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Abstract The development of a non-invasive glucose monitoring technique is very important because it would tremendously diminish the need to puncture the skin when taking blood samples and help diabetic patients in controlling their blood glucose levels and in treating Diabetes Mellitus. The focus of this thesis is on measuring the effect of glucose on the light scattering properties of a tissue-simulating phantom and biological tissues in vitro. Optical coherence tomography (OCT), the pulsed photoacoustic (PA) technique, and the time-of-flight (TOF) technique are used in the measurements and their capabilities for detecting changes in the scattering properties are evaluated and compared with each other. The theoretical background of the techniques, light propagation and PA wave generation are briefly explained. The glucose-induced changes in light scattering are also reviewed. The measurement results with the OCT and the PA technique from Intralipid, pig whole blood, and mouse skin tissue samples show that the glucose-induced changes are larger in the biological tissues than in the Intralipid phantom. The PA measurements show that although the PA signals are stronger at a wavelength of 532 nm than at 1064 nm, the glucose-induced change in the peak-to-peak value of the PA signal measured from pig whole blood is larger at a wavelength of 1064 nm than at 532 nm. The TOF measurements with a streak camera show that the scattering-related changes in the registered pulse shapes occur mainly in the rising part of the pulses. The utilization of fiber-optic measurement heads enabled the detection of back-scattered photons at different distances from the emitting fiber. Although all the techniques are able to detect changes induced by large glucose concentrations (0–5000 mg/dl) in Intralipid, the effect of glucose on the scattering properties of Intralipid is so weak that the techniques failed to detect changes with lower (50–500 mg/dl) concentrations. The measurements of biological samples with the PA technique and with the OCT also demonstrate capabilities to measure glucose concentrations in the physiologically relevant range (18–450 mg/dl) as well. The results compare well with earlier literature and also confirm some earlier findings.

Abstract Optical coherence tomography (OCT) is a modern rapidly developing technique for non-invasive imaging of the internal structure of optically non-uniform objects based on the principles of low-coherent interferometry. However, multiple scattering of light in the objects under study brings distortions to the images obtained by OCT. The analysis of formation of the OCT signals is required for understanding the role of multiple scattering in this formation and providing recommendations for optimal configuration of a measuring setup. In the present thesis formation of the OCT signals and images is analyzed implementing Monte Carlo simulations of light propagation in scattering media. Blood, intralipid solution, human skin and paper samples are chosen as the objects under study due to the interest in the diagnostics of these objects in biomedicine and paper industry. Multilayer models of skin phantoms, skin and paper were developed in the frames of the present study for simulation of OCT signals and two-dimensional OCT images of these objects. The contribution of different scattering orders as well as different fractions of photons (least and multiply scattered, diffusive and non-diffusive) to these images was found allowing to evaluate the maximal depth of non-distorted imaging in each particular case. The simulated OCT images were compared to the experimental ones demonstrating qualitative similarity. This fact allowed the author to analyze qualitatively the influence of parameters of the OCT setup on the images which have also been acquired in this work. The formation of the OCT images of paper samples with various refractive index matching liquids was also studied.

