Cystoscopic Optical Coherence Tomography and Ultrahigh Resolution Optical Doppler Tomography for Quantitative Structural and Functional Imaging
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This dissertation presents the design, development as well as preclinical and clinical validations of a cystoscopic optical coherence tomography (OCT) system and an ultrahigh resolution optical Doppler tomography (ODT) system for quantitative structural and functional imaging. The core of this dissertation can be divided into three sections. In the first section of the dissertation, which includes Chapter 3-Chapter 4, we validated the design and development of cystoscopic OCT (COCT) for bladder cancer diagnosis in vivo. To break the penetration depth barrier of the light, endoscopic imaging via fiber-optic technique has been developed. In this dissertation, we focused on bladder cancer diagnosis and management. A microelectromechanical systems (MEMS) mirror based front view COCT system was developed, optimized and validated in the operating room. The touch-and-see feature enables user friendly OCT examinations. Based on 220 cases, MEMS mirror based COCT provided a sensitivity of 92.4% and a specificity of 85.2% for clinical bladder cancer diagnosis. To further enhance early bladder cancer diagnosis in the outpatient, we proposed, designed and developed a hybrid flexible cystoscopic OCT (FCOCT) system. The miniature size (i.e., <2mm) enables smooth integration of the probe into the commercial cystoscopes used in the outpatient examinations. Since the probe is flexible, for those lesions located close to the bladder neck, full access can be achieved by articulating the tip of the cystoscope. Moreover, with a field of view of >8mm, FCOCT allows in vivo tumor boundary delineation and guided tumor resection. In the second section of the dissertation, including Chapter 5-Chapter 7, quantitative image analysis based computer aided diagnosis (CAD) approach was demonstrated. Conventional OCT diagnosis was based on descriptive and qualitative features. To provide quantitative and objective diagnosis, we developed a CAD approach based on enface image analysis of the increased urothelial heterogeneity induced by carcinogenesis. To overcome the limitation of small field of view, we designed a comparative study to evaluate the utilities and potential limitations of current optical imaging techniques for early bladder cancer diagnosis. The results of this study demonstrated the potential of narrow band imaging (NBI)-guided cystoscopic OCT to effectively enhance the efficacy and efficiency of current cystoscopic procedure in the diagnosis of bladder cancer. At the same time, we showed that high resolution OCT with 3D image segmentation and analysis enabled delineation of morphological details of the human fetal membrane and early detection of microscopic chronic pseudocysts. In the last section of the dissertation, from Chapter 8 to Chapter 11, we designed, developed and validated the ultrahigh resolution optical Doppler tomography (??ODT) system for brain functional imaging. Functional imaging has been achieved with Doppler OCT by probing the blood flow information. To enable microvascular imaging, we developed an ultrahigh resolution ODT system with ~1.8??m axial resolution and <10??m/s sensitivity. Moreover, we proposed a frequency binning algorithm to increase the dynamic range ~20 times to enable both slow capillary flow and fast branch flow imaging. By taking advantages of the Doppler effect, we demonstrated a label free method to separate veins from arteries at large field of view. The performance of the ??ODT system was validated with an acute cocaine challenge model, and cocaine elicited micro ischemia was observed 45 minutes after cocaine administration, which was exacerbated with repeated administration. To decode the mystery of Doppler effect on capillary flow, we proposed a new method termed particle counting ultrahigh resolution ODT (pc-??ODT), which enables label free accurate red blood cell (RBC) velocity measurement based on the transient phase information. To investigate the contrast differences between ODT and optical coherence angiography (OCA), we performed both phantom and in vivo animal studies and discovered that the high contrast of OCA was partially due to the enhancement from the Brownian motion of the red and white blood cells. With the in depth understanding of the Doppler technique from previous studies, we further improved the performance of the ODT system by employing optimized optical design, newly developed contrast agent (e.g., intralipid for flow enhancement) and smart scanning protocol. With the enhanced ODT system, the chronic cocaine effect on the cerebral blood flow was investigated based on a rodent model.