Après une introduction brève de l’historique de l’imagerie dermatologique non invasive, ce travail est divisé 3 parties. 1) Présentation d’un projet de développement d’un tomographe à cohérence optique miniaturisé, peu onéreu devant permettre une diffusion de cette technique aux dermatologues exerçant en dehors des hôpitaux. Il s’agi d’un projet ANR DOCT-VCSEL Portable Optical Coherence Tomography with MEMS-VCSEL swept- sources for skin analysis ANR 2015 / Défi sociétal « Vie, Santé et Bien-Etre » Axe 13 « Technologies pour la santé » 2) Présentation d’un projet dont le but est l’identification de lésions cutanées cancéreuses au moyen d’un nouvel OCT haute définition développé par la société DAMAE, issue de l’Institut supérieur d’Optique de Palaiseau. Il s’agit d’un dispositif qui sera dans un premier temps réservé aux centre d’excellence en imagerie dermatologique. 3) la reprise des 52 publications ayant trait à l’imagerie cutanée auxquelles j’ai participé et référencées dans les bases de données internationales au 31 décembre 2016. Ce travail couvre l’ensemble de l’imagerie non invasive dermatologique moderne et aborde des sujets qui n’avaient jamais été étudié de la sorte. Notamment les muqueuses et l’appareil oculaire antérieur mais aussi l’identification par microscopie confocale des marge chirurgicales ou l’association microscopie confocale spectrométrie Raman / After a brief introduction to the history of non-invasive dermatological imaging, this work is divided into 3 parts. 1) Presentation of a project for the development of a low-cost miniaturized optical coherence tomograph to allow dissemination of this technique to dermatologists practicing outside hospitals. This is an ANR project: DOCT-VCSEL Portable Optical Coherence Tomography with MEMS-VCSEL swept-sources for skin analysis ANR 2015 / Societal Challenge "Life, Health and Welfare" Axis 13 “Technologies for Health" 2) Presentation of a project whose goal is the identification of cancer skin lesions by means of a new high definition OCT developed by the company DAMAE, resulting from the Higher Institute of Optics of Palaiseau. It is a device that will initially be reserved for centers of excellence in dermatological imaging. 3) Presentation of 52 publications related to skin imaging, in which I participated, and referenced in the international databases as of December 31, 2016. This work covers all modern dermatological non-invasive imaging and addresses Subjects that had never been studied in this way. Notably the mucous membranes and the anterior ocular apparatus but also the identification by confocal microscopy of the surgical margins or the association confocal microscopy Raman spectrometry

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the United States in people who are 50 and older. The safety and efficacy of aflibercept for the treatment of late stage neovascular AMD (NAMD) has been demonstrated by clinical trials among several populations; however, it is unclear whether all NAMD patients respond in the same manner as was studied in the clinical trials. The purpose of this study was to examine if populations of patients treated with aflibercept for the treatment of NAMD were significantly different from one another in terms of health characteristics, treatment regimens, and treatment outcomes. The burden of treatment theory was used to guide this study. Data collected from electronic medical records were used to investigate NAMD characteristics 199 patients from 3 private, retinal practices in the United States. Data were analyzed using one-way ANOVA, 2, Spearman's correlation, and point-biserial correlation tests. The results of this study showed the specific retinal practice populations of NAMD patients treated with aflibercept were generally similar with respect to selected health characteristics, treatment regimens, and treatment outcomes. By using the information reported from this research, public health initiatives can be developed that focus on the need for early detection of AMD to capture changes that represent NAMD and move to early treatment for better outcomes. The positive social change that could result from this research is that retinal specialists may gain insight into the use and outcomes of aflibercept treatment.

