A novel optical coherence tomography (OCT) design and application of OCT in inhaled drug delivery system

Optical coherence tomography (OCT) is a high-resolution imaging technique which has attracted considerable attention in applications ranging from medical imaging to various non-destructive testing in the manufacturing industries. More specifically, the utility of OCT in respiratory medicine and pharmaceutical industry includes the in-vivo anatomical imaging of biological conduits (e.g. upper airway) and the quantitative evaluation of pharmaceutical products (e.g. quality control of tablet coatings). In many of these applications, the classical OCT features a probing arm that focuses a light beam on a single spot of the sample, and cross-sectional images are acquired by flying the beam across the sample using electromechanical scanners. Despite its suitability for miniature probe design and higher detection sensitivity over parallel illumination techniques (e.g. full-field OCT), such a serial scanning technique can be inefficient for some applications. For example, the real-time visualisation of heterogeneous and dynamic deformation of upper airway muscles during respiration would benefit from simultaneous measurements of airway shape using multiple imaging units that are significantly spaced and at distinct longitudinal locations. From the clinical perspective, the detailed assessment of dynamic airway geometry is not only useful to predict the deposition efficacy of inhaled drugs but is also useful to shed light on other respiratory diseases such as sleep apnoea. Therefore, the development of an OCT technique that allows concurrent measurement of the airway geometry from distinct locations with the suitability of implementing them in products with a small footprint is desirable. The studies in this thesis can be broadly categorised into two major groups: (1) the design and development of a novel multi-beam OCT technique, and (2) the demonstration of the potential applications of OCT in inhaled drug delivery.

The first two studies focus on the development and performance analysis of a multi-beam OCT design that features linearly distributed imaging units along the length of the probing arm. System developments are demonstrated in both time-domain (TD) and spectral-domain (SD) OCT technologies with minimal or no modification to the basic OCT components such as the broadband light source, detection unit and the interferometer. In both modalities, a broadband light spectrum was sliced into three different spectral sections using a cascade of wavelengthmodulating optics (i.e. dichroic splitters) inserted in the sample arm of the interferometer. In doing so, the different spectral sections carry distinct spatial information which was decoded using either similar configuration of optics in the detection unit for the TD-OCT or signal post-processing for the SD-OCT. Experimental results of the spectral slicing process and the interference pattern properties such as axial resolutions and spurious side-lobes in the depth-resolved PSF showed good correlation with simulations. The imaging performance of the systems was further illustrated by scanning 3D-printed phantoms, and tomographic images were used to assess the surface imperfection of the sample and the depth sensitivity of the systems. The key innovation in these group of studies are the suitability of the system for a compact probe design due to the longitudinal arrangement of the multiple scanning heads, the provision of specific delay lines for each spectral section, the optimal cost of the overall system (e.g. low per-channel cost), and the scalability of the system (e.g. more number of channels). The compact probing arm design with adjustable spacing between imaging locations makes the new system a promising tool for a wide range of applications such as the visualisation of the effect of endoscopic surgical manoeuvres at sites distant from a specific area of interest, quantification of dynamic morphology of biological conduits and fast inspection of large products in the manufacturing industry. In some research settings, such as a pharmaceutical laboratory, a multichannel OCT probe with small footprint would be beneficial to conduct experiments in a space-constrained environment while enabling parallel acquisition from multiple sample locations.

The second group of studies aims to demonstrate the functionality of OCT in inhaled drug delivery system by performing in-vitro measurement of dry powder deposition. In the pharmaceutical industry that develops inhalation drug delivery systems, although there are methods available to measure total and regional drug particles deposition, methods that can provide the detailed drug deposition profile at high spatial resolution is absent. In one of the studies, an optically accessible replica of the upper airway and the tracheobronchial tree were developed to perform inhalation experiments at three flow rates (40 L/min, 60 L/min and 80 L/min). Drug deposition at different sites of the airway model was determined and quantified from OCT images of the deposition layer. The experimental results reveal local drug deposition details, including the thickness, spatial deposition pattern and micro-cavities in the depositionlayer, that would be useful to assess the efficacy of inhalation drug delivery systems. In the second study, a simple method of characterising the dissolution behaviour of drug powder was demonstrated using the Transwell system with an artificial membrane (inserts) separating the powder deposition and the dissolution medium. The rate of powder particles transfer from the donor to the receptor chamber was measured indirectly by quantifying the powder deposition thickness at different time intervals using OCT. Besides, an electrochemical test was performed to compare the trend of temporal thickness change with the conventional concentration-time analysis of dissolution. The results indicate that accurate quantification of the temporal change in the thickness of the deposition layer using OCT may help to estimate the dissolution rate without undertaking the analytical procedure and to assess the effect of formation and thickness of deposition layer on the dissolution profile.