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The ability to create large-scale high-resolution models of biological tissue provides an excellent opportunity for expanding our understanding of tissue structure and function. This is particularly important for brain tissue, where the majority of function occurs at the cellular and sub-cellular level. However, reconstructing tissue at sub-cellular resolution is a complex problem that requires new methods for imaging and data analysis. In this dissertation, I describe a prototype microscopy technique that can image large volumes of tissue at sub-cellular resolution. This method, known as Knife-Edge Scanning Microscopy (KESM), has an extremely high data rate and can capture large tissue samples in a reasonable time frame. We can therefore image complete systems of cells, such as whole small animal organs, in a matter of days. I then describe algorithms that I have developed to cope with large and complex data sets. These include methods for improving image quality, tracing filament networks, and constructing high-resolution anatomical models. These methods are highly parallel and designed to allow users to segment and visualize structures that are unique to high-throughput microscopy data. The resulting models of large-scale tissue structure provide much more detail than those created using standard imaging and segmentation techniques.

Tissue optical clearing aims to increase the penetration depth of near-collimated light in biological tissue to enhance optical diagnostic, therapeutic, and cosmetic procedures. Previous studies have shown the effects of chemical optical clearing on tissue optical properties. Drawbacks associated with chemical clearing include the introduction of potentially toxic exogenous chemicals into the tissue, poor site targeting, as well as slow transport of the chemicals through tissue. Thus, alternative clearing methods have been investigated. Mechanical compression is one such alternative tissue optical clearing technique. The mechanisms of action of mechanical compression may be similar to those of chemical clearing, though they have yet to be investigated systematically. This research describes the design and execution of a number of procedures useful for the quantification of the tissue optical clearing effects of localized mechanical compression. The first experimental chapter presents the effects of compression on image resolution and contrast of a target imaged through ex vivo biological tissue. It was found that mechanical optical clearing allowed recovery of smaller targets at higher contrast sensitivity when compared to chemical clearing. Also, thickness-independent tissue clearing effects were observed. In the second experimental chapter, dynamic changes in tissue optical properties, namely scattering and absorption coefficients (?s' and ?a, respectively) were monitored during a controlled compression protocol using different indentation geometries. A reduction in ?s' and ?a was evident for all indentation geometries, with greater changes occurring with smaller surface area. Results indicate that localized mechanical compression may be harnessed as a minimally-invasive tissue optical clearing technique. / Master of Science

Uma das dificuldades da dosimetria na área de Terapia com Laser de Baixa Intensidade (TLBI) é conhecer a distribuição da luz nos tecidos biológicos. Esse conhecimento pode ser obtido com o uso de materiais que simulem as características ópticas dos tecidos. O objetivo desse trabalho é produzir e avaliar simuladores (phantoms) sólidos em formato semelhante a dedos. Para construí-los as partículas espalhadoras testadas foram Al2O3 alfa, Al2O3 gama e microesferas de vidro, e diversas tintas foram avaliadas como absorvedores. As partículas e tintas foram adicionadas a resinas transparentes e parafina. Tecidos de suíno foram experimentados e foi possível avaliar qualitativamente as características de absorção e espalhamento de pele, músculo e tecido adiposo. Objetivando estudar in vivo a distribuição da luz, dedos de 48 voluntários foram iluminados e o padrão da luz que atravessa esses dedos foi quantificado levando em consideração os tons de pele e as espessuras. Comparando as amostras não biológicas estudadas com os tecidos suínos, concluímos que a parafina tingida simula bem a difusão causada por pele e que a resina com 10% de nano partículas de Al2O3 simula o espalhamento gerado por tecido adiposo. A partir desses dados foram confeccionados seis simuladores de dedos: três pequenos (14 mm) e três grandes (18 mm), em três tons de pele. Concluímos que os dedos e os simuladores apresentaram características de absorção e espalhamento semelhantes. Esses simuladores poderão ser usados na prática clínica com a finalidade de otimizar tratamentos em LBI e PDT. / One of difficulties on dosimetry for Low Level Laser Therapy is to know the light distribution inside the illuminated tissue. This knowledge can be obtained with the use of materials that simulate the optical properties of tissues. The aim of this work is to produce and evaluate solid finger shaped phantoms. To build the phantoms, the scattering particles tested were alpha and gamma Al2O3 and glass microspheres. Various inks were evaluated as absorbers. The particles and inks were added to transparent resins and paraffin. Swine tissues were tested and it was possible to qualitatively evaluate the scattering and absorption characteristics of skin, muscle and adipose tissue. To study light distribution in vivo, fingers of 48 volunteers were illuminated and the pattern of light transmitted through these fingers was quantified taking into accounts the skin tones and thicknesses. Comparing the non-biological samples with the swine tissues one can conclude that the dyed paraffin simulates the diffusion and absorption caused by skin and that the resin with alpha Al2O3 nanoparticles (10%) simulates the scattering generated by fat. According to this information, six finger simulators were made, three of them of small size (14 mm) and three of them of large size (18 mm); for each size, each simulator has a different skin tone. The fingers and simulators showed similar absorption and scattering characteristics. These simulators can be used in clinical practice in order to optimize LLLT and PDT treatments.