The utilisation of near-infraredR aman spectroscopyfo r the discrimination of cancersa nd pre-cancers from normal tissue in the acro-digestive tract has been evaluated. A commercially available Raman microspectrometehr as been modified to provide optimum throughput, sensitivity and fluorescence suppression for epithelial tissue measurements. Laser excitation at 830nmw as demonstratedto be optimum. High quality (SN ratio 15-20) NIR-Raman spectrah ave been acquired from oesophageaal nd laryngeal tissues in time scales under 30 seconds. Pathological groupings covering the full range of normal and neoplastic tissues in the organs of interest have been studied. Both fresh (snap frozen) and formalin fixed tissue samples were investigated,f irstly to indicate whether tissue-typesc an be distinguishedi n vivo and secondlyt o demonstrateth e use of Raman spectroscopya s a tool for classificationi n the pathology lab. Results using multivariate statistical techniques to distinguish between spectra from specimens exhibiting different tissue pathologies have been extremely promising. Crossvalidation of the spectral predictive models has shown that three groups of larynx tissue can be separated with sensitivities and specificities of between 86 and 90% and 87 and 95% respectively. Oesophageal prediction models have demonstrated sensitivities and specificities of 84 to 97% and 93 to 98% respectively for a three-group consensus model and 73 to 100% and 92 to 100% for an eight-groupc onsensusm odel. Epithelial tissues including stomach, tonsil, endometrium, bladder and prostate have been studiedt o identify further tissuesw hereR amans pectroscopym ay be employedf or detection of disease.S pectraw ere similar to those obtainedf rom oesophagusa nd larynx, although sufficiently different for distinct discriminant models to be required. This work has demonstratedth e genericn atureo f Ramans pectroscopyfo r the detectiona nd classification of cancersa nd pre-cancerousle sionsi n many tissues.T he evidencep rovided by this study indicatest hat utilisation of Ramans pectroscopyfo r non-invasived etectiona nd classification of diseaseis a distinct possibility. Potentiald ifficulties in the transferabilityf rom in vitro to in vivo have been evaluated and no significant barriers have been observed. However, further in vivo probe development and optimisation will be required before 'optical biopsy' with Ramans pectroscopyc anb ecomea reality.

Dental erosion has been defined as a chemical process that involves the dissolution of enamel and dentine by acid(s) not derived from bacteria when the surrounding aqueous phase is under-saturated with tooth mineral. Clinically however, dental erosion hardly ever occurs exclusively from the other modes of tooth wear such as abrasion and attrition. Hence the term erosive wear has been proposed and used to describe erosion-facilitated wear.With the prevalence of erosive wear being reported to be on the rise among children and adolescents in many countries, a plethora of oral health products such as dentifrices and mouth rinses had been put forward with claims of increasing the resistance of the enamel and / or dentine from being demineralised. However, the efficacy of these oral health products is still widely questionable as the studies carried out were mainly in vitro and / or in situ studies and the contradictory results were reported by different groups of researchers.The above mentioned discrepancies are often due to non-standardised in vitro and in situ study designs of erosion studies. Parameters such as type of acid used, concentration of acid used, duration of acid exposure, inclusion or exclusion of abrasion in the study model, ex vivo or in vivo acid challenge, ex vivo or in vivo treatment with oral health product and the nature of pellicle on the specimen are often varied.The availability of an detection tool which could be used to measure demineralisation on natural tooth surface in vivo would exclude many of the inevitable variability in in situ and in vitro study design, such as the simulation of the intra oral conditions in which the erosion challenge and intervention take place and the nature of the pellicle formed on the specimens. Hence with an in vivo detection tool, it is hopeful that the efficacy of any interventions would be evaluated more accurately and its results expounded to a wider context. It would be useful if the tool was sensitive to the very early stages of the erosion process as this would entail shorter and more economical study designs. Arising from the problems discussed above, potential non-invasive assessment methods that could be used clinically to measure demineralisation were explored and it was found that two optical methods, Optical Coherence Tomography (OCT) and Quantitative Light-induced Fluorescence (QLF) were potential methods for the tasks.The studies described in this thesis were divided into three main big sections; the first being the in vitro validation work of the two optical methods (Chapter 5 and 6), the second, validation of these methods in situ (Chapter 7) and finally the assessment of the efficacy of a high fluoride dentifrice on early enamel erosion using these two methods (Chapter 8).In the in vitro validation (Chapter 5), it was demonstrated that both QLF and OCT were able to detect erosion-interval related changes in natural surface samples eroded with orange juice for 60 minutes. However, results of Multiple Linear Regression and Paired t test suggest that QLF was more sensitive than OCT in the detection of demineralisation changes in this particular experimental setting. QLF demonstrated a R2 value of 0.590 while the best of the OCT outcome measure demonstrated a R2 value of 0.319.Further in vitro study (Chapter 6) was performed to explore the use of a moistened-exposed surface as a reference method for both OCT and QLF as it was felt that it would be beneficial if a coated reference area which posts as an additional step for error could be done away with. Results of this study showed that the moistened-exposed surface could be used a reference method for QLF only but not for OCT. Furnished with the findings of the above mentioned in vitro validation studies, an in situ validation of both the optical methods was performed (Chapter 7). It was found that OCT and QLF were able to longitudinally measure in situ demineralisation on polished and natural surfaced enamel which were subjected to 150 minutes of in vivo exposure to orange juice. Similar to the results of the in vitro study, QLF was found to be more sensitive than OCT in the detection of demineralisation changes on natural surfaced enamel. The last in situ study (Chapter 8) was to evaluate whether there was a protective effect of treating human enamel with a high-concentrated fluoride dentifrice during an active erosion phase and whether OCT and QLF were able to detect the protective effect. It was found that treating natural surface enamel with a 5000ppm NaF dentifrice increased its resistance against concurrent in vivo erosive challenge with an orange juice challenge. QLF was able to detect the protective effect of the 5000ppm NaF dentifrice on natural surface enamel against early in vivo erosion with an orange juice challenge regime while OCT did not.

