Novel Bio-Chips for real-time detection of acidification in the tumour microenvironment
File(s)
Author(s)
Beykou, Melina
Type
Thesis or dissertation
Abstract
Cancer incidence remains a global public health concern. Timely diagnosis leads to a diverse set of treatment and disease management avenues to increase quality of life. Tumour acidification, primarily due to a metabolic phenomenon, the Warburg effect, has yet to be harnessed for early diagnostic technologies. Concurrently, ion imaging has emerged as a sensitive and rapid technology to detect ion fluctuations. The Ion-Sensitive Field-Effect Transistor (ISFET) harbours an innate pH sensitivity and has been implemented in Complementary Metal-Oxide Semiconductor (CMOS) technology, rendering it a Lab-on-Chip technology amenable to scalable diagnostics. In this thesis we present the amalgamation of ISFETs and cell culture for cancer detection, where the morphodynamics and physiological responses of cells at the sensor interface play a central role in evaluating this technology for cancer diagnosis applications. We investigate the pH changes associated with cell cultures under standard laboratory conditions and show that tumorigenic cells acidify their extracellular environment, despite excess buffering capacity of commercial media formulations. Investigation into the biocompatibility of the ISFET array implemented in unmodified CMOS, yields evidence supporting the use of ISFETs in physiologically relevant applications. Cancer cell volume, viability and adhesion remain comparable to plastic culture vessels. Surface treatment with collagen, fibronectin, or poly-l-ornithine and laminin (PLOL) recovered mechano-responsiveness, Sensor sensitivity was not inhibited. We implement a dual assay on the Titan array to 1) detect net pH change in cancer cell cultures in a short time-course and 2) rapid pH changes known to coordinate the stages of mitosis. Cell mitosis is corroborated using timelapse microscopy to determine the coordination of the population undergoing nuclear envelope breakdown. Finally, morphological, proteomic and extracellular pH changes associated with a senescent-like profile derived in breast cancer cells treated with CDK4/6 inhibitor, Palbociclib reveals the potential of pH as a biomarker for drug-resistant cell states and subtypes.
Date Issued
2024-10-01
Date Awarded
2025-08-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Georgiou, Pantelis
Moser, Nicolas
Sponsor
Cancer Research UK
Imperial College London
Grant Number
A26234
Publisher Department
Department of Electrical and Electronic Engineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)