<p>Optical coherence tomography is an imaging modality with an outstanding resolution. During the project, a time domain OCT system based on a Michelson fibre interferometer was implemented and put into operation. A super-luminescent diode with a centre wavelength of 1295nm and a bandwidth of 45nm was selected as light source and a linear variable delay line as reference. Basic tests were made on phantoms constructed of filter foils and on gel-like agar slices with optical properties similar to human tissue. It was shown that the achievable resolution was at least 36um and can be increased. The system can easily be enhanced to create two-dimensional images.</p> / <p>Optische Kohärenztomographie ist ein bildgebendes Verfahren mit einer hervorragenden räumlichen Auflösung. Im Laufe des Projekts wurde ein OCT-System basierend auf einem faseroptischen Michelson-Interferometer implementiert und in Betrieb genommen. Als Lichtquelle wurde eine Superlumineszenzdiode mit einer Mittenwellenlänge von 1295nm und einer Bandbreite von 45nm gewählt. Eine variable optische Verzögerungsleitung diente als Referenz. Erste Messungen an Filterfolien und gelähnlichen Agarphantomen, die die optischen Eigenschaften von menschlichem Gewebe nachbildeten, lieferten eine räumliche Auflösung von mindestens 36um. Durch die modulare Bauweise ist das System leicht für zweidimensionale Aufnahmen erweiterbar.</p>

Optical coherence tomography is an imaging modality with an outstanding resolution. During the project, a time domain OCT system based on a Michelson fibre interferometer was implemented and put into operation. A super-luminescent diode with a centre wavelength of 1295nm and a bandwidth of 45nm was selected as light source and a linear variable delay line as reference. Basic tests were made on phantoms constructed of filter foils and on gel-like agar slices with optical properties similar to human tissue. It was shown that the achievable resolution was at least 36um and can be increased. The system can easily be enhanced to create two-dimensional images. / Optische Kohärenztomographie ist ein bildgebendes Verfahren mit einer hervorragenden räumlichen Auflösung. Im Laufe des Projekts wurde ein OCT-System basierend auf einem faseroptischen Michelson-Interferometer implementiert und in Betrieb genommen. Als Lichtquelle wurde eine Superlumineszenzdiode mit einer Mittenwellenlänge von 1295nm und einer Bandbreite von 45nm gewählt. Eine variable optische Verzögerungsleitung diente als Referenz. Erste Messungen an Filterfolien und gelähnlichen Agarphantomen, die die optischen Eigenschaften von menschlichem Gewebe nachbildeten, lieferten eine räumliche Auflösung von mindestens 36um. Durch die modulare Bauweise ist das System leicht für zweidimensionale Aufnahmen erweiterbar.

A new approach to the absolute measurement of two-dimensional optical path differences is presented in this thesis. The method, which incorporates a white light interferometer and a hyperspectral imaging system, is referred to as Hyperspectral Interferometry. A prototype of the Hyperspectral Interferometry (HSI) system has been designed, constructed and tested for two types of measurement: for surface profilometry and for depth-resolved displacement measurement, both of which have been implemented so as to achieve single shot data acquisition. The prototype has been shown to be capable of performing a single-shot 3-D shape measurement of an optically-flat step-height sample, with less than 5% difference from the result obtained by a standard optical (microscope) based method. The HSI prototype has been demonstrated to be able to perform single-shot measurement with an unambiguous 352 (m depth range and a rms measurement error of around 80 nm. The prototype has also been tested to perform measurements on optically rough surfaces. The rms error of these measurements was found to increase to around 4× that of the smooth surface. For the depth-resolved displacement field measurements, an experimental setup was designed and constructed in which a weakly-scattering sample underwent simple compression with a PZT actuator. Depth-resolved displacement fields were reconstructed from pairs of hyperspectral interferograms. However, the experimental results did not show the expected result of linear phase variation with depth. Analysis of several possible causes has been carried out with the most plausible reasons being excessive scattering particle density inside the sample and the possibility of insignificant deformation of the sample due to insufficient physical contact between the transducer and the sample.