Optical coherence tomography (OCT) and Photoacoustic microscopy (PAM) are two noninvasive, high-resolution, three-dimensional, biomedical imaging modalities based on different contrast mechanisms. OCT detects the light backscattered from a biological sample either in the time or spectral domain using an interferometer to form an image. PAM is sensitive to optical absorption by detecting the light-induced acoustic waves to form an image. Due to their complementary contrast mechanisms, OCT and PAM are suitable for being combined to achieve multimodal imaging. In this dissertation, an optical coherence photoacoustic microscopy (OC-PAM) system was developed for in vivo multimodal retinal imaging with a pulsed broadband NIR light source. To test the capabilities of the system on multimodal ophthalmic imaging, the retina of pigmented rats was imaged. The OCT images showed the retinal structures with quality similar to conventional OCT, while the PAM images revealed the distribution of melanin in the retina since the NIR PAM signals are generated mainly from melanin in the posterior segment of the eye. By using the pulsed broadband light source, the OCT image quality highly depends on the pulse-to-pulse stability of the light source without averaging. In addition, laser safety is always a concern for in vivo applications, especially for eye imaging with a pulsed light source. Therefore, a continuous wave (CW) light source is desired for OC-PAM applications. An OC-PAM system using an intensity-modulated CW superluminescent diode was then developed. The system was tested for multimodal imaging the vasculature of a mouse ear in vivo by using Gold Nanorods (GNRs) as contrast agent for PAM, as well as excised porcine eyes ex vivo. Since the quantitative information of the optical properties extracted from the proposed NIR OC-PAM system is potentially able to provide a unique technique to evaluate the existence of melanin and lipofuscin specifically, a phantom study has been conducted and the relationship between image intensity of OCT and PAM was interpreted to represent the relationship between the optical scattering property and optical absorption property. It will be strong evidence for practical application of the proposed NIR OC-PAM system.

A multilayered system is a good model for many optical systems. An optical coherence tomography (OCT) system can provide fundamental information about the refractive index distribution of the sample and enables images to be corrected for geometric accuracy, but this requires the separation of refractive index and physical thickness for each layer from the measured optical paths. In this thesis a novel approach for simultaneous extraction of index and thickness of multi layer systems and the last medium index of refraction in a single experiment using only the object’s spectral response available by any Fourier Domain OCT system without using any additional outside measurements is introduced. The method is based on a novel matrix equation that uses the reflected spectrum from the object and the measured optical thickness. In the presence of slight error of measuring optical thickness, the parameters extraction has wavenumber dependency. A novel method is used to select the suitable set of spectral components that reduces the extracted parameters error. The parameters extraction method is followed by a fitting process for optimized results. The method works the best for low contrast index distribution even in the presence of relatively large optical thickness measurement error.

