Abstract
Molecular and system biology research has focused on dissecting the biochemical and mechanical signalling processes that influence the molecular basis of cellular behaviour over the last five decades. Despite the overwhelming insight, there is still much to learn about how extracellular stimuli affect physical and physiological cell behaviour. Here, we go beyond the status quo to study the role bioelectrical signalling has on the physical and pathophysiological behaviour of cell populations. We utilise highly sensitive large area electrodes (2-10 mm2) that exploit the large Helmholtz-Guoy-Chapman double layer capacitance to (i) examine the role of bioelectrical signalling in breast cancer metastasis, (ii) follow the electrochemical changes of the differentiation process of midbrain floor plate progenitors (mFPPs) to midbrain neurons, (iii) explore how manipulating the extracellular pH could trigger seizure-like spikes among a glioblastoma-derived multi-cellular astrocyte population and (iv) how the incorporation of state-of-the-art conducting materials such as poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and carbon nanotubes (CNT) could improve the topography and sensitivity of large area electrodes in order to monitor the minute electrical activity of GBM astrocytes.Utilising both a weakly and a strongly metastatic breast cancer (BCa) cell lines, we were able to demonstrate the activation of voltage-gated sodium channels (VGSCs) in metastatic BCa that could be pharmacologically inhibited. The incorporation of electrochemical impedance spectroscopy (EIS) allowed real-time, non-invasive monitoring of the electrochemically distinctive processes of sedimentation, differentiation and maturation of mFPPs to midbrain neurons. The deliberate extracellular acidification of a glioblastoma-derived astrocyte population triggered paroxysmal seizure-like bursting activity. This activity was then targeted by inhibitors of acid-sensing ion channels (ASICs) confirming the functional presence of these channels in glioblastoma astrocytes. Finally, the integration of a mixture of PEDOT:PSS and CNT (1:1) considerably decreased our electrode’s interfacial impedance resulting in a more pronounced signal-to-noise ratio (SNR). This allowed the further examination of the activity of glioblastoma-derived astrocytes. Collectively, these findings highlight the ultra-sensitive nature of the large area electrodes which provide a platform upon which future cancer and drug discovery research can be conducted.
| Date of Award | 23 Nov 2022 |
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| Original language | English |
| Awarding Institution |
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| Sponsors | Schlumberger |
| Supervisor | David Tosh (Supervisor) & Paulo Rocha (Supervisor) |