Este trabalho apresenta um procedimento para medir a condutividade de tecidos biológicos do tórax de suínos in vivo. Este procedimento permitirá um aumento da resolução em imagens de TIE, por descrever a probabilidade de ocorrência deste tipo de imagens em uma população. A TIE é uma técnica, recentemente desenvolvida, de obtenção de imagens médicas e de monitoração de tecidos biológicos. Dados os potenciais elétricos medidos no contorno e as correntes injetadas num corpo, esta técnica estima a distribuição de condutividade em seu interior. Os dados experimentais de condutividade em tecidos de tórax de suínos são utilizados para compor um atlas anatômico, que é utilizado como uma regularização do problema inverso da TIE. Tecidos biológicos conduzem eletricidade e suas propriedades elétricas como condutividade e permitividade podem sofrer alterações em função do estado fisiológico. Determinados estados do tecido biológico estão associados a variações de estrutura física ou de composição iônica e podem estar acompanhados de mudanças nas propriedades elétricas passivas. Estas mudanças de propriedades elétricas podem constituir imagens médicas funcionais. Os animais utilizados para a realização dos ensaios têm peso entre 25 e 30 kg. As medições serão realizadas utilizando-se um analisador de impedância e um condutivímetro experimental com 125 kHz de frequência. / This paper presents a procedure for measuring conductivity in biological tissues of swine chests in vivo. This will allow an increase of resolution in images of EIT, describing the probability of occurrence in such images in a population sample. The EIT is a recently developed technique for obtaining medical images and monitoring biological tissues. Given the measured electrical potentials in a body boundary and current injected inside it, this technique estimates the distribution of conductivity inside such body. The experimental conductivity data in tissues of swine chests are used to compose an anatomical atlas, used as a regularization of EIT inverse problem. Biological tissues are conductive and their electrical properties, like conductivity and permittivity, may change depending on the physiological state. Certain biological tissue states are associated with changes in physical structure or ionic composition and may be dependent by changes in tissues passive electrical properties. These changes in electrical properties can be functional medical images. The animals used for the experiments have weight between 25 and 30 kg. These measurements are performed using an impedance analyzer and an experimental conductivimeter with 125 kHz of frequency.

Soft biological tissue material models in the literature are frequently limited to integer order constitutive relations where the order of differentiation of stress and/or strain is integer-valued. However, it has been demonstrated that fractional calculus theory applied in soft tissue material model formulation yields more accurate and reliable soft tissue material models. In this study, firstly a fractional order (where the order of differentation of stress in the constitutive relation is non-integer-valued) linear viscoelastic material model for soft tissues is fitted to force-displacement-time indentation test data and compared with two different integer order linear viscoelastic material models by using MATLAB&reg / optimization toolbox. After the superiority of the fractional order material model compared to integer order material models has been shown, the linear fractional order material model is extended to its nonlinear counterpart in finite deformation regime. The material model developed is assumed to be isotropic and homogeneous. v A user-subroutine is developed for the material model formulated to implement it into the commercial finite element software Msc.Marc 2010. The user-subroutine developed is verified by performing a small strain finite element analysis and comparing the results obtained with linear viscoelastic counterpart of the model on MATLAB&reg / . Finally, the unknown coefficients of the fractional order material model are identified by employing the inverse finite element method. A material parameter set with an amount of accuracy is determined and the material model with the parameters identified is capable of simulating the three different indentation test protocols, i.e., &ldquo / relaxation&rdquo / , &ldquo / creep&rdquo / and &ldquo / cyclic loading&rdquo / protocols with a good accuracy.