<p>Accurate quantification of anatomical and pathological structures in the eye is crucial for the study and diagnosis of potentially blinding diseases. Earlier and faster detection of ophthalmic imaging biomarkers also leads to optimal treatment and improved vision recovery. While modern optical imaging technologies such as optical coherence tomography (OCT) and adaptive optics (AO) have facilitated in vivo visualization of the eye at the cellular scale, the massive influx of data generated by these systems is often too large to be fully analyzed by ophthalmic experts without extensive time or resources. Furthermore, manual evaluation of images is inherently subjective and prone to human error.</p><p>This dissertation describes the development and validation of a framework called graph theory and dynamic programming (GTDP) to automatically detect and quantify ophthalmic imaging biomarkers. The GTDP framework was validated as an accurate technique for segmenting retinal layers on OCT images. The framework was then extended through the development of the quasi-polar transform to segment closed-contour structures including photoreceptors on AO scanning laser ophthalmoscopy images and retinal pigment epithelial cells on confocal microscopy images. </p><p>The GTDP framework was next applied in a clinical setting with pathologic images that are often lower in quality. Algorithms were developed to delineate morphological structures on OCT indicative of diseases such as age-related macular degeneration (AMD) and diabetic macular edema (DME). The AMD algorithm was shown to be robust to poor image quality and was capable of segmenting both drusen and geographic atrophy. To account for the complex manifestations of DME, a novel kernel regression-based classification framework was developed to identify retinal layers and fluid-filled regions as a guide for GTDP segmentation.</p><p>The development of fast and accurate segmentation algorithms based on the GTDP framework has significantly reduced the time and resources necessary to conduct large-scale, multi-center clinical trials. This is one step closer towards the long-term goal of improving vision outcomes for ocular disease patients through personalized therapy.</p> / Dissertation

Nichtglaukomatöse Optikusatrophien führen nicht nur zu einer Verminderung der Dicke der retinalen Nervenfaserschicht (RNFL) sondern auch zu einer Reduktion des Makulavolumens. In dieser Arbeit wurde mit Hilfe der optischen Kohärenztomographie (OCT) untersucht, welche Schichten der Makula von Dickenveränderungen als Folge einer Optikusatrophie betroffen sind. Es wurden 27 Patienten mit nichtglaukomatösen Optikusatrophien unterschiedlicher Ätiologie (postneuritische, hereditäre und traumatische Atrophien) und 21 augengesunde Kontrollpersonen untersucht. OCT-Scans der RNFL und der Makula wurden mit Hilfe des Stratus OCT 3000 (Carl Zeiss Meditec) durchgeführt. Die axialen Reflektivitätsprofile der radialen Scans wurden aus den exportierten JPEG-Bildern an zwölf Punkten in je 1,5mm Entfernung von der Foveola vermessen und gemittelt. Das charakteristische Reflektivitätsprofil mit fünf Intensitätsmaxima und vier Intensitätsminima wurde der Lokalisation der einzelnen Makulaschichten zugeordnet. Die von nichtglaukomatöser Optikusatrophie betroffenen Augen wiesen im Vergleich zu den Augen der augengesunden Normalpersonen signifikant (p<0,05) reduzierte RNFL-Dicken (um 35,5% reduziert) und Makulavolumen-Werte (um 11,8% reduziert) auf. Bei allen untersuchten Formen der Optikusatrophie waren nicht nur die makuläre Nervenfaserschicht (MNFL) sondern alle inneren Schichten der Makula verdünnt. Die mittlere Reduktion betrug 21,2% für die MNFL, 39,7% für die Ganglienzellschicht, 33,2% für die innere plexiforme Schicht und 9,4% für die innere Körnerzellschicht im Vergleich zu den Werten der Normalpersonen. Veränderungen der äußeren Netzhautschichten traten nur bei den posttraumatischen Atrophien auf. Eine Beurteilung der Dicke aller einzelnen Netzhautschichten aus OCT-Scans ist mit Hilfe geräteintegrierter Software bisher noch nicht möglich. Die quantitative Analyse der axialen Reflektivitätsprofile aus exportierten OCT-Bildern stellt eine geeignete Methode zur Beschreibung des Verlaufs und der Lokalisation von Makulaveränderungen bei Optikusatrophien verschiedener Genese dar.

