Biomedical fibre optic time-correlated single-photon counting spectroscopy with CMOS SPAD line arrays

Abstract

In times of economic constraint, an ageing population and antimicrobial resistance, medical challenges must be met by exploring new pathways to improve diagnostics, prevention and specialised treatments. Lung diseases include a wide range of conditions and exhibit high morbidity and mortality rates, especially for actively ventilated patients in intensive care units. The aim of this PhD is to develop systems for endoscopic sensing in size restricted regions such as the alveolar space in the distal lung. The systems are based on miniaturised and disposable single optical fibres and a custom CMOS SPAD line sensor capable of time-resolved single photon detection. Standard optical fibres are suitable for single-use medical devices and allow access to remote locations in the lung. Applying advanced time-resolving detector technology has the potential to overcome common limitations of intensity-based spectroscopy. Two common sensing technologies – Raman and fluorescence spectroscopy – are investigated. Fluorescence spectroscopy is a powerful tool for tissue diagnostics providing insight into the molecular composition and local environment through changes in the fluorescence intensity, spectral properties, and lifetime. Raman spectroscopy reveals the chemical ‘fingerprint’ of molecules under investigation, but is impeded by an inherently weak signal. The visibility of the Raman signal can be significantly enhanced by utilising the different time profiles of unwanted background signals and the Raman signal. The systems are exemplified for differentiating normal and abnormal tissue, detecting pathogens and measuring key physiological parameters such as pH, facilitated by fluorescent markers and Raman reporters. Time-resolved fluorescence lifetime spectroscopy successfully demonstrates its potential for pH-sensing, distinguishing between normal and tumorous tissue, and detecting fluorescent labelled bacteria, all through a miniaturised optical fibre. Time-gated Raman spectroscopy enables pH-sensing with Raman reporters, functionalised gold nanoshells deposited on the fibre tip, with an improved pH sensitivity of 0.06 pH units