Depuis les observations par Poiseuille au XVIIIe de réseaux microvasculaires de petits vertébrés,la microcirculation sanguine a fait l'objet d'abondantes études. Une spécificité mise en avant par le médecin français est la forte hétérogénéité de la distribution des globules rouges dans ces réseaux. En dépit du lien étroit qui lie la fraction volumique locale des globules rouges(hématocrite) à l'oxygénation des tissus environnants, le couplage entre l'architecture microvasculaire et la micro-hémodynamique est encore mal compris. Le sang est un fluide complexe composé de globules rouges, cellules très déformables, suspendus dans du plasma.Dans les vaisseaux de petits diamètres, i.e. du même ordre de grandeur voire plus petits que la taille caractéristique d'un globule rouge (~10µm), le sang possède des propriétés rhéologiques atypiques induites par la structuration locale de l'écoulement et les hétérogénéités d'hématocrite qui en résultent dans la section droite. Ces hétérogénéités se traduisent, aux bifurcationsdivergentes, par une répartition non proportionnelle des débits de globules rouges et de plasma entre les deux branches filles. L'hématocrite de l'une d'elles est alors plus élevé que celui de labranche d'entrée, alors qu'il est plus faible dans l'autre branche. Cet effet, connu sous le nom d'effet de séparation de phase, induit une très grande hétérogénéité de l'hématocrite à l'échelle du réseau. L'objectif de cette thèse est d'étudier l'apparition de ces hétérogénéités, de l'échelle du vaisseau à l'échelle du réseau, dans des conditions expérimentales contrôlées et pour des régimes de confinement et d'hématocrite représentatifs des écoulement sanguins de la partie terminale du lit microvasculaire (artérioles, capillaires et veinules de diamètres inférieurs à 20 µm).De nombreuses données expérimentales ont été acquises in vivo, mais elles sont sujettes à de fortes incertitudes quant à la forme et aux dimensions de la section droite des vaisseaux, mais aussi soumises aux effets de régulations physiologiques des débits (e.g. par vasoconstriction ou vasodilatation). A notre connaissance, du fait des contraintes expérimentales inhérentes aux régimes de confinement et d'hématocrite des plus petits vaisseaux de la microcirculation, très peu d'études in vitro dans ces conditions ont été menées. Tout d'abord, nous présentons les profils de vitesse des globules rouges et les profils d'hématocrite obtenus grâce à une nouvelle méthode de mesure de concentration développée pendant ce travail, dans des canaux uniques de taille comprise entre 5 et 20µm, et dans une large gamme d'hématocrite. Nous proposons une paramétrisation générale semi-empirique de ces profils, qui prend en compte la présence d'unecouche d'exclusion plasmatique, observée quelle que soit la taille du canal aux faibleshématocrites. Ensuite, nous présentons une étude paramétrique de l’effet de séparation dephase. Nous montrons que les résultats obtenus sont indépendants, dans les régimes étudiés, de l’angle de la bifurcation et du débit de la branche d’entrée. Ces résultats sont en général en bon accord avec un modèle simple qui s’appuie sur la paramétrisation précédente des profils d'hématocrite et de vitesse des globules rouges et suppose l'existence d'une ligne séparatrice de fluides dans la section droite de la branche mère. Ces résultats suggèrent que les globules rouges peuvent être décrits par un fluide équivalent, y compris dans les conditions de très fortconfinement. Enfin, nous reportons pour la première fois des résultats quantitatifs liés à la distribution de l'hématocrite dans des réseaux modèles. Nous montrons notamment quel'asymétrie des profils d'hématocrite dans les branches amonts distribue les globules rouges en enrichissant le cœur du réseau au détriment des bords. Nous comparons nos résultats à ceux d’un modèle non-linéaire de type réseau classique proposant des corrections prenant en compte cette asymétrie. / Since the very first observations of microvascular networks in small animals by Jean-MariePoiseuille in the XVIIIth century, the blood microcirculation has been extensively studied. One ofthe most striking feature highlighted by the French physicist is the highly heterogeneousdistribution of the red blood cells throughout microvessel networks. Despite the intimate linkbetween local red blood cell volume fraction (hematocrit) and surrounding tissue oxygenation, thecoupling between microvascular architecture and micro-hemodynamics is still poorly understood.Blood is a complex fluid, mainly composed of highly deformable red blood cells suspended inplasma. Thus in vessels with small diameter, i.e. of same order or smaller than the characteristicsize of a single red blood cell (~ 10µm), blood exhibits non-standard rheological propertiesinduced by the structuration of the flow and the heterogeneous distribution of the hematocrit withinthe cross section. This heterogeneity triggers a non propotionnal distribution of red blood cell andplasma flow rates between the daughter branches of a diverging bifurcation. One of the daughterbranch has a higher hematocrit than the feeding branch, while the other has a lower hematocrit.This effect, known as the phase separation effect, leads to hematocrit heterogeneities at networkscale. The goal of this thesis is to study the emergence of these heterogeneities, from the scale ofa single vessel to the scale of a network, in controlled experimental conditions and regimes ofconfinement and hematocrit representative of blood flow in the terminal parts of the microvascularbed (arterioles, capillaries and venules with diameters below 20µm). Many experimental data havebeen obtained textit{in vivo}, but these are subject not only to strong uncertainties regarding theshape and the dimensions of the vessel cross section, but also to physiological flow rate regulation(e.g. through vasoconstriction or vasolidation). To our knowledge, due to the highly challengingexperimental constraints, only very few in vitro studies have been performed. First, we presentred blood cell velocity and hematocrit profiles, obtained thanks to a new measure of red blood cellconcentration developped during this work in single channels of size ranging from 5 to 20 micronsand for a broad range of hematocrit values. We derive a semi-empirical parameterization of theseprofiles that takes into account the presence of a cell-free layer observed at low hematocrit values,for the whole range of channel sizes studied. We then present a parametric study of phaseseparation. Our results show that in the studied regimes, this effect depends neither on thebifurcation angle nor on the entry branch flow rate. These results are in general in good agreementwith a simple model that assumes the existence of a fluid separating streamline in the entrybranch cross section and relies on the above parameterization of the red blood cell velocity andhematocrit profiles. These results suggest that in spite of their cellular nature the red blood cellscan be treated as an equivalent fluid even in very high confinement regimes. Finally, we report forthe first time quantitative results related to the hematocrit distribution in model networks. Wenotably show that asymmetry of the hematocrit profile in the upstream branches leads the redblood cells into the center of the network while its edges are depleted. Our results are comparedwith a classical non-linear network type model corrected to take this asymmetry into account.