Οι εμποτισμένες με φάρμακα μεταλλικές ενδοπροθέσεις (DES) έχει αποδειχθεί ότι ελαχιστοποιούν την υπερπλασία του ενδοθηλίου των στεφανιαίων αγγείων. Η υπερπλαστική αντίδραση του ουροθηλίου είναι το πιο συχνή επιπλοκή της χρήσης των μεταλλικών ενδοπροθέσεων στον ουρητήρα. Στην παρούσα μελέτη αξιολογήσαμε τις εμποτισμένες με zotarolimus μεταλλικές ενδοπροθέσεις (ZES- Endeavor Resolute, Medtronics Inc, USA) στον ουρητήρα χοίρων και κουνελιών. Μέθοδος: Μία ZES and μία συνήθης μεταλλική ενδοπρόθεση (BMS) τοποθετήθηκαν στον κάθε ουρητήρα 10 χοίρων και 6 κουνελιών. Η τοποθετήση έγινε κυστεοσκοπικά. Αξονική τομογραφία (CT) έγινε για την αξιολόγηση των ουρητήρων του χοίρου και ενδοφλέβιος πυελογραφία (IVP) έγινε για τον ίδιο σκοπό στα κουνέλια. Το πρόγραμμα παρακολούθησης περιλάμβανε CT ή IVP κάθε εβδομάδα για τις επόμενες 4 εβδομάδες για τους χοίρους και 8 εβδομάδες για τα κουνέλια. Σπινθηρογραφήματα νεφρών πριν την τοποθέτηση των ενδοπροθέσεων και κατά την 3 εβδομάδα παρακολούθησης έλαβε χώρα σε όλα τα ζώα. Οπτική τομογραφία συνοχής (OCT) χρησιμοποιήθηκε για την εκτίμηση της κατάστασης του αυλού και τοιχώματος των ουρητήρων που έφεραν τις ενδοπροθέσεις. Ιστοπαθολογική εξέταση των ουρητήρων με τις ενδοπρόθεσεις έγινε με τα παρασκευάσματα να έχουν στερεοποιηθεί σε glycol-methacrylate ρητίνη. Αποτελέσματα: Υπερπλαστική αντίδραση διαπιστώθηκε και στους δύο τύπους ενδοπροθέσεων. Οι BMS ενδοπροθέσεις αποφράχτηκαν πλήρως σε 7 ουρητήρες χοίρων ενώ οι ουρητήρες των ιδίων ζώων που έφεραν ZES ενδοπρόθεση έφεραν υπερπλαστική αντίδραση αλλά δεν κατέληγαν σε απόφραξη. Δύο ουρητήρες κουνελιών με BMS ενδοπροθέσεις αποφράχτηκαν τελείως ενώ όλες οι ZES ενδοπροθέσεις δε συσχετίστηκαν με απόφραξη του ουρητήρα. Διαπιστώθηκε έκπτωση της λειτουργίας 7 νεφρών χοίρων και 2 κουνελιών που είχαν ουρητήρες με αποφραγμένες ενδοπροθέσεις. Η OCT έδειξε αυξημένη υπερπλαστική αντίδραση σε ουρητήρες που έφεραν BMS ενδοπρόθεση σε σχέση με ZES. Παρόλα αυτά, η ιστοπαθολογική εξέταση έδειξε υπερπλαστική αντίδραση παρούσα σε όλες τις ενδοπροθέσεις αλλά σημαντικά περισσότερη υπερπλαστική αντίδραση στις BMS ενδοπροθέσεις. Συμπέρασμα: Οι ZES ενδοπροθέσεις στους ουρητήρες χοίρων και κουνελιών δε συσχετίστηκαν με υπερπλαστική αντίδραση που οδηγούσε σε απόφραξη της ενδοπρόθεσης. Αυτές οι ενδοπροθέσεις συσχετίστηκαν με σημαντικά μικρότερη υπερπλαστική αντίδραση συγκριτικά με τις BMS ενδοπροθέσεις ενώ η φλεγμονώδης αντίδραση ήταν παρόμοια και στους δύο τύπους ενδοπροθέσεων. / Drug eluting stents (DES) proved to minimize neointimal hyperplasia in coronary vessels. Hyperplastic reaction is the most common unwelcome event related to the use of metal mesh stents in the ureter. We evaluated the effect of zotarolimus eluting stent (ZES- Endeavor Resolute, Medtronics Inc, USA) in porcine and rabbit ureter. Methods: A ZES and a bare metal stent (BMS) were inserted in each ureter of 10 pigs and 6 rabbits. The insertion was performed by retrograde approach. Computerized tomography (CT) was used for the evaluation of porcine ureters while intraoperative intravenous pyelography (IVP) for rabbit ureters. The follow-up included CT or IVP every week for the following 4 weeks for pigs and 8 weeks for rabbits. Renal scintigraphies were performed prior to stent insertion and during the 3rd week in all animals. Optical coherence tomography (OCT) has been used for the evaluation of the luminal and intraluminal condition of the stented ureters. Histopathologic examination of the stented ureters embedded in glycol-methacrylate was performed. Results: Hyperplastic reaction was present in both stent types. BMSs in 7 porcine ureters were completely obstructed while porcine ureters stented with ZES had hyperplastic tissue which did not result in obstruction. Two rabbit ureters stented by BMS were occluded while no ZES was associated with ureteral obstruction. The function of the 7 porcine renal units and the two rabbit units with obstructed stented ureter was compromised. The OCT revealed increased hyperplastic reaction in the ureters stented by BMSs in comparison to ZESs. Although, hyperplastic reaction was present in all cases, pathology examination revealed significantly more hyperplastic reaction in BMSs. Conclusion: ZESs in the pig and rabbit ureter were not related to hyperplastic reaction resulting in stent occlusion. These stents were related to significantly lower hyperplastic reaction in comparison to BMSs while inflammation rates were similar for both stent types.