Este trabalho apresenta um procedimento para medir a condutividade de tecidos biológicos do tórax de suínos in vivo. Este procedimento permitirá um aumento da resolução em imagens de TIE, por descrever a probabilidade de ocorrência deste tipo de imagens em uma população. A TIE é uma técnica, recentemente desenvolvida, de obtenção de imagens médicas e de monitoração de tecidos biológicos. Dados os potenciais elétricos medidos no contorno e as correntes injetadas num corpo, esta técnica estima a distribuição de condutividade em seu interior. Os dados experimentais de condutividade em tecidos de tórax de suínos são utilizados para compor um atlas anatômico, que é utilizado como uma regularização do problema inverso da TIE. Tecidos biológicos conduzem eletricidade e suas propriedades elétricas como condutividade e permitividade podem sofrer alterações em função do estado fisiológico. Determinados estados do tecido biológico estão associados a variações de estrutura física ou de composição iônica e podem estar acompanhados de mudanças nas propriedades elétricas passivas. Estas mudanças de propriedades elétricas podem constituir imagens médicas funcionais. Os animais utilizados para a realização dos ensaios têm peso entre 25 e 30 kg. As medições serão realizadas utilizando-se um analisador de impedância e um condutivímetro experimental com 125 kHz de frequência. / This paper presents a procedure for measuring conductivity in biological tissues of swine chests in vivo. This will allow an increase of resolution in images of EIT, describing the probability of occurrence in such images in a population sample. The EIT is a recently developed technique for obtaining medical images and monitoring biological tissues. Given the measured electrical potentials in a body boundary and current injected inside it, this technique estimates the distribution of conductivity inside such body. The experimental conductivity data in tissues of swine chests are used to compose an anatomical atlas, used as a regularization of EIT inverse problem. Biological tissues are conductive and their electrical properties, like conductivity and permittivity, may change depending on the physiological state. Certain biological tissue states are associated with changes in physical structure or ionic composition and may be dependent by changes in tissues passive electrical properties. These changes in electrical properties can be functional medical images. The animals used for the experiments have weight between 25 and 30 kg. These measurements are performed using an impedance analyzer and an experimental conductivimeter with 125 kHz of frequency.

Uma das dificuldades da dosimetria na área de Terapia com Laser de Baixa Intensidade (TLBI) é conhecer a distribuição da luz nos tecidos biológicos. Esse conhecimento pode ser obtido com o uso de materiais que simulem as características ópticas dos tecidos. O objetivo desse trabalho é produzir e avaliar simuladores (phantoms) sólidos em formato semelhante a dedos. Para construí-los as partículas espalhadoras testadas foram Al2O3 alfa, Al2O3 gama e microesferas de vidro, e diversas tintas foram avaliadas como absorvedores. As partículas e tintas foram adicionadas a resinas transparentes e parafina. Tecidos de suíno foram experimentados e foi possível avaliar qualitativamente as características de absorção e espalhamento de pele, músculo e tecido adiposo. Objetivando estudar in vivo a distribuição da luz, dedos de 48 voluntários foram iluminados e o padrão da luz que atravessa esses dedos foi quantificado levando em consideração os tons de pele e as espessuras. Comparando as amostras não biológicas estudadas com os tecidos suínos, concluímos que a parafina tingida simula bem a difusão causada por pele e que a resina com 10% de nano partículas de Al2O3 simula o espalhamento gerado por tecido adiposo. A partir desses dados foram confeccionados seis simuladores de dedos: três pequenos (14 mm) e três grandes (18 mm), em três tons de pele. Concluímos que os dedos e os simuladores apresentaram características de absorção e espalhamento semelhantes. Esses simuladores poderão ser usados na prática clínica com a finalidade de otimizar tratamentos em LBI e PDT. / One of difficulties on dosimetry for Low Level Laser Therapy is to know the light distribution inside the illuminated tissue. This knowledge can be obtained with the use of materials that simulate the optical properties of tissues. The aim of this work is to produce and evaluate solid finger shaped phantoms. To build the phantoms, the scattering particles tested were alpha and gamma Al2O3 and glass microspheres. Various inks were evaluated as absorbers. The particles and inks were added to transparent resins and paraffin. Swine tissues were tested and it was possible to qualitatively evaluate the scattering and absorption characteristics of skin, muscle and adipose tissue. To study light distribution in vivo, fingers of 48 volunteers were illuminated and the pattern of light transmitted through these fingers was quantified taking into accounts the skin tones and thicknesses. Comparing the non-biological samples with the swine tissues one can conclude that the dyed paraffin simulates the diffusion and absorption caused by skin and that the resin with alpha Al2O3 nanoparticles (10%) simulates the scattering generated by fat. According to this information, six finger simulators were made, three of them of small size (14 mm) and three of them of large size (18 mm); for each size, each simulator has a different skin tone. The fingers and simulators showed similar absorption and scattering characteristics. These simulators can be used in clinical practice in order to optimize LLLT and PDT treatments.

