The long-term objective of this research is to quantify transport in tumor microcirulation. The specific anim of this renewal application are to investigate the detailed fluid flow profile within the interstitial space of living tissues and to determine the contribution of convective transport to the overall transport of macromolecules in norman and cancerous tissues. The expermental phase of this research will involve the determination of the diffusion coefficient, D, and the convective velocity field, v, for the transport of various macromoles in normal (mature granulation) as well as neoplastic (VX2 carcinoma) tissues in the rabbit ear chamber preparation. The measured transport characteristics will be correlated to the properties of the macromolecule (size, charge, configuration) and the tissue (norman versus tumor). Fluorescence recovery after photobleaching (FRAP) will be used to discriminate between convection and diffusion. This technique involves laser irradiation of a select region of the fluorescence-bathed interstitium to create a well- defined area of low fluorescence intensity. The fluorophore concentration within this bleached region is monitored as a funciton of space and time, and is analyzed to determine the intersitial convective velocity and the interstitial diffusion coefficient. Investigation into the heterogeneity of the convective velocity will also provide information on the detailed flow profile within the intersitial space tissues. The theoretical phase of the research will involve mathematical nodeling of the fluorescence recovery after photobleaching for arbitrary intersitial flow fields to determine accurately a convective velocity profile and a diffusion coefficient frrom analysis of the obtained data. The fluid flow in the interstitum will also be modeled in order to investigate the Starling mechanism of fluid exhange between a microvessel and the surrounding interstitial space. The significant tissue characteristics governing the velocity profile will be determined. The fiver- matrix model for intersitial transport will be improved, incorporating convection and viscous/hydrodynamic hindrance in the analysis, leading to a more accurate description of transport in vivo. The proposed investigation will provide the first measure of the magnitude and direction of convective velocity in the interstitium. The results obtained will be of value to physiologists in developing a better understanding of Starling's hypothesis of transcapillary exchange, and in characterizing interstitial transport in tissues; and to cancer researchers and oncologist in improving current methods of cancer detection and treatment.
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