The Shannon sampling framework is widely used for discrete representation of analog bandlimited signals, starting from samples taken at the Nyquist rate. In many practical applications, signals are not bandlimited. In order to accommodate such signals within the Shannon-Nyquist framework, one typically passes the signal through an anti-aliasing filter, which essentially performs bandlimiting. In applications such as RADAR, SONAR, ultrasound imaging, optical coherence to-mography, multiband signal communication, wideband spectrum sensing, etc., the signals to be sampled have a certain structure, which could manifest in one of the following forms: (i) sparsity or parsimony in a certain bases; (ii) shift-invariant representation; (iii) multi-band spectrum; (iv) finite rate of innovation property, etc.. By using such structure as a prior, one could devise efficient sampling strategies that operate at sub-Nyquist rates. In this Ph.D. thesis, we consider the problem of sampling and reconstruction of finite-rate-of-innovation (FRI) signals, which fall in one of the two classes: (i) Sum-of-weighted and time-shifted (SWTS) pulses; and (ii) Sum-of-weighted exponential (SWE). Finite-rate-of-innovation signals are not necessarily bandlimited, but they are specified by a finite number of free parameters per unit time interval. Hence, the FRI reconstruction problem could be solved by estimating the parameters starting from measurements on the signal. Typically, parameter estimation is done using high-resolution spectral estimation (HRSE) techniques such as the annihilating filter, matrix pencil method, estimation of signal parameter via rotational invariance technique (ESPRIT), etc.. The sampling issues include design of the sampling kernel and choice of the sampling grid structure. Following a frequency-domain reconstruction approach, we propose a novel technique to design compactly supported sampling kernels. The key idea is to cancel aliasing at certain set of uniformly spaced frequencies and make sure that the rest of the frequency response is specified such that the kernel follows the Paley-Wiener criterion for compactly supported functions. To assess the robustness in the presence of noise, we consider a particular class of the proposed kernel whose impulse response has the form of sum of modulated splines (SMS). In the presence of continuous-time and digital noise cases, we show that the reconstruction accuracy is improved by 5 to 25 dB by using the SMS kernel compared with the state-of-the-art compactly supported kernels. Apart from noise robustness, the SMS kernel also has polynomial-exponential reproducing property where the exponents are harmonically related. An interesting feature of the SMS kernel, in contrast with E-splines, is that its support is independent of the number of exponentials. In a typical SWTS signal reconstruction mechanism, first, the SWTS signal is trans formed to a SWE signal followed by uniform sampling, and then discrete-domain annihilation is applied for parameter estimation. In this thesis, we develop a continuous-time annihilation approach using the shift operator for estimating the parameters of SWE signals. Instead of using uniform sampling-based HRSE techniques, operator-based annihilation allows us to estimate parameters from structured non-uniform samples (SNS), and gives more accurate parameters estimates. On the application front, we first consider the problem of curve fitting and curve completion, specifically, ellipse fitting to uniform or non-uniform samples. In general, the ellipse fitting problem is solved by minimizing distance metrics such as the algebraic