The purpose of this manuscript is to establish a unified theory of porohyperelasticity with transport and growth and to demonstrate the capability of this theory using a finite element model developed in MATLAB. We combine the theories of volumetric growth and mixed porohyperelasticity with transport and swelling (MPHETS) to derive a new method that models growth of biological soft tissues. The conservation equations and constitutive equations are developed for both solid-only growth and solid/fluid growth. An axisymmetric finite element framework is introduced for the new theory of growing MPHETS (GMPHETS). To illustrate the capabilities of this model, several example finite element test problems are considered using model geometry and material parameters based on experimental data from a porcine coronary artery. Multiple growth laws are considered, including time-driven, concentrationdriven, and stress-driven growth. Time-driven growth is compared against an exact analytical solution to validate the model. For concentration-dependent growth, changing the diffusivity (representing a change in drug) fundamentally changes growth behavior. We further demonstrate that for stress-dependent, solid-only growth of an artery, growth of an MPHETS model results in a more uniform hoop stress than growth in a hyperelastic model for the same amount of growth time using the same growth law. This may have implications in the context of developing residual stresses in soft tissues under intraluminal pressure. To our knowledge, this manuscript provides the first full description of an MPHETS model with growth. The developed computational framework can be used in concert with novel in-vitro and in-vivo experimental approaches to identify the governing growth laws for various soft tissues.

Cette thèse a porté sur la construction de densités d'énergie de déformation permettant de décrire le comportement non linéaire de matériaux anisotropes tels que les tissus biologiques souples (ligaments, tendons, parois artérielles etc.) ou les caoutchoucs renforcés par des fibres. Les densités que nous avons proposées ont été élaborées en se basant sur la théorie mathématique des polynômes invariants et notamment sur le théorème de Noether et l'opérateur de Reynolds. Notre travail a concerné deux types de matériaux anisotropes, le premier avec une seule famille de fibre et le second avec quatre familles. Le concept de polyconvexité a également été étudié car il est notoire qu'il joue un rôle important pour s'assurer de l'existence de solutions. Dans le cas d'un matériau comportant une seule famille de fibre, nous avons démontré qu'il était impossible qu'une densité polynomiale de degré quelconque puisse prédire des essais de cisaillement avec un chargement parallèle puis perpendiculaire à la direction des fibres. Une densité polynomiale linéaire combinée avec une fonction puissance a permis de contourner cet obstacle. Dans le cas d'un matériau comportant quatre familles de fibre, une densité polynomiale a permis de prédire correctement des résultats d'essai en traction bi-axiale extraits de la littérature. Les deux densités proposées ont été implémentées avec la méthode des éléments finis et en langage C++ dans le code de calcul universitaire FER. Pour se faire, une formulation lagrangienne totale a été adoptée. L'implémentation a été validée par des comparaisons avec des solutions analytiques de référence que nous avons exhibée dans le cas de chargements simples conduisant à des déformations homogènes. Des exemples tridimensionnels plus complexes, impliquant des déformations non-homogènes, ont également été étudiés. / This thesis has focused on the construction of strain energy densities for describing the non-linear behavior of anisotropic materials such as biological soft tissues (ligaments, tendons, arterial walls, etc.) or fiber-reinforced rubbers. The densities we have proposed have been developed with the mathematical theory of invariant polynomials, particularly the Noether theorem and the Reynolds operator. Our work involved two types of anisotropic materials, the first with a single fiber family and the second with a four-fiber family. The concept of polyconvexity has also been studied because it is well known that it plays an important role for ensuring the existence of solutions. In the case of a single fiber family, we have demonstrated that it is impossible for a polynomial density of any degree to predict shear tests with a loading parallel and then perpendicular to the direction of the fibers. A linear polynomial density combined with a power-law function allowed to overcome this problem. In the case of a material made of a four-fiber family, a polynomial density allowed to correctly predict bi-axial tensile test data extracted from the literature. The two proposed densities were implemented in C++ language in the university finite element software FER by adopting a total Lagrangian formulation. This implementation has been validated by comparisons with reference analytical solutions exhibited in the case of simple loads leading to homogeneous deformations. More complex three-dimensional examples, involving non-homogeneous deformations, have also been studied.