Advances in endoscopic optical coherence tomography: shining light on new diagnostic pathways

Visual inspection is a powerful tool that doctors have for medical assessment. Given the limit imposed by scattering and absorption of light into tissue, visual inspection can only provide information over the most superficial layers of the human body. The advent of medical imaging revolutionized the medical practice with imaging modalities such X-ray computed tomography (CT) and magnetic resonance imaging (MRI) and stimulated the development of new imaging technologies. Among the imaging technologies developed, optical imaging enables to reveal details with 10-100 times higher resolution than CT and MRI. However, optical imaging techniques suffers from limited penetration depth within biological tissues. To circumvent this shortcoming, endoscopes have been developed to enable imaging of internal organs. The focus of this thesis is optical coherence tomography (OCT), an interferometric optical imaging technique that allows to create cross-sectional images of tissue. After a brief introduction (Chapter 1), the fundamental principles of OCT and its extensions adopted in this thesis are discussed (Chapter 2). In this thesis, polarization-sensitive OCT (PS-OCT), an extension of conventional OCT, which makes use of polarization properties of light was adopted to highlight birefringent tissues. Form birefringence is exhibited by several tissue types with fiber-like structures (e.g. smooth muscle, collagen, fibrosis), therefore PS-OCT is particularly valuable to highlight the presence of specific tissue types which are birefringent. A PS-OCT system was developed and used for in-vivo imaging of the human lungs. Moreover, an endoscope suitable for lung airway imaging was developed and adopted to perform endobronchial PS-OCT imaging of human lungs. In chapter 3, endobronchial PS-OCT was used to visualize and quantify airway smooth muscle in severe asthma patients undergoing bronchial thermoplasty (BT) treatment. In chapter 4, the use of endobronchial PS-OCT was extended to interstitial lung disease (ILD) patients, in which the amount of pulmonary fibrosis was assessed. Results of the studies presented in chapter 3 and 4 suggest that PS-OCT holds the potential as imaging modality to study airway remodeling in asthma patients and to evaluate pulmonary fibrosis in ILD patients respectively. Although (PS-)OCT has potential for structural imaging it is not able to provide molecular imaging contrast and distinguish the presence of specific cell types within the tissue. Molecular imaging contrast can be achieved with fluorescence molecular imaging, which relies on the use of targeted fluorescent tracers: fluorophores conjugated to a tumor-specific target. Among targeted fluorescent tracers, monoclonal antibodies fluorescently labelled with near infrared (NIR) fluorophores can target specific tumor targets by targeting tumor cell receptors or signaling proteins (immuno- near infrared fluorescence, immuno-NIRF). A dual-modality system in which OCT was combined with immuno-NIRF imaging (immuno-OCT) was developed, as described in chapter 5. The dual modality system developed for immuno-OCT imaging was demonstrated to image ex-vivo esophageal specimens resected from patients with different stages of esophageal cancer. In the study presented in chapter 5, the immuno-OCT system proved to have the sensitivity needed to detect early stage of esophageal cancer with administration of an imaging dose of NIR fluorescently labeled monoclonal antibodies. Moreover, OCT provided morphological information over the esophageal tissue complementing immuno-NIRF, which provided tissue molecular information allowing to reveal the heterogeneity of the tumor microenvironment. Results of this ex-vivo study suggest that immuno-OCT could have potential to enhance early diagnosis of esophageal cancer. However, results should be further validated in-vivo. To this purpose, chapter 6 was dedicated to the design of a dual-modality capsule endoscope that in future will be demonstrated to perform in-vivo immuno-OCT imaging in patients diagnosed with esophageal cancer. Finally, chapter 7, discusses future research directions and a potential translation of the PS-OCT system into the medical-devices market.