<p>The main objective of the study was to investigate skeletal muscle force production during isometric contractions, active muscle stretches and shortenings. The motivation behind this work is to improve the dominant model of muscle contraction force generation based on the theories of Hill. The effect of force modification was observed after concentric and eccentric contractions and also stretch-shortening cycles. It has been shown that this force modification is not related to lengthening/shortening velocity, and the steady-state force after non-isometric contractions can be well described by initial isometric force and mechanical work performed by and on the muscle during length variations. The time constants calculated for isometric force redevelopment appeared to be in certain relations with those for initial isometric force development, an observation which extended our basis for ongoing muscle modeling. The main method of the project consists in two extensive series of experiments on mouse skeletal muscles. Analysis of the first series of experiments, concentric contractions, with an emphasis on the force depression has been presented in Paper 1. Paper 2 is based on contractions with various stretches and shortenings as well as their combination, force modification and its predictor are the quantities of interest. The third part of the project is also based on the second series of experiments. Timing aspects of the force production were calculated there.</p>

The main objective of the study was to investigate and simulate skeletal muscleforce production during and after isometric contractions, active muscle lengtheningand active muscle shortening. The motivation behind this work was to improve thedominant model of muscle force generation based on the theories of Hill from 1938. Effects of residual force enhancement and force depression were observed after concentric and eccentric contractions, and also during stretch-shortening cycles. It wasshown that this force modification is not related to lengthening/shortening velocity, butinstead the steady-state force after non-isometric contractions can be well describedby an initial isometric force to which a modification is added. The modification isevaluated from the mechanical work performed by and on the muscle during lengthvariations. The time constants calculated for isometric force redevelopment appearedto be in certain relations with those for initial isometric force development, an observation which extended our basis for muscle modelling. A macroscopic muscular model consisting of a contractile element, and paralleland series elastic elements was supplemented with a history component and adoptedfor mouse soleus muscle experiments. The parameters from the experiment analysis, particularly the force modification after non-isometric contractions and the timeconstants, were reproduced by the simulations. In a step towards a general implementation, the history modification was introduced in the muscluloskeletal model ofOpenSim software, which was then used for simulations of full body movements. / QC 20120525

The main objective of the study was to investigate skeletal muscle force production during isometric contractions, active muscle stretches and shortenings. The motivation behind this work is to improve the dominant model of muscle contraction force generation based on the theories of Hill. The effect of force modification was observed after concentric and eccentric contractions and also stretch-shortening cycles. It has been shown that this force modification is not related to lengthening/shortening velocity, and the steady-state force after non-isometric contractions can be well described by initial isometric force and mechanical work performed by and on the muscle during length variations. The time constants calculated for isometric force redevelopment appeared to be in certain relations with those for initial isometric force development, an observation which extended our basis for ongoing muscle modeling. The main method of the project consists in two extensive series of experiments on mouse skeletal muscles. Analysis of the first series of experiments, concentric contractions, with an emphasis on the force depression has been presented in Paper 1. Paper 2 is based on contractions with various stretches and shortenings as well as their combination, force modification and its predictor are the quantities of interest. The third part of the project is also based on the second series of experiments. Timing aspects of the force production were calculated there. / QC 20120209

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