L'objectif de ce travail de recherche est le développement d'un système fibré d'imagerie point par point d'auto fluorescence multi-excitation, de tissus biologiques en utilisant la technique de fluorescence hyperspectrale et l'étude d'un système de tomographie optique cohérente comme possible modalité supplémentaire. La première partie de ce rapport présente les propriétés optique des tissus biologiques et les fluorophores pertinents pour la détection de tumeurs cancéreuses. La deuxième partie présente l'instrumentation du système d'imagerie de fluorescence et l'analyse hyperspectrale des résultats obtenus in vitro.Il est démontré la pertinence de ce type d'analyse qui permet de déterminer la concentration de certains fluorophores. La troisième partie présente le système de tomographie optique cohérente appelé "scan free" OCT car il permet de réaliser des images sans déplacement d'éléments optiques. Ce système est caractérisé et présente des fonctionnalités intéressantes comme la compensation de la dispersion dépendante de la profondeur. Les divers résultats obtenus montrent que ces deux techniques sont complémentaires car elles apportent des informations de nature différentes. La première technique donne de se informations sur la composition biochimique des tissus, la seconde donne des information sur la structure. / The aim of this activity is the development of a mono point imaging fiber system which uses hyperspectral multi-excitation auto fluorescence technique for biological tissues and the study of an Optical Coherence Tomography system like another modality. At first, this report presents the optical properties of biological tissues and the relevant fluorophores for cancerous tumors detection. Secondly, the fluorescence imaging system instrumentation and hyperspectral analysis are presented with in vitro results. The third part presents the "scan free" optical coherence tomography system which is able to image without optical displacement. It's characterized and have interesting functionality like depth dependant dispersion compensation. These both techniques are complementary because they get different kind of information. The information of the first one is about biochemical composition of the tissues and the information of the second one is about the stucture.

Orientador: Vital Paulino Costa / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Aplicadas / Made available in DSpace on 2018-08-24T05:07:57Z (GMT). No. of bitstreams: 1 VidottiPimenta_VanessaGoncalves_D.pdf: 6967367 bytes, checksum: 6f865b9b0ad4158ca43a18b2ff974544 (MD5) Previous issue date: 2014 / Resumo: O presente estudo teve como objetivo investigar a sensibilidade e especificidade dos classificadores de aprendizagem de máquina (MLC) e da tomografia de coerência óptica de domínio espectral (SD-OCT) para o diagnóstico de glaucoma. Sessenta e dois pacientes com glaucoma e defeito de campo visual inicial a moderado, e 48 indivíduos saudáveis foram incluídos. Todos os participantes foram submetidos a um exame oftalmológico completo, perimetria automatizada acromática e medida da espessura da camada de fibras nervosas da retina com SD-OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, Califórnia, EUA). Uma curva ROC (receiver operating curve) foi obtida para cada parâmetro do SD-OCT: espessura média, espessura nos quatro quadrantes (temporal, superior, nasal e inferior) e a espessura a cada hora de relógio. Posteriormente, foram testados os seguintes MLCs construídos a partir dos dados do OCT: Árvore de Decisão (CTREE), Random Forest (RAN), Bagging (BAG), Adaptative Boosting (ADA), Ensemble Selection (ENS), Multilayer Perceptrons (MLP), Rede de Funções de Base Radial (RBF), Naive-Bayes (NB), Support Vector Machine - Linear (SVMl) e Support Vector Machine - Gaussian (SVMg). Áreas sob as curvas ROC (aROCs) foram obtidas para cada parâmetro do SD-OCT e para cada MLC. A média de idade foi de 57,0 ± 9,2 anos para os indivíduos saudáveis e de 59,9 ± 9,0 anos para os pacientes com diagnóstico de glaucoma (p=0,103). Valores do &quot;mean deviation¿ (MD) foram de -4,1 ± 2,4 dB para pacientes com glaucoma e -1,5 ± 1,6 dB para indivíduos normais (p<0,001). Os parâmetros do SD-OCT com as maiores aROCs foram: quadrante inferior (0,813), espessura média global (0,807), 7 horas (0,765) e 6 horas de relógio (0,754). As aROCs dos classificadores variaram de 0,785 (ADA) a 0,818 (BAG). A aROC obtida com o BAG não foi significativamente diferente da aROC obtida com o melhor parâmetro isolado do SD-OCT (p=0,932). O SD-OCT mostrou boa acurácia diagnóstica em um grupo de pacientes com glaucoma inicial a moderado. Os MLCs não melhoraram a sensibilidade e a especificidade do SD-OCT para o diagnóstico do glaucoma / Abstract: This study aimed to investigate the sensitivity and specificity of machine learning classifiers (MLC) and spectral domain optical coherence tomography (SD-OCT) for the diagnosis of glaucoma. Sixty-two patients with early to moderate glaucomatous visual field damage and 48 healthy individuals were included. All subjects underwent a complete ophthalmologic examination, achromatic standard automated perimetry, and RNFL imaging with SD-OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, California, USA). Receiver operating characteristic (ROC) curves were obtained for all SD-OCT parameters: average thickness, four quadrants (temporal, superior, nasal and inferior) and 12 clock hour measurements. Subsequently, the following MLCs were tested: Classification Tree (CTREE), Random Forest (RAN), Bagging (BAG), AdaBoost M1 (ADA), Ensemble Selection (ENS), Multilayer Perceptron (MLP), Radial Basis Function (RBF), Naive-Bayes (NB), and Support Vector Machine (SVM). Areas under the ROC curves (aROCs) were obtained for each parameter and each MLC. The mean age was 57.0 ± 9.2 years for healthy individuals and 59.9 ± 9.0 years for glaucoma patients (p=0.103). Mean deviation values were ¿4.1 ± 2.4 dB for glaucoma patients and ¿1.5 ± 1.6 dB for healthy individuals (p<0.001). The SD-OCT parameters with the greater aROCs were inferior quadrant (0.813), average thickness (0.807), 7 o¿clock position (0.765), and 6 o¿clock position (0.754). The aROCs obtained with classifiers varied from 0.785 (ADA) to 0.818 (BAG). The aROC obtained with BAG was not significantly different from the aROC obtained with the best single SD-OCT parameter (p=0.932). SD-OCT showed good diagnostic accuracy in a group of patients with early to moderate glaucoma. In this series, MLCs did not improve the sensitivity and specificity of SD-OCT for the diagnosis of glaucoma / Doutorado / Oftalmologia / Doutora em Ciências Médicas

Orientador: Vital Paulino Costa / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T18:27:45Z (GMT). No. of bitstreams: 1 Barella_KleytonArlindo_D.pdf: 7085227 bytes, checksum: 6f0489a5abce751aee2f5fb29f968473 (MD5) Previous issue date: 2015 / Resumo: O presente estudo teve como objetivo investigar a acurácia dos classificadores de aprendizagem de máquina (MLCs) utilizando parâmetros da camada de fibras nervosas retiniana (CFNR) e do disco óptico (DO) obtidos com um tomógrafo de coerência óptica de domínio espectral (SD-OCT) para o diagnóstico de glaucoma. Cinquenta e sete pacientes com defeito de campo visual glaucomatoso leve a moderado e 46 indivíduos normais foram incluídos. Todos os 103 pacientes foram submetidos a exame oftalmológico completo, perimetria automatizada acromática (Humphrey Field Analyzer II®, Carl Zeiss Meditec Inc., Dublin, CA, EUA) e tomografia com um SD-OCT (Cirrus® SD-OCT; Carl Zeiss Meditec Inc., Dublin, CA, EUA). Obtiveram-se curvas ROC (receiver operating characteristic) para cada