distance, geometric distance, etc.. It is known that when the samples are measured from an incomplete ellipse, such fitting techniques tend to estimate biased ellipse parameters and the estimated ellipses are relatively smaller than the ground truth. By taking into account the FRI property of an ellipse, we show how accurate ellipse fitting can be performed even to data measured from a partial ellipse. Our fitting technique first estimates the underlying sampling rate using annihilating filter and then carries out least-squares regression to estimate the ellipse parameters. The estimated ellipses have lesser bias compared with the state-of-the-art methods and the mean-squared error is lesser by about 2 to 10 dB. We show applications of ellipse fitting in iris images starting from partial edge contours. We found that the proposed method is able to localize iris/pupil more accurately compared with conventional methods. In a related application, we demonstrate curve completion to partial ellipses drawn on a touch-screen tablet. We also applied the FRI principle to imaging applications such as frequency-domain optical-coherence tomography (FDOCT) and nuclear magnetic resonance (NMR) spectroscopy. In these applications, the resolution is limited by the uncertainty principle, which, in turn, is limited by the number of measurements. By establishing the FRI property of the measurements, we show that one could attain super-resolved tomograms and NMR spectra by using the same or lesser number of samples compared with the classical Fourier-based techniques. In the case of FDOCT, by assuming a piecewise-constant refractive index of the specimen, we show that the measurements have SWE form. We show how super-resolved tomograms could be achieved using SNS-based reconstruction technique. To demonstrate clinical relevance, we consider FDOCT measurements obtained from the retinal pigment epithelium (RPE) and photoreceptor inner/outer segments (IS/OS) of the retina. We show that the proposed method is able to resolve the RPE and IS/OS layers by using only 40% of the available samples. In the context of NMR spectroscopy, the measured signal or free induction decay (FID) can be modelled as a SWE signal. Due to the exponential decay, the FIDs are non-stationary. Hence, one cannot directly apply autocorrelation-based methods such as ESPRIT. We develop DEESPRIT, a counterpart of ESPRIT for decaying exponentials. We consider FID measurements taken from amino acid mixture and show that the proposed method is able to resolve two closely spaced frequencies by using only 40% of the measurements. In summary, this thesis focuses on various aspects of sub-Nyquist sampling and demonstrates concrete applications to super-resolution imaging.

Retinal nerve fiber layer measurement in patients with Alzheimer's disease The current ophthalmologist's possibilities in diagnostics of Alzheimer's disease Alzheimer disease (AD) is the most common cause of dementia syndrome and mild cognitive impairment. To enroll the disease most securely there are used so called biomarkers using evidence of changed brain metabolism by pozitron emission tomography (PET) and in cerebrospinal fluid or the brain's structure magnetic resonance imaging (MRI). These methods are expensive, organisationally and temporally challenging and burdening for the patients. According to that reasons we are still seeking for alternative attitudes suitable for early diagnosis. The evaluation of thickness of retinal nerve fiber layer (RNFL) which is well accessible to examination through optical aparatus of the eye could be one of the options. The aim of our work was to present current knowledges about Alzheimer's disease targeting relations of Alzheimer's disease and an ophthalmological finding. In the next part of this paper we introduce the retinal nerve fiber layer measurement by optical coherence tomography (OCT) as a potential diagnostics method by screening of patients with Alzheimer's disease and to present our results measured in our cohort of patients. The studied cohort...