Optical Coherence Tomography (OCT) is a novel optical imaging technique that has assumed significant importance in bio-medical imaging in the last two decades because it is non-invasive and provides accurate, high resolution images of three dimensional cross-sections of body tissue, exceeding the capabilities of the current predominant imaging technique –ultrasound. In this thesis, high resolution OCT is investigated for in vivo detection of abnormal skin pathology for the early diagnosis of cancer. The technology presented is based on a dynamic focusing microscopic imaging probe conceived for skin imaging and the detection of abnormalities in the epithelium. A novel method for dynamic focusing in the biological sample using liquid crystal (LC) lens technology to obtain three dimensional images with invariant resolution throughout the cross-section and depth of the sample is presented and discussed. Two different skin probe configurations that incorporate dynamic focusing with LC lenses, one involving a reflective microscope objective sub-system, and the other involving an all-refractive immersion microscope objective sub-system are investigated. In order to ensure high resolution imaging, a low coherence broadband source, namely a femtosecond mode-locked Ti: sapphire laser centered at a wavelength of approximately 800nm is used to illuminate the sample. An in-depth description and analysis of the optical design and predicted performance of the two microscope objectives designed for dynamic three dimensional imaging at 5ìm resolution for the chosen broadband spectrum is presented.

Time domain Optical Coherence Tomography (TD-OCT), first reported in 1991, makes use of the low temporal coherence properties of a NIR broadband laser to create depth sectioning of up to 2mm under the surface using optical interferometry and point to point scanning. Prior and ongoing work in OCT in the research community has concentrated on improving axial resolution through the development of broadband sources and speed of image acquisition through new techniques such as Spectral domain OCT (SD-OCT). In SD-OCT, an entire depth scan is acquired at once with a low numerical aperture (NA) objective lens focused at a fixed point within the sample. In this imaging geometry, a longer depth of focus is achieved at the expense of lateral resolution, which is typically limited to 10 to 20 [micro]m. Optical Coherence Microscopy (OCM), introduced in 1994, combined the advantages of high axial resolution obtained in OCT with high lateral resolution obtained by increasing the NA of the microscope placed in the sample arm. However, OCM presented trade-offs caused by the inverse quadratic relationship between the NA and the DOF of the optics used. For applications requiring high lateral resolution, such as cancer diagnostics, several solutions have been proposed including the periodic manual re-focusing of the objective lens in the time domain as well as the spectral domain C-mode configuration in order to overcome the loss in lateral resolution outside the DOF. In this research, we report for the first time, high speed, sub-cellular imaging (lateral resolution of 2 [micro]m) in OCM using a Gabor domain image processing algorithm with a custom designed and fabricated dynamic focus microscope interfaced to a Ti:Sa femtosecond laser centered at 800 nm within an SD-OCM configuration. It is envisioned that this technology will provide a non-invasive replacement for the current practice of multiple biopsies for skin cancer diagnosis. The research reported here presents three important advances to this technology all of which have been demonstrated in full functional hardware conceived and built during the course of this research. First, it has been demonstrated that the coherence gate created by the femtosecond laser can be coupled into a scanning optical microscope using optical design methods to include liquid lens technology that enables scanning below the surface of skin with no moving parts and at high resolution throughout a 2x2x2 mm imaging cube. Second, the integration the variable-focus liquid lens technology within a fixed-optics microscope custom optical design helped increase the working NA by an order of magnitude over the limitation imposed by the liquid lens alone. Thus, this design has enabled homogenous axial and lateral resolution at the micron-level (i.e., 2 [micro]m) while imaging in the spectral domain, and still maintaining in vivo speeds. The latest images in biological specimens clearly demonstrate sub-cellular resolution in all dimensions throughout the imaging volume. Third, this new modality for data collection has been integrated with an automated Gabor domain image registration and fusion algorithm to provide full resolution images across the data cube in real-time. We refer to this overall OCM method as Gabor domain OCM (GD-OCM). These advantages place GD-OCM in a unique position with respect to the diagnosis of cancer, because when fully developed, it promises to enable fast and accurate screening for early symptoms that could lead to prevention. The next step for this technology is to apply it directly, in a clinical environment. This step is underway and is expected to be reported by the next generation of researchers within this group.

Les ultrasons focalisés de haute intensité (HIFU) représentent une modalité de traitement du cancer de la prostate dont la place est en évolution. La première partie de ce travail a porté sur l'étude des résultats cliniques obtenus d'une part en traitement de première intention, d'autre part en situation de rattrapage et enfin en situation clinique complexe. Ces résultats ont également été évalués en fonction des différentes évolutions techniques des appareils. Les données obtenues ont permis de préciser les résultats oncologiques et fonctionnels et de définir les points faibles des traitements par HIFU. La seconde partie de ce travail a porté sur le développement préclinique et clinique d'une nouvelle sonde de traitement à focalisation dynamique. Pour cela, un modèle animal a été mis au point afin de tester la capacité du système à préserver la paroi rectale tout en permettant de réaliser des traitements profonds et/ou de grand volume. Il s'agissait d'un modèle porcin avec utilisation du caecum détubulisé et fixé sur le foie. Les traitements par HIFU étaient appliqués au foie à travers le caecum vascularisé. Ces essais ont permis de définir les paramètres de traitement global de la glande et les paramètres de traitement focal avec tirs suspendus. Grâce à ces résultats, des études cliniques ont débuté d'abord avec un prototype puis avec la dernière version d'appareil de traitement par HIFU : le Focal One / High Intensity Focused Ultrasound (HIFU) is a therapeutic option for localized prostate cancer with an evolving place. The first part of this work include the clinical results of HIFU for prostate cancer as the first line treatment, salvage treatment, and in challenging clinical cases. Those results were also evaluated according to the technical evolution of the devices. Oncological, functional outcomes as well as weak point of HIFU have been drawn with the obtained data. The second part of this work was the preclinical and clinical development of the new dynamic focusing probe. For this, an animal model has been developed in order to evaluate the capacity of the probe to spear the rectal wall while treating large and deep lesion. It was a porcine model with a part of the caecum fixed onto the liver. HIFU treatments were applied on the liver through the vascularized colon. Treatment parameters for whole gland ablation as well as focal treatment were developed based on the pathology report. Clinical trial have been started based on those treatment parameters, first with the prototype and then with the Focal One®

The aim of the master’s thesis, is to get acquainted with the dynamic focusing in conventional ultrasound systems, to modify this method for ultrasound computer tomography and to realize and interpret this modification on simulated and real data in a transparent graphic interface. The modification of the dynamic focusing was executed for the 3D ultrasound computer tomograph developed in Karlsruhe. Simulated data, that are necessary for focusing, were generated by existing program, which was adjusted. The new created program of the dynamic focusing was tested and evaluated with those simulated and real data.