Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Microcirculatory functions in glial tumors are abnormal. High permeability leads to the formation of cerebral edema. Low blood flow may compromise the delivery of chemotherapeutic agents into tumor tissue. The purpose of this thesis was to examine the microcirculation in a glioma model in order to obtain a quantitative picture of how abnormal function relates to microvascular network structure.;A model of human malignant glioma was developed by implantation of multicellular spheroids into the brains of rats. The vessels in the tumor were permeable to exogenous tracers. Grossly, tracer leakage was correlated with tumor growth but microscopically, it appeared that in vivo leakage of serum protein was heterogeneous. Regional blood flow, as measured by autoradiography, was 57% lower in the tumor than in cortex. A combination of perfusion and injection techniques were used to resolve microvascular perfusion in the model. Stereologic and morphometric techniques were used for acquisition of data from digitized images of the brains. The total microvessel length in the tumor tissue was found to be 80% less than that in the cortex (222 {dollar}\pm{dollar} 15, 1093 {dollar}\pm{dollar} 49 mm/mm{dollar}\sp3{dollar}) (mean {dollar}\pm{dollar} standard error of the mean). However, only 50% (111 {dollar}\pm{dollar} 17 mm/mm{dollar}\sp3{dollar}) of the total length of vessel in the tumor was perfused. Because tumor microvessels were significantly wider in diameter (7.79 {dollar}\pm{dollar} 0.51, 3.81 {dollar}\pm{dollar} 0.14 {dollar}\mu{dollar}m) and longer (102 {dollar}\pm{dollar} 5, 64 {dollar}\pm{dollar} 4 {dollar}\mu{dollar}m) than microvessels in cortex, the total volume fraction of the microvascular compartment in the two tissues was not significantly different. However, the volume fraction actively perfused in the tumor was 50% less. The surface area of the microvascular compartment that would be functional in exchange under these conditions, was 50% of the total in tumor, and 80% of that in cortex. This heterogeneous perfusion of individual microvessels in viable tumor tissue may account for the low flow observed clinically and experimentally in intracranial tumors, and the heterogeneous leakage from microvessels in tumor tissue. Since the microvessels in tumors are very permeable, the flux of a substance into tumors is probably critically dependent on flow in the active volume.



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