changes mediated by macrophage lineage cells (marginal zone macrophages in the spleen or microglia in the brain). The toxicological effects of GO on the splenic structure and function were also explored. The results indicate that the intravenously administered thoroughly characterised GO sheets did not jeopardise the splenic structure or function. Regarding the nose-to-brain focused study, the effect of GO sheet lateral dimension on the extent of translocation was investigated. GO sheet lateral dimension was inversely related to extent to which GO sheets could translocate from the nose to the brain following intranasal administration, with the GO sheets of lowest lateral dimensions translocating to the greatest extent. A fraction of the translocated GO sheets was seen to diffuse to distal regions of the brain past the initially encountered olfactory bulb. The findings of this work have implications that are relevant to potential clinical applications, where biodegradability is a critical parameter. Moreover, it is crucial for helping to complete the toxicological profile of GO. Nonetheless, further studies are necessary to understand the molecular mechanisms by which the observed in vivo biodegradation occurs and the identities of the by-products that are generated as a result of this process.

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Kostas Kostarelos (Supervisor), Sarah Haigh (Supervisor) & Cyrill Bussy (Supervisor)