um dos 17 parâmetros da CFNR (espessura média, espessura nos quatro quadrantes (temporal, superior, nasal e inferior), espessura de cada uma das 12 horas de relógio) e para cada um dos os seis parâmetros do DO (área da rima, área do disco, volume da escavação, relação escavação/disco vertical, relação escavação/disco média e relação área escavação/disco). Posteriormente, foram testados os seguintes MLCs: Bagging (BAG), Naive-Bayes (NB), Support Vector Machine - Linear (SVML), Support Vector Machine - Gaussian (SVMG), Multilayer Perceptrons (MLP), Rede de Funções de Base Radial (RBF), Random Forest (RAN), Ensemble Selection (ENS), Árvore de Decisão (CTREE) e Adaptative Boosting (ADA). Compararam-se áreas sob as curvas ROC (aROCs) obtidas para cada parâmetro do SD-OCT e para cada um dos 10 MLCs. A idade média foi de 56,5 ± 8,9 anos para os indivíduos normais e 59,9 ± 9,0 anos para os pacientes glaucomatosos (p=0,054). Valores médios do "mean deviation" (MD) foram de -1,4 ± 1,6 dB para os indivíduos normais e -4,0 ± 2,4 dB para os pacientes glaucomatosos (p<0,001). Os parâmetros do SD-OCT com as maiores aROCs foram: relação área escavação/disco (0,846) e relação escavação/disco média (0,843). aROCs obtidas com os classificadores variaram de 0,687 (CTREE) a 0,877 (RAN). A aROC obtida com o classificador RAN testado com 13 parâmetros (0,877) não foi significativamente diferente da aROC obtida com o melhor parâmetro isolado do SD-OCT (0,846) (p=0,542). Os MLCs mostraram boa acurácia, mas não melhoraram significativamente a sensibilidade e especificidade do Cirrus® SD-OCT para o diagnóstico de glaucoma / Abstract: This study aimed to investigate the diagnostic accuracy of machine learning classifiers (MLCs) using retinal nerve fiber layer (RNFL) and optic nerve head (ONH) parameters obtained with spectral domain optical coherence tomography (SD-OCT) for the diagnosis of glaucoma. Fifty-seven patients with early to moderate glaucomatous visual field damage and 46 normal individuals were recruited. All 103 individuals underwent a complete ophthalmological examination, achromatic standard automated perimetry (Humphrey Field Analyzer II®, Carl Zeiss Meditec Inc., Dublin, CA, USA) and tomography with SD-OCT (Cirrus® SD-OCT; Carl Zeiss Meditec Inc., Dublin, CA, USA). Receiver operating characteristic (ROC) curves were built for each one of the 17 RNFL parameters (average thickness, four quadrants (temporal, superior, nasal and inferior), 12 clock-hour measurements) and each one of the six ONH parameters (rim area, disc area, cup volume, vertical cup/disc ratio, average cup/disc ratio and cup/disc area ratio). Subsequently, the following MLCs were tested: Bagging (BAG), Naive-Bayes (NB), Support Vector Machine ¿ Linear (SVML), Support Vector Machine - Gaussian (SVMG), Multilayer Perceptrons (MLP), Radial Basis Functions (RBF), Random Forest (RAN), Ensemble Selection (ENS), Classification Tree (CTREE) and Adaptative Boosting (ADA). Areas under ROC curves (aROCs) obtained for each SD-OCT parameter and 10 MLCs were compared. The mean age was 56,5 ± 8,9 years for normal individuals and 59,9 ± 9,0 years for glaucoma patients (p=0,054). Mean MD (mean deviation) values were -1,4 ± 1,6 dB for normal individuals and -4,0 ± 2,4 dB for glaucoma patients (p<0,001). SD-OCT parameters with the greatest aROCs were: cup/disc area ratio (0,846) and average cup/disc ratio (0,843). aROCs obtained with classifiers varied from 0,687 (CTREE) to 0,877 (RAN). The aROC obtained with RAN (0,877) tested with 13 parameters was not significantly different from the aROC obtained with the best single SD-OCT parameter (0,846) (p=0,542). MLCs showed good diagnostic accuracy but did not improve the sensitivity and specificity of Cirrus® SD-OCT for the diagnosis of glaucoma / Doutorado / Oftalmologia / Doutor em Ciências Médicas