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Analyses de sensibilité et d'identifiabilité globales : application à l'estimation de paramètres photophysiques en thérapie photodynamique

Abstract : Photodynamic therapy (PDT) is a treatment of dysplastic tissues such as cancers. Mainly, it involves the selective uptake and retention of the photosensitizing drug (photosensitizer, PS) in the tumor, followed by its illumination with light of appropriate wavelength. The PS activation is thought to produce, after multiple intermediate reactions, singlet oxygen at high doses (in the presence of molecular oxygen) and thereby to initiate apoptotic and necrotic death of tumor. The PDT efficiency stems from the optimal interaction between these three factors: photosensitizing agent (its chemical and photobiological properties), light (illumination conditions) and oxygen (its availability in the target tissue). The relative contribution of each of these factors has an impact on the effectiveness of treatment. It is a dynamic process and the objective of the thesis is to characterize it by a mathematical model. The points raised relate primarily to the determination of a dynamic model of the photodynamic phase (production of singulet oxygen), to the global analyses of identifiability and sensitivity of the parameters of the model thus built. The main difficulties of this work are the nonlinearity structure of the photophysical model, the large range of possible values (up to four decades) of the unknown parameters, the lack of information (only one measured variable over six state variables), the limited degrees-of-freedom for the choice of the laser light stimulus (input variable).Another issue concerns the links between the non-identifiability of parameters and the properties of global sensitivity functions. Two relationships between these two concepts are presented. We stress the need to remain cautious about the parameter identifiability conclusions based on the sensitivity study. In perspective, these results could lead to the development of new approaches to test the non-identifiability of parameters in an experimental framework.
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Simona Orosanu Dobre. Analyses de sensibilité et d'identifiabilité globales : application à l'estimation de paramètres photophysiques en thérapie photodynamique. Autre. Université Henri Poincaré - Nancy 1, 2010. Français. ⟨NNT : 2010NAN10101⟩. ⟨tel-